A Phase Ib / II Trial of Tarloxotinib and Sotorasib in Patients With KRAS G12C Mutations
Phase: PHASE1
Conditions: Non-Small Cell Lung Cancer
Sponsor: Medical University of South Carolina

CTO # 103408 
Protocol version February 27, 2023 
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NCT #: 05313009 
 
MUSC CTO #: 103408 
 
A PHASE 1B TRIAL OF TARLOXOTINIB AND SOTORASIB IN PATIENTS WITH 
KRAS G12C MUTATIONS 
 
 
PRINCIPAL INVESTIGATOR: 
STATISTICIAN: 
Mariam Alexander, MD PhD 
Elizabeth G. Hill, Ph.D. 
Medical University of South Carolina 
Medical University of South Carolina 
86 Jonathan Lucas St 
86 Jonathan Lucas St 
Charleston, SC 29425 
Charleston, SC 29425 
Phone: 843/792-4271 
Phone: 843/876-1115 
FAX: 843/876-1963 
FAX: 843/876-1963 
E-mail: alexanma@musc.edu 
E-mail: hille@musc.edu 
 
CO-INVESTIGATOR: 
John Wrangle, MD MPH 
Medical University of South Carolina 
86 Jonathan Lucas St 
Charleston, SC 29425 
Phone: 843/792-7786 
FAX: 843/876-1963 
E-mail: wrangle@musc.edu 
 
 
COORDINATING OFFICE: 
Sponsor-Investigator Support Unit 
Hollings Cancer Center Clinical Trials Office 
1 South Park Circle, Bldg. 1, Suite 503 
Charleston, SC 29407 
Phone: 843-792-9321 
Fax: 843-876-1962 
 
 
 
PROTOCOL VERSION HISTORY 
Version 1 dated August 17, 2021 
Version 2 dated October 6, 2021 
Version 3 dated February 27, 2023 

CTO # 103408 
Protocol version February 27, 2023 
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SYNOPSIS 
 
Study Number 
103408 
Sponsor 
Rain Therapeutics 
Phase 
Phase IB 
Objectives 
Primary Objectives 
- To evaluate the RP2D, safety, and tolerability of tarloxotinib in combination with sotorasib 
in patients with KRAS G12C mutated advanced non-small cell lung cancer (NSCLC) 
-To evaluate the tumor objective response rate (ORR) assessed by RECIST 1.1 criteria of the 
combination of tarloxotinib with sotorasib 
Secondary Objectives 
To evaluate other measures of efficacy of the combination of tarloxotinib with sotorasib in 
patient with KRAS G12C mutated advanced NSCLC 
Study Design 
This is a Phase IB dose expansion trial with safety lead-in evaluating the safety, clinical 
activity/efficacy of the combination of tarloxotinib and sotorasib in patients with KRAS G12C 
mutation who have progressed on any small molecule targeting KRAS G12C mutant Non- 
Small Cell lung cancer. 
Treatment 
Sotorasib 960 mg PO daily + tarloxotinib IV weekly at the combination RP2D 
determined in the safety lead-in 
Treatment cycle: Day 1, 8, 15, 22 of every 28-day cycle 
Tumor assessment every 8 weeks 
Eligibility 
Inclusion 
1) Histologically confirmed diagnosis of squamous or non-squamous NSCLC with KRAS 
G12C mutation 
2) Unresectable or metastatic disease 
3) No available treatment with curative intent 
4) Must have previously received treatment with a platinum-containing chemotherapy 
regimen. Additional prior therapies for metastatic KRAS G12C mutated NSCLC are also 
permitted. 
5) Must have previously received at least one month trial of sotorasib or a therapy targeting 
KRAS G12C mutation with documented progression. If sotorasib dose from prior therapy was 
reduced for toxicity, patients that meet the above criteria are expected to receive study 
treatment at the reduced dose. 
6) Must have measurable or evaluable disease as defined by RECIST 1.1 
7) Age >18 years 
8) Life expectancy of at least 3 months 
9) Recovery from adverse effect of prior therapy at the time of enrollment 
10) Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 
11) Laboratory values within the screening period: 
a) Absolute neutrophile count > 1000/mm3 
b) Platelet count > 100,000 /mm3 
c) Hemoglobin > 8 in the absence of transfusions for at least 2 weeks 
d) Total bilirubin < 1.5 x upper limit of normal (or < 3 x ULN if associated with liver 
metastases or Gilbert’s disease) 
e) Aspartate transaminase (AST) or alanine transaminase (ALT) < 3 x ULN (or < 5x ULN 
if associated with liver metastases 
f) Creatinine clearance (CrCl) > 60 mL/min calculated by CKD-EPI or MDRD 
12) Women of child-bearing potential agrees to use contraception while participating in the 
study and for a period of 6 months following termination of study treatment 
13) Completed informed consent process 

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14) Willing to comply with clinical trial instructions and requirements. 
Exclusion 
1) Active, untreated brain metastases. Patients are eligible if brain metastases are previously 
treated and asymptomatic.  Patients must be neurologically stable and on a stable or tapering 
dose of corticosteroids for at least 2 weeks prior to C1D1. 
2) History of intestinal disease or major gastric surgery likely to alter absorption of study 
treatment or inability to swallow pills 
3) Congestive heart failure > NYHA Class 3 
4) QTc > 480 milliseconds or family history of Long QT syndrome 
5) Ongoing need for a medication with a known risk of Torsades de Pointes that cannot be 
switched to alternative treatment prior to study entry. 
6) Pregnancy or breast feeding 
7) Has other known non-KRAS G12C activating oncogene-driver mutations, including 
but not limited to: ALK, ROS1, RET, BRAF, NTRK1/2/3, MET, EGFR 
8) Previously have received anti-EGFR or anti-HER2 TKIs 
9) Previously have received anti-EGFR or anti-HER2 monoclonal antibodies 
10) Clinically active or symptomatic interstitial lung disease 
11) Known concurrently 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. 
12) Infection requiring systemic treatment within 7 days prior to cycle 1 day1. 
13) Patients with known hypersensitivity to either tarloxotinib, sotorasib, or any of the 
ingredients. 
Criteria for 
Efficacy 
Evaluation 
Objective response (OR = CR+PR) measured by CT and assessed per RECIST 1.1. Complete 
response (CR) and Partial response (PR) require confirmatory CT repeat assessment at least 4 
weeks after the first detection of response 
Criteria for Safety 
Evaluation 
Dose-limiting toxicities, treatment-emergent adverse events, treatment-related adverse events, 
clinically significant changes in vital signs, electrocardiograms, laboratory tests 
Statistical 
Methods 
Analysis Populations 
The following analysis sets will be defined for this study. 
The safety analysis set comprises all enrolled patients who receive any quantity of study 
treatment, regardless of eligibility. The safety evaluation will be performed based on the first 
dose of study treatment a patient receives, regardless of the patient’s cohort assignment. The 
safety analysis set will be used for all dosing/exposure and safety analyses. 

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The DLT-evaluable population (safety lead-in only) comprises patients who have either 
completed the DLT-observation period (1 cycle, 28 days) and received at least 75% of 
planned doses of the tarloxotinib and sotorasib combination in cycle 1 or have discontinued 
study treatment or study participation before completing cycle 1 due to a DLT. 
The intention to treat (ITT) analysis set comprises all patients in the safety analysis set 
eligible for study inclusion and who meet the inclusion criteria for dose expansion, including 
eligible safety lead-in patients treated at the combination RP2D. This analysis set will be used 
for all efficacy analyses. 
Safety lead-in 
A minimum of 6 patients and as many as 18 patients will be enrolled in a safety lead-in cohort 
to evaluate the safety of the combination of tarloxotinib and sotorasib. Sotorasib will be held 
at a fixed dose of 960 mg QD (the approved dose) while the starting dose of tarloxotinib will 
be the monotherapy RP2D equal to 150mg/m2 QW (dose level 1 [DL1]). Following a 3+3 
algorithm, an initial 3 patients will be enrolled at DL1. If 0 or 1 of 3 patients experience a 
DLT, an additional 3 patients will be enrolled to DL1. DL1 will be declared the combination 
RP2D (RP2Dc) if at most 1 of 6 patients treated at DL1 experience a DLT. Alternatively, if 
there are 2 or more DLTs observed at DL1, 3 patients will be enrolled at DL -1 and the 3+3 
rules repeated for safety evaluation. The RP2Dc will be the highest DL at which at most 1 
patient of 6 experiences a DLT. If DL -2 is considered too toxic, additional dose levels below 
DL -2 may be evaluated for safety. 
Dose expansion 
Once the tarloxotinib RP2Dc is reached, an expansion cohort of up to 12 patients will be 
enrolled to evaluate the safety of the combination of tarloxotinib and sotorasib. Eligible safety 
lead-in patients treated at the RP2Dc will be included in the expansion cohort. 

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TABLE OF CONTENTS 
1 
SCHEMA .................................................................................................................................... 6 
2 
OBJECTIVES AND ENDPOINTS......................................................................................... 7 
3 
BACKGROUND ........................................................................................................................ 7 
4 
SUBJECT SELECTION ........................................................................................................ 11 
5 
SUBJECT REGISTRATION ................................................................................................ 13 
6 
TREATMENT ......................................................................................................................... 14 
7 
DRUG INFORMATION ...........................................................................................................23 
8 
CONCOMITANT THERAPY .............................................................................................. 29 
9 
STUDY ASSESSMENTS ....................................................................................................... 30 
10 DEFINITION OF ENDPOINTS ........................................................................................... 33 
11 STATISTICAL CONSIDERATIONS..................……………………………………………………34 
12 CORRELATIVE STUDIES .................................................................................................. 39 
13 ADVERSE EVENT REPORTING REQUIREMENTS ................................................... 39 
14 DATA COLLECTION AND ANALYSIS ........................................................................... 43 
15 ETHICAL AND REGULATORY CONSIDERATIONS ................................................. 43 
16 REFERENCES ........................................................................................................................ 44 

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STAGE 2: EFFICACY 
(n=12) 
Sotorasib 960 mg PO daily 
+ tarloxotinib IV weekly at 
the combination RP2D 
(RP2Dc). 
Objectives: safety and 
confirmation 
Treatment cycle: Day 1, 8, 
15, 22 of every 28-day cycle 
Tumor assessment every 8 
weeks 
Bayesian toxicity continuous 
safety monitoring 
1 SCHEMA 
This is a Phase IB dose expansion trial with safety lead-in evaluating the safety, clinical 
activity/efficacy of the combination of tarloxotinib and sotorasib in patients with KRAS G12C 
mutation who have progressed on any small molecule targeting KRAS G12C mutant Non-Small 
Cell lung cancer. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assessment: 
Imaging 
Toxicity assessment 
 
 
 
 
 
 
Primary Endpoint: Safety and 
tolerability; ORR 
Secondary Endpoint: DOR, 
DCR, BOR, PFS, OS 
 
 
 
 
3+3 design to de-escalate tarloxotinib dosing based on DLTs 
Dose level 
Sotorasib 
Tarloxotinib 
-2 
960 mg PO daily 
75 mg/m2 IV weekly 
-1 
960 mg PO daily 
100 mg/m2 IV weekly 
0 (full dose) 
960 mg PO daily 
150 mg/m2 IV weekly 
STAGE 1: SAFETY LEAD IN 
(n=6-18, depending on number 
of DLs explored) 
3+3 design dependent on DLTs 
Sotorasib 960 mg PO daily + 
tarloxotinib 150 mg/m2 IV weekly 
(DL1). 
Objectives: safety and efficacy 
Treatment cycle: Day 1, 8, 15, 22 
of every 28 day cycle 
Tumor assessment every 8 weeks 
Patient Population: 
KRAS G12C mutated 
NSCLC who have 
progressed on sotorasib 
Any histology 
EGFR/ALK/BRAF/MET 
exon 14/ROS/RET 
negative 
ECOG PS 0/1 
Age>18 
Any PD-L1 TPS score 

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2 OBJECTIVES AND ENDPOINTS 
 
2.1 PRIMARY OBJECTIVE 
 
Objectives 
Endpoints 
To evaluate the RP2D, safety, and tolerability 
of tarloxotinib in combination with sotorasib 
in patients with KRAS G12C mutated 
advanced non-small cell lung cancer 
(NSCLC). 
Dose-limiting toxicities, treatment-emergent adverse 
events, treatment-related adverse events, clinically 
significant changes in vital signs, electrocardiograms, 
laboratory tests 
To evaluate the tumor objective response rate 
(ORR) assessed by RECIST 1.1 criteria of the 
combination of tarloxotinib with sotorasib 
Objective response (OR = CR+PR) measured by CT and 
assessed per RECIST 1.1. Complete response (CR) and 
Partial response (PR) require confirmatory CT repeat 
assessment at least 4 weeks after the first detection of 
response 
 
2.2 SECONDARY OBJECTIVES 
 
 
Objectives 
Endpoints 
To evaluate other measures of efficacy of the 
combination of tarloxotinib with sotorasib in 
patient with KRAS G12C mutated advanced 
NSCLC 
- Duration of response (DOR) as measured from the date 
of first response to date of disease progression or death 
- Disease control rate (DCR)based on patient who had 
CR or PR or Stable disease (SD) for at least 2 cycles (8 
weeks) 
- Best overall response (BOR) 
- Progression free survival (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 
- Overall survival (OS) as measured from the date of first 
study drug dose to the date of death by any cause 
 
 
 
3 BACKGROUND 
 
3.1 STUDY RATIONALE 
 
3.1.1 Introduction 
KRAS acts as a key protein in transducing signals from cell surface receptors, such as receptor 
tyrosine kinases (RTKs) into cells to initiate a network of cytoplasmic and nuclear signaling 
cascades that mediate key processes, such as cell cycle entry and cell survival that regulate 

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normal tissue homeostasis(1). Due to the central importance of KRAS in mediating critical 
cellular processes, there are significant interconnected signaling feedback pathways that protect 
normal cells from uncontrolled proliferation and cell death. These signaling feedback pathways 
are also activated by tumor cells upon inhibition of mutated KRAS, which may result in intrinsic 
or acquired resistance to small molecule KRAS G12C inhibitors. Pre-clinical studies in non-small 
cell lung cancer (NSCLC) have shown that a key pathway that may be activated upon KRAS 
inhibition is the upstream ERBB RTKs, which provides the rationale for dual KRAS and ERBB 
blockade in overcoming resistance mechanisms in KRAS mutated NSCLC(2). 
 
3.1.2 Non-small cell lung cancer 
Lung cancer is the second most common cancer and the leading cause of cancer death in the 
United States. There were approximately 247,270 new cases of lung cancer that occurred in 2020 
(3). Prior studies have reported that lung cancer resulted in more deaths than breast cancer, 
prostate cancer, colorectal cancer, and leukemia combined in men ≥40 years old and women ≥60 
years old. The past decade has seen a revolution of new advances in the management of non- 
small cell lung cancer (NSCLC) with remarkable progresses in screening, diagnosis, and 
treatment.  The advances in systemic treatment have been driven primarily by the development 
of molecularly targeted therapeutics, immune-checkpoint inhibitors and anti-angiogenic agents, 
all of which have transformed this field with significantly improved patient outcomes. Despite 
these advances, most patients with advanced NSCLC have incurable disease, particularly after 
failure of a platinum-based chemotherapy regimen and check point inhibitors. 
 
3.1.3 KRAS G12C mutated lung cancer 
One of the earliest identified molecular drivers of NSCLC is the GTPase transductor protein 
called KRAS. It is a member of the RAS family of oncogenes and at the apex of multiple 
signaling pathways central to tumor cell proliferation. KRAS mutant lung cancers have worse 
outcomes in both early stage and advanced metastatic settings, illustrating the critical need for 
novel agents targeting KRAS-driven NSCLC. KRAS G12C mutations are present in ~15% of 
lung adenocarcinomas and 0-8% of other cancers(2). The missense mutation at codon 12 
interferes with the GTPase, activating protein mediated GTP hydrolysis and shifting the 
equilibrium between the signaling-competent KRAS-GTP and signaling incompetent KRAS- 
GDP in favor of the GTP bound state. This process links upstream cell surface receptors such as 
the ERBB family (EGFR, HER-2, HER-3, HER-4) to downstream pathways such as 
RAF/MEK/ERK and PI3K/AKT/mTOR which leads to uncontrolled cell proliferation and 
survival. 
 
Attempts to identify small molecular inhibitors of KRAS have been unsuccessful for many years 
as there was a lack of a clearly defined deep pocket in the structure of RAS outside of the 
nucleotide binding site and the challenge of targeting the nucleotide binding site due to 
extraordinarily high affinity of GTP. Recently, several pioneering studies have identified small 
molecule cysteine-reactive inhibitors that covalently modify the mutant KRAS G12C protein to 
reveal an allosteric switch II pocket(4, 5). The induction of the structurally disordered pocket by 
these small molecule inhibitors converts the GTP preference of naïve KRAS G12C to the 
inactive GDP bound state, impairing its interaction with downstream effectors. 

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AMG510/Sotorasib was the first KRAS G12C inhibitor to the enter the clinic. A Phase I/II 
clinical trial involving 129 patients included 59 patients with KRAS G12C mutated NSCLC who 
had progressed on prior standard therapies. Patients were enrolled in dose escalation and 
expansion cohorts to receive daily sotorasib monotherapy (960 mg PO daily) (6). At a median 
follow up of 12.2 months, approximately 50% of NSCLC patients demonstrated tumor 
regression with a confirmed objective response rate (ORR) of 37.1% (95% CI 28.6-46.2%) and a 
disease control rate (DCR) of 80.6% (95% CI 72.6-87.2%). The median time to objective 
response was 1.4 months and median duration of response was 10 months, with median 
progression free survival (PFS) of 6.8 months. The FDA has now accepted a new drug 
application and granted it a priority review for the treatment of patients with KRAS G12C mutant 
locally advanced or metastatic NSCLC following at least 1 prior systemic treatment, with an 
expected decision date by August 2021. 
 
Although the results from these early-stage clinical trials showed promise, ~50% of KRAS G12C 
mutant NSCLC patients failed to respond to therapy and rate of relapse is high calling for the 
need for novel combinations to overcome intrinsic and acquired resistance mechanisms in this 
subset of patients. 
 
3.1.4 Rationale for the combination of KRAS G12C inhibitors with pan-ERBB inhibition 
It was previously thought that constitutively active oncogenic KRAS induces growth factor 
independence. However, recent evidence has suggested that specific KRAS mutant isoforms such 
as KRAS G12C may be regulated by upstream activation of several receptor tyrosine kinases. 
Lito et. al. demonstrated that concurrent EGFR and G12C inhibition potentiated growth 
inhibition in two different KRAS G12C mutant NSCLC cell lines(7). The pattern of RTK 
dependence appears to vary between KRAS G12C mutant cancer but numerous RTKs are 
involved in the adaptive feedback mechanism to G12C inhibition. This may be mediated through 
an adaptive RAS pathway activation. Misale et. al., identified several RTK inhibitors exhibiting 
strong synergies with G12 inhibitors(8). Umelo et. al. examined RTK dependent cell lines to 
provide evidence that in a group of mutant KRAS G12C NSCLC lines, HER2 and HER3 are 
major upstream signaling activators(9). They examined several NSCLC lines to shows that EGF 
or NRG1 beta stimulation can strongly enhance the amount of active RAS in cells harboring 
oncogenic KRAS G12C, which suggest that some KRAS mutant cancers retain sensitivity to 
upstream stimuli emanating from extracellular signaling via the ERBB pathway. Silencing 
oncogenic KRAS in EGFR/HER dependent cells reduced cellular growth and induced a modest 
apoptotic signal. The depletion of KRAS expression by mutant specific siRNA was accompanied 
by a reduction in AKT phosphorylation in the ERBB dependent subset and activation of STAT3, 
which suggests a feedback loop via STAT3 that re-establishes oncogenic signaling thereby 
compensating for the loss of AKT survival signals. Pan ERBB inhibition in these KRAS G12C 
mutated NSCLC lines resulted in a potent suppression of growth and inhibition of receptor 
signaling and downstream signaling effectors. Thus, sole silencing of oncogenic KRAS may not 
be an effective therapeutic strategy in KRAS-addicted cancers since upstream events and 
feedback loops are likely to attenuate or annul the effects of the therapeutic intervention. 
These pre-clinical studies provide a solid ground to evaluate the use of pan-ERBB inhibitors in 
combination with KRAS G12C inhibitors in patients with KRAS mutant lung tumors. 

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3.1.5 Tarloxotinib 
Tarloxotinib is a recently discovered novel prodrug that releases a potent, irreversible pan-ERBB 
(EGFR, HER2 and HER4) TKI. It is designed to be inactive under normal oxygen conditions but 
undergoes fragmentations under low oxygen conditions (hypoxia) to release the potent 
irreversible active metabolite (tarloxotinib-E) that has activity against both normal and mutant 
versions of the ERBB family(10). Selective production of tarloxotinib-E under hypoxic 
conditions generates a therapeutic window where it is selectively activated in hypoxic tumor 
regions to deliver higher drug delivery to tumor tissue. This reduces systemic exposure which 
avoids on-target EGFR related toxicities than standard EGFR TKI. In a mouse xenograft model 
of a human derived EGFR exon 20 insertion, intra-tumoral tarloxotinib-E levels were 20 time 
higher than skin and 50 times higher than plasma demonstrating selective tumor conversion. This 
strategy broadens the therapeutic window leading to improved efficacy, while reducing toxicity. 
Multiple pre-clinical studies have further demonstrated the efficacy of tarloxotinib compared to 
standard EGFR inhibitors(11). 
Phase I clinical trials to determine the MTD and DLTs of tarloxotinib, enrolled 27 patients with 
locally advanced or metastatic solid tumors(12). Of the patients that received tarloxotinib as a 
weekly 1-hour infusion, 6 patients received the drug at the recommended Phase 2 dose of 150 
mg/m2 with good tolerance. 
 
 
3.1.6 Combination of Sotorasib with Tarloxotinib 
The combination of tarloxotinib with sotorasib is poised to provide highly specific tumor 
inhibition while targeting the vertical KRAS signaling pathway with minimal toxicity. The 
combination is unlikely to result in clinically relevant drug-drug interaction (DDI) based on 
absorption, metabolism, elimination or protein-binding. Tarloxotinib is intravenously 
administered while sotorasib is a small molecule that is administered orally; no absorption 
interactions are expected. 
 
Table 2 provides a comparison of the toxicity noted in Phase I/II clinical trials of these two 
drugs. The safety profile is expected to be generally non-overlapping with the exception of 
gastrointestinal adverse events that include nausea and diarrhea. 
 
 
3.1.7 Comparison of Toxicity reported in the individual Phase I/II studies of Sotorasib and 
Tarloxotinib 
Adverse 
events 
Tarloxotinib (n=23) 
Sotorasib (n=129) 
Any 
grade 
>G3 
Any grade >G3 
QTc 
prolongation 
60.9% 
34.8% 
- 
- 
Rash 
acneiform 
43.5% 
4.3% 
- 
- 
Diarrhea 
21.7% 
4.3% 
29.5% 
2.3% 
Nausea 
21.7% 
0% 
20.9% 
1.6% 
Fatigue 
33.3% 
0% 
23.3% 
2.3% 

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Vomiting 
- 
- 
17.8% 
3.9% 
Abdominal 
pain 
- 
- 
17.8% 
3.1% 
Dyspnea 
- 
- 
16.3% 
2.3% 
Cough 
- 
- 
15.5% 
0% 
Back pain 
- 
- 
14.7% 
1.6% 
Decreased 
appetite 
- 
- 
14.7% 
1% 
Headache 
- 
- 
14.0% 
0% 
AST 
elevation 
- 
- 
13.2% 
2.3% 
anemia 
- 
- 
13.2% 
4.7% 
dizziness 
- 
- 
13.2% 
0% 
ALT 
elevation 
- 
- 
11.6% 
0% 
Constipation 
- 
- 
10.9% 
0% 
Pyrexia 
- 
- 
10/9% 
0% 
Insomnia 
- 
- 
10.1% 
0% 
Myalgia 
- 
- 
10.1% 
0% 
Peripheral 
edema 
- 
- 
10.1% 
0% 
Arthralgia 
- 
- 
10.1% 
1.6% 
 
 
 
4 SUBJECT SELECTION 
 
4.1 INCLUSION CRITERIA 
 
Patients eligible for study participation must meet all the following criteria: 
 
1) Histologically confirmed diagnosis of squamous or non-squamous NSCLC with KRAS 
G12C mutation 
2) Unresectable or metastatic disease 
3) No available treatment with curative intent 
4) Must have previously received treatment with at a platinum-containing chemotherapy 
regimen. Additional prior therapies for metastatic KRAS G12C mutated NSCLC are also 
permitted. 
5) Must have previously received at least one month trial of sotorasib or a therapy targeting 
KRAS G12C mutation with documented progression. If sotorasib dose from prior therapy 
was reduced for toxicity, patients that meet the above criteria are expected to receive study 
treatment at the reduced dose. 
6) Must have measurable or evaluable disease as defined by RECIST 1.1 
7) Age >18 years 

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8) Life expectancy of at least 3 months 
9) Recovery from adverse effect of prior therapy at the time of enrollment 
10) Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 
11) Laboratory values within the screening period: 
a) Absolute neutrophile count > 1000/mm3 
b) Platelet count > 100,000 /mm3 
c) Hemoglobin > 8 in the absence of transfusions for at least 2 weeks 
d) Total bilirubin < 1.5 x upper limit of normal (or < 3 x ULN if associated with liver 
metastases or Gilbert’s disease) 
e) Aspartate transaminase (AST) or alanine transaminase (ALT) < 3 x ULN (or < 5x 
ULN if associated with liver metastases 
f) Creatinine clearance (CrCl) > 60 mL/min calculated by CKD-EPI or MDRD 
12) Women of child-bearing potential agrees to use contraception while participating in the 
study and for a period of 6 months following termination of study treatment 
13) Completed informed consent process 
14) Willing to comply with clinical trial instructions and requirements. 
4.2 EXCLUSION CRITERIA 
 
Patients eligible for study participation CANNOT meet any of the following criteria: 
 
1) Active, untreated brain metastases. Patients are eligible if brain metastases are previously treated  
and asymptomatic.  Patients must be neurologically stable and on a stable or tapering dose of  
corticosteroids for at least 2 weeks prior to C1D1. 
 
2) History of intestinal disease or major gastric surgery likely to alter absorption of study 
treatment or inability to swallow pills 
 
3) Congestive heart failure > NYHA Class 3 
 
4) QTc > 480 milliseconds or family history of Long QT syndrome 
 
5) Ongoing need for a medication with a known risk of Torsades de Pointes that cannot be 
switched to alternative treatment prior to study entry. 
 
6) Pregnancy or breast feeding 
 
7) Has known activating non-KRAS G12C oncogene-driver mutations, including but 
not limited to: ALK, ROS1, RET, BRAF, NTRK1/2/3, MET, EGFR. 
 
8) Previously have received anti-EGFR or anti-HER2 TKIs 
 
9) Previously have received anti-EGFR or anti-HER2 monoclonal antibodies 
 
10) Clinically active or symptomatic interstitial lung disease 

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11) Known concurrently 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. 
 
12) Infection requiring systemic treatment within 7 days prior to cycle 1 day 1. 
 
13) Patients with known hypersensitivity to either tarloxotinib, sotorasib, or any of the 
ingredients. 
 
4.3 INCLUSION OF WOMEN AND MINORITIES 
 
Both men and women of all races and ethnic groups are eligible for this trial. 
 
 
5 SUBJECT REGISTRATION 
 
The Hollings Cancer Center’s Sponsor-Investigator Support Unit (SIS Unit) will provide patient 
registration services for the study. The SIS Unit will conduct a patient eligibility audit review of 
all eligibility source documents prior to patient registration. These procedures are outlined in the 
MUSC 103408 Operations Manual. After obtaining signed informed consent and completion of 
required baseline assessments, eligible subjects will be registered. A unique subject number will 
be assigned to each patient. The SIS Unit will issue a patient registration confirmation email to 
the enrolling study team at the time of registration which will include the patient’s study ID 
number. 
 
5.1 SUBJECT RECRUITMENT 
 
Subjects will be recruited from the existing patient population of the Hollings Cancer Center 
thoracic medical oncology clinics. 
 
5.1.1 INFORMED CONSENT PROCESS 
 
The principles of informed consent are described by Federal Regulatory Guidelines (Federal 
Register Vol. 46, No. 17, January 27, 1981, part 50) and the Office for Protection from Research 
Risks Reports: Protection of Human Subjects (Code of Federal Regulations 45 CFR 46). They 
must be followed to comply with FDA regulations for the conduct and monitoring of clinical 
investigations. 

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Informed consent will be obtained by personnel who are qualified by education, training, and 
experience to perform the task. The Sponsor-Investigator will not use the services of study 
personnel for whom sanctions have been invoked where there has been scientific misconduct or 
fraud. 
Investigators must ensure that subjects are clearly and fully informed about the purpose, potential 
risks, and other critical issues regarding clinical studies in which they volunteer to participate. 
The approved consent form will adhere to the ethical principles that have their origin in the 
Declaration of Helsinki. 
5.1.2 RECRUITMENT METHODS 
 
Subjects will be recruited via internal and external patient referrals to Hollings Cancer Center, 
multidisciplinary tumor board meetings in which new and ongoing patient cases are reviewed, 
and the existing patient population of the Principal Investigator and Sub-Investigators. 
5.1.3 SETTING 
The study will be conducted at Hollings Cancer Center and other potential designated 
sub-sites to be determined. 
 
6 TREATMENT/STUDY INTERVENTION 
 
6.1 
STUDY TREATMENT AND TREATMENT SCHEDULE 
 
This is a traditional safety and efficacy study of Sotorasib and Tarloxotinib for patients with 
KRAS G12C mutant NSCLC. Treatment will be administered on an outpatient basis. 
 
Sotorasib will be administered at a recommended Phase 2 dose of 960 mg PO daily. 
 
All patients will receive a weekly tarloxotinib infusion at the RP2Dc determined in the safety 
lead-in portion of the trial administered as a 1-hour IV infusion on Days 1, 8, 15, and 22 of each 
28-day cycle until disease progression or unacceptable toxicity. 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. 
 
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. In the safety 
lead-in portion of the study, an initial 3 patients will be treated at Dose Level 1 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]). The dose level for subsequent patient cohorts will be determined using standard 3+3 
dose escalation/de-escalation rules using the dose levels indicated in table below. 
 
 
3x3 design to de-escalate tarloxotinib dosing based on DLTs 

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Dose level 
Sotorasib 
Tarloxotinib 
-2 
960 mg PO daily 
75 mg/m2 IV weekly 
-1 
960 mg PO daily 
100 mg/m2 IV weekly 
0 (full dose) 
960 mg PO daily 
150 mg/m2 IV weekly 
 
 
6.2 DEFINITION OF DOSE-LIMITING TOXICITY (DLT) 
 
Toxicities will be graded according to the NCI Common Toxicity Criteria scale version 5.0. If 
multiple toxicities are seen, the presence of DLT should be based on the most severe toxicity 
grade experienced. DLT will be defined as any of the following events occurring during 
treatment with study drugs and is deemed possibly, probably or definitely attributable to the 
study drugs: 
• Any Grade 3 or 4 thrombocytopenia, anemia and/or neutropenia. 
• Any other non-hematologic Grade 3 or 4 toxicity that is clinically significant, 
excluding alopecia. 
• Any grade 3 nausea, vomiting or diarrhea that persists > 72 hours despite the use of 
maximal medical intervention and/or prophylaxis as indicated by good clinical 
practice and the judgment of the investigator. 
• Any grade 4 vomiting or diarrhea regardless of duration. 
• Failure to recover from toxicities to be eligible for re-treatment within 4 weeks. 
• Any death not clearly due to the underlying disease or extraneous causes, and for any 
toxicity requiring permanent discontinuation of study drug(s). 
• Hy’s law, defined as: AST or ALT > 3 x the upper limit of normal (ULN) with 
concurrent increase in total bilirubin > 2 x ULN without evidence of cholestasis or 
alternative explanations, (e.g., viral hepatitis, disease progression in the liver, etc.) 
• Neutropenic fever 
 
 
6.3 DOSE ESCALATION RULES 
 
Dose escalation/de-escalation in the safety lead-in portion of the trial will follow a standard 3+3 
algorithm. Please refer to section 11, Statistical Considerations, for additional details. 
 
6.4 DOSE MODIFICATIONS 
This study will utilize the CTCAE (NCI Common Terminology Criteria for Adverse Events) 
Version 5.0 for toxicity and Serious Adverse Event reporting. A copy of the CTCAE Version 
5.0.0 can be downloaded from the CTEP home page (http://ctep.cancer.gov). All appropriate 
treatment areas should have access to a copy of the CTCAE Version 5.0. 

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6.5 TREATMENT AND RETREATMENT CRITERIA 
 
The results of tumor assessments are 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 clinically indicated, 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 Principal Investigator. 
o If other electrolytes (e.g., 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: 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 Principal Investigator 
and possible dose/schedule modification and/or study treatment discontinuation discussed. 
 
6.5.1 Treatment Beyond Progression 
Patients with disease progression may continue to receive the combination of tarloxotinib and 
sotorasib if, in the opinion of the Treating Investigator, the patient is still benefiting (e.g., 
asymptomatic systemic progression or local symptomatic progression) following discussion with 
and approval by the Principal Investigator. In addition, the following criteria must be met: 
• Absence of clinical symptoms or signs indicating clinically significant disease 
progression 
• No decline in performance status 
• Absence of rapid disease progression or threat to vital organs or critical anatomical 
sites (e.g., CNS metastasis, respiratory failure due to tumor compression, spinal cord 
compression) requiring urgent alternative medical intervention 
 
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 Principal Investigator. 
 
6.5.2 Tarloxotinib Dose Modifications 
All patients will receive a weekly tarloxotinib infusion at the RP2Dc determined in the safety 
lead-in portion of the trial administered as a as a weekly 1-hour IV infusion on Days 1, 8, 15, and 

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22 of each 28-day cycle until disease progression or unacceptable toxicity. All patients will begin 
study treatment 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 below. 
Dose level reductions will be in a step-wise fashion. If a patient requires more than 2 dose level 
reductions, tarloxotinib will be permanently discontinued. 
 
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 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 Principal Investigator. 
 
Should a dose reduction for sotorasib be required, given the potential for overlapping toxicities 
and challenges in attributing toxicities to one drug in a combination therapy, a dose reduction in 
tarloxotinib should also be considered. 
 
Dose level 
Sotorasib 
Tarloxotinib 
0 (full dose) 
960 mg PO daily 
150 mg/m2 IV weekly 
-1 
480 mg PO daily 
100 mg/m2 IV weekly 
-2 
240 mg PO daily 
75 mg/m2 IV weekly 
 
 
6.5.3 Treatment Guidelines for QTc Prolongation 
 
Immediate medical management of patients will be based on the following: 
 
a. Baseline: A pre-infusion (baseline) ECG will be obtained on all patients, if the 
automated measurements indicate a QTcF of ≥ 450 msec 
b. The single QTcF will be verified by manually measuring at least 3 complexes within 
the ECG and determining the average QTcF 
c. 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 
d. If it is determined that the manually read QTcF ≥ 450 msec, the Principal 
Investigator should be contacted to discuss the clinical significance of the reading 
and to determine if it is appropriate to move forward with the infusion. 
e. 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 

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during a patient’s visit, depending on the degree of the prolongation, as indicated in 
this section and per institutional standards. 
 
Note: Dose modification will be based on the average QTcF using the manual 
measurements. 
 
f. 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 this section below. 
g. Patients who experience ≥ Grade 3 QTc prolongation must be assessed by the 
Investigator (or qualified designee) prior to discharge. 
6.5.4 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 

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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 
• 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 
≤ 500 msec QTcF 
• Obtain ECGs prior to and hourly (for at least 4 hours) following the 
next tarloxotinib infusion 
Grade 4 
• 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 
TdP or polymorphic 
ventricular tachycardia, 
signs/symptoms of 
serious arrhythmia 
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 visit depending on the degree of the prolongation and per institutional 
standards. 

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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. 
6.5.5 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 
the table below. 
 
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 
• Interrupt tarloxotinib infusion 
• 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 
• After symptoms resolve to baseline, 
resume future tarloxotinib infusions to 
50% of the initial infusion rate 

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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 
• Interrupt tarloxotinib infusion 
• 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*, and/or adjusted 
premedication after discussion with the 
Principal Investigator 
• If Grade 3 infusion reaction recurs after 
this initial dose reduction, then reduce 
the tarloxotinib dose to 75 mg/m2 for 
subsequent doses 
• After symptoms resolve to baseline, 
resume future tarloxotinib infusions to 
50% of the initial infusion rate 
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 Principal 
Investigator 
6.5.6 Treatment Guidelines for Other Non-Hematologic Toxicity 
 
The table below provides treatment guidelines for treating tarloxotinib non-hematologic 
toxicities other than QT prolongation and infusion-related reactions. 

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Toxicity 
(CTCAE v5.0) 
Details 
Hold Dose 
Dose Levels After 
Recovery to ≤ Grade 2 or 
Baseline 
Grade 2 
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 
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 
Pulmonary embolism that 
is adequately treated 
Hold dose until 
resolution to Grade 0 or 
1 
120 mg/m2; if recurs, then 
second reduction to 75 
mg/m2 
Grade 4 
All other life-threatening 
conditions 
Treatment to be 
discontinued 
Not applicable 
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 
 
 
6.5.7 Compliance 

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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, 
• ECG monitoring, and 
 
• AE monitoring. 
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. 
 
7 DRUG INFORMATION 
 
Tarloxotinib will be administered intravenously once weekly. Sotorasib will be self- 
administered orally by subjects daily. 
 
7.1 TARLOXOTINIB 
 
7.1.1 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. 
 
7.1.2 Tarloxotinib Dose Calculation 
All patients will receive a weekly tarloxotinib infusion at the RP2Dc determined in the safety 
lead-in portion of the trial. administered as a 1-hour IV infusion on Days 1, 8, 15, and 22 of each 
28-day cycle until disease progression or unacceptable toxicity. 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: 

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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. 
 
7.1.3 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. 
 
7.1.4. 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. 
 
7.1.5 Dose Delays 
All dose schedule modifications of > 1 day must be discussed with the Principal Investigator (or 
designee). Intentional cycle delays of > 1 day (e.g., patient vacation, physician requested “drug 
holiday”) must be approved by the Principal Investigator (or designee). Study visits will align 
with tarloxotinib infusion days. If a tarloxotinib dose must be delayed > 3 days, this will be 
considered a missed dose. 
 
7.1.6 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. 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 Principal Investigator 
should be informed as soon as possible. The infusion should be rescheduled based on 
Investigator judgment, taking into consideration the patient’s safety. 
 
7.1.7 Supportive Care 
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. 

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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. 
 
7.1.8 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: 

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Potassium Supplementation Guidelines Pre-infusion 
Serum Potassium 
(mEq/L) 
Potassium Supplementation 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) 
 
 
7.2 SOTORASIB 
 
7.2.1 Description 
Sotorasib is an inhibitor of the RAS GTPase family. The molecular formula is C30H30F2N6O3, 
and the molecular weight is 560.6 g/mol. The chemical name of sotorasib is 6-fluoro-7-(2-fluoro- 
6-hydroxyphenyl)-(1M)-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]-4-[(2S)-2- methyl-4-(prop-2- 
enoyl)piperazin-1-yl]pyrido[2,3-d]pyrimidin-2(1H)-one. 
 
Sotorasib has pKa values of 8.06 and 4.56. The solubility of sotorasib in the aqueous media 
decreases over the range pH 1.2 to 6.8 from 1.3 mg/mL to 0.03 mg/mL. 
Sotorasib is supplied as film-coated tablets for oral use containing 120 mg. Inactive ingredients 
in the tablet core are microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, 

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and magnesium stearate. The film coating material consists of polyvinyl alcohol, titanium 
dioxide, polyethylene glycol, talc, and iron oxide yellow. 
7.2.2 Mechanism of Action 
Sotorasib is an inhibitor of KRASG12C, a tumor-restricted, mutant-oncogenic form of the RAS 
GTPase, KRAS. Sotorasib forms an irreversible, covalent bond with the unique cysteine of 
KRASG12C, locking the protein in an inactive state that prevents downstream signaling without 
affecting wild-type KRAS. Sotorasib blocked KRAS signaling, inhibited cell growth, and 
promoted apoptosis only in KRAS G12C tumor cell lines. Sotorasib inhibited KRASG12C in 
vitro and in vivo with minimal detectable off-target activity. In mouse tumor xenograft models, 
sotorasib-treatment led to tumor regressions and prolonged survival, and was associated with 
anti-tumor immunity in KRAS G12C models. 
7.2.3 Toxicology 
Carcinogenicity studies have not been performed with sotorasib. 
Sotorasib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay and was not 
genotoxic in the in vivo rat micronucleus and comet assays. 
 
Fertility/early embryonic development studies were not conducted with sotorasib. There were no 
adverse effects on female or male reproductive organs in general toxicology studies conducted in 
dogs and rats. 
7.2.4 Pharmacology 
Sotorasib exposure-response relationships and the time course of the pharmacodynamic response 
are unknown. 
The pharmacokinetics of sotorasib have been characterized in healthy subjects and in patients 
with KRAS G12C-mutated solid tumors, including NSCLC. Sotorasib exhibited non-linear, 
time-dependent, pharmacokinetics over the dose range of 180 mg to 960 mg (0.19 to 1 time the 
approved recommended dosage) once daily with similar systemic exposure (i.e., AUC0-24h and 
Cmax) across doses at steady-state. Sotorasib systemic exposure was comparable between film- 
coated tablets and film-coated tablets predispersed in water administered under fasted conditions. 
Sotorasib plasma concentrations reached steady state within 22 days. No accumulation was 
observed after repeat LUMAKRAS dosages with a mean accumulation ratio of 0.56 (coefficient 
of variation (CV): 59%). 
 
Absorption: 
The median time to sotorasib peak plasma concentration is 1 hour. 
Effect of Food: 
When 960 mg LUMAKRAS was administered with a high-fat, high-calorie meal (containing 
approximately 800 to 1000 calories with 150, 250, and 500 to 600 calories from protein, 
carbohydrate and fat, respectively) in patients, sotorasib AUC0-24h increased by 25% compared 
to administration under fasted conditions. 

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   Distribution: 
The sotorasib mean volume of distribution (Vd) at steady state is 211 L (CV: 135%). In vitro, 
sotorasib plasma protein binding is 89%. 
 
Elimination: 
The sotorasib mean terminal elimination half-life is 5 hours (standard deviation (SD): 2). At 960 
mg LUMAKRAS once daily, the sotorasib steady state apparent clearance is 26.2 L/hr (CV: 
76%). 
Metabolism: 
The main metabolic pathways of sotorasib are non-enzymatic conjugation and oxidative 
metabolism with CYP3As. 
Excretion: 
After a single dose of radiolabeled sotorasib, 74% of the dose was recovered in feces (53% 
unchanged) and 6% (1% unchanged) in urine. 
Specific Populations: 
No clinically meaningful differences in the pharmacokinetics of sotorasib were observed based 
on age (28 to 86 years), sex, race (White, Black and Asian), body weight (36.8 to 157.9 kg), line 
of therapy, ECOG PS (0, 1), mild and moderate renal impairment (eGFR: ≥ 30 mL/min/1.73 
m2), or mild hepatic impairment (AST or ALT < 2.5 × ULN or total bilirubin < 1.5 × ULN). The 
effect of severe renal impairment or moderate to severe hepatic impairment on sotorasib 
pharmacokinetics has not been studied. 
7.2.5 Supplier 
Amgen Pharmaceuticals 
 
7.2.6 Sotorasib Dosage and Administration 
The recommended dosage of sotorasib is 960 mg (eight 120 mg tablets) orally once daily until 
disease progression or unacceptable toxicity. Take sotorasib at the same time each day with or 
without food. Swallow tablets whole. Do not chew, crush or split tablets. On the days of 
Tarloxotinib infusion, Sotorasib should be taken at the same time as the start of the infusion. 
 
7.2.7 Missed Doses 
If a dose of sotorasib is missed by more than 6 hours, take the next dose as prescribed the next 
day. Do not take 2 doses at the same time to make up for the missed dose. If vomiting occurs 
after taking sotorasib, do not take an additional dose. Take the next dose as prescribed the next 
day. 
 
7.2.8 Dose Modifications for Adverse Reactions 

CTO # 103408 
Protocol version February 27, 2023 
29 
 
 
 
 
Dose level -1 
480mg once daily 
Dose level -2 
240mg once daily 
 
Sotorasib should be discontinued if further dose reduction is indicated below 240mg once daily. 
 
Adverse reaction 
Dosage modification 
Grade 2 AST or ALT 
elevation with symptoms 
Grade 3-4 AST or ALT 
• Hold sotorasib dosing 
until recovery to 
Grade 1 or resolution 
• Resume sotorasib 
dosing at the next 
lower dose level 
AST or ALT > 3 x ULN with 
total bilirubin > 2 x ULN in 
the absence of alternative 
causes 
• Permanently 
discontinue sotorasib 
Interstital Lung Disease 
(ILD) or pneumonitis, any 
grade 
• Hold sotorasib dosing 
if either is suspected 
• Permanently 
discontinue sotorasib 
dosing if either is 
confirmed 
Grade 3 nausea or Grade 3-4 
vomiting despite appropriate 
supportive care (including 
anti-emetic therapy) 
• Hold sotorasib dosing 
until recovery to 
Grade 1 or resolution 
• Resume sotorasib 
dosing at the next 
lower dose level 
 
 
8 
CONCOMITANT THERAPY 
 
8.1 PERMITTED MEDICATIONS 
 
All medications (prescription and non-prescription/OTC) and blood products taken within 14 days of 
Cycle 1 Day 1 until the EOT visit 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. 
8.2 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 

CTO # 103408 
Protocol version February 27, 2023 
30 
 
 
• 
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. 
 
• 
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 Torsades de Pointes. 
 
• 
Acid-Reducing Agents – avoid coadministration with proton pump inhibitors (PPI) and 
H2 receptor antagonists. If an acid-reducing agent cannot be avoided, adjust 
administration of sotorasib to be 4 hours before or 10 hours after a local antacid. 
 
• Strong CYP3A4 Inducers: Avoid coadministration with strong CYP3A4 inducers 
 
• CYP3A4 Substrates: Avoid coadministration with CYP3A4 substrates for which minimal 
concentration changes may lead to therapeutic failures of the substrate. If 
coadministration cannot be avoided, adjust the substrate dosage in accordance to its 
prescribing Information. 
 
• P-gp substrates: Avoid coadministration with P-gp substrates for which minimal 
concentration changes may lead to serious toxicities. If coadministration cannot be 
avoided, decrease the substrate dosage in accordance with its Prescribing Information. 
 
9 STUDY ASSESSMENTS 
 
9.1 GENERAL GUIDELINES 
 
Prior to any study specific activities, the subject must be aware of the nature of his/her disease and 
willingly consent to the study after being informed of study procedures, the experimental therapy, 
possible alternatives, risks and potential benefits. 

CTO # 103408 
Protocol version February 27, 2023 
31 
 
 
 
 
 
9.2 STUDY CALENDAR 
 
 
SCHEDULE OF 
EVENTS8 
SCR C1 
D1 
C1 
D8 
C1 
D15 
C1 
D22 
C2 
D1 
C2 
D8 
C2 
D15 
C2 
D22 
C3+ 
D1 
C3+ 
D8 
C3+ 
D15 
C3+ 
D22 
EOT6 
SFU6 
LTFU 
Informed consent 
X 
Eligibility review 
X 
Medical History 
X 
Physical Exam 
X 
X 
X 
X 
X 
X 
ECOG Performance 
Status 
X 
X 
X 
X 
X 
X 
Vital signs9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pre-infusion 
30, 60, and 90 mins 
after EOI 
ECG 12-lead 
X 
X 
X 
Pre-infusion 
EOI 
1h after EOI1  
2h after EOI1 
3h after EOI1 
4h after EOI1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CBCD 
X 
X 
X 
X 
X 
X 
CMP 10 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Magnesium 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Phosphorous 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum potassium 
EOI 
3h post EOI 
X 
X 
X 
X 
Urinalysis 
X 
B-HCG2 
X 
X 
X 
X 
Biomarker 
samples/ctDNA 
samples3 
X 
X 
X 
Potassium 
Supplementation4 
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 
Sotorasib dosing 
***Continuous dosing*** 
Tumor Assessment5 X 
*** Every 8 weeks (+/- 5 days) from Cycle 1 Day 1*** 
Concomitant Meds 
***Every visit*** 
Adverse Events 
Assessment 
***Every visit*** 
Survival status 
X 

CTO # 103048 
Protocol version November 3, 2022 
32 
 
 
 
 
CT = Computed tomography, ECOG = Eastern Cooperative Oncology Group, EOI = End of 
Infusion, EOT = End of Treatment, SFU = Safety Follow-up, MRI = Magnetic Resonance 
Imaging, PET= Positron Emissions Tomography, QTcF = Corrected QT interval as calculated 
according to Fridericia’s formula, SCR = Screening period 
 
1 For patients with Grade 3 QTcF prolongation (≥ 501 msec or > 60 msec increase compared to 
pre-infusion), repeat ECG every 15 to 30 mins until resolved to Grade 2 (481 to 500 msec) or 
lower (≤480 msec) and then obtain ECGs every hour up to 4 hours post infusion, or longer as 
clinically indicated. 
2 Serum pregnancy test at baseline, then urine pregnancy test, for women of childbearing 
potential 
3 Collect blood for biomarkers per correlatives manual. 
4 If required. See section 7, potassium supplementation. 
5 Perform radiographic assessments according to institutional practice. Include CT or MRI of the 
chest and abdomen, and if applicable, brain CT or MRI, bone scan, or PET-CT at screening. The 
baseline tumor assessment is required within 28 days prior to first dose of tarloxotinib. PET-CT 
may be substituted for a contrasted CT of the chest and abdomen if tumor measurements are 
obtained per RECIST 1.1 criteria.  The same imaging modality used for baseline imaging must 
be used for subsequent tumor assessments in each patient. 
6The EOT visit should be conducted within +/- 7 days of the last dose of tarloxotinib, and the 
safety follow-up should occur 30 days (+/- 7 days after the last dose of tarloxotinib). 
7Patients may be followed for survival status every 3 months for up to 6 months after the last 
patient on study visit (LPV) at the investigator’s discretion. 
8Informed consent, medical history and physical exam/ECOG status to be obtained within 28 
days of Cycle 1 Day 1. Baseline labs and ECG are to be obtained within 14 days of Cycle 1 
Day 1. 
9 Vital signs should include: Height (at screening only), weight, blood pressure, temperature, 
respirations, and O2 saturation. 
10 Liver function testing to be performed every 3 weeks for the first 3 months, then monthly as 
clinically indicated. 
 
Cycles are 28 days in length. Study visits have a +/- 1 day window to allow for holidays or 
other rescheduling reasons, to be documented in the research record. 
9.3 CRITERIA FOR REMOVAL FROM PROTOCOL TREATMENT 
 
Subjects may discontinue study treatment at any time. Any subject who discontinues treatment 
will be asked to return to the study center to undergo end of treatment assessments as outlined 
within Study Calendar (Section 7.2). The primary reason for discontinuation should be recorded. 
In the absence of treatment delays due to adverse events, treatment may continue until one of the 
following criteria applies: 
 
• Radiographic disease progression 
• Clinical disease progression 

CTO # 103048 
Protocol version November 3, 2022 
33 
 
 
• Inter-current illness that would, in the judgment of the investigator, affect assessments of 
clinical status to a significant degree or require discontinuation of study drugs 
• Completion of protocol treatment. 
• Unacceptable toxicity 
• Death 
• Subject may withdraw from the study at any time for any reason. 
• Treatment delay for unacceptable duration for any toxicity in the opinion of the 
investigator 
• Concomitant treatment with a prohibited medication 
• Subject non-compliance 
 
9.4 DURATION OF FOLLOW UP 
 
Subjects may be followed for survival status every 3 months for up to 6 months after the last 
patient on study visit (LPV) at the investigator’s discretion. 
 
10 DEFINITION OF ENDPOINTS 
 
10.1 
PRIMARY EFFICACY ENDPOINT 
 
Objective response (OR = CR+PR) measured by CT and assessed per RECIST 1.1. Complete 
response (CR) and partial response (PR) require confirmatory CT repeat assessment at least 4 
weeks after the first detection of response. 
 
10.2 
SECONDARY EFFICACY ENDPOINTS 
 
1) Duration of response (DOR) as measured from the date of first response (CR or PR) to date 
of disease progression (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started) or death. 
 
2) Disease control rate (DCR) based on patient who had CR or PR or Stable disease (SD) for at 
least 2 cycles (8 weeks). 
 
3) Best overall response (BOR) determined from a sequence of responses assessed. Two 
objective status determinations of CR before progression are required for a BOR of CR. Two 
determinations of PR or better before progression, but not qualifying for a CR, are required for a 
BOR of PR. A minimum timeframe of 8 weeks is required for a BOR of SD. 
 
3) Progression free survival (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. 
 
4) Overall survival (OS) as measured from the date of first study drug dose to the date of death 
by any cause. 

CTO # 103048 
Protocol version November 3, 2022 
34 
 
 
 
 
 
 
10.3 
SAFETY ENDPOINTS 
 
Primary safety endpoints are Dose-limiting toxicities, treatment-emergent adverse events, 
clinically significant changes in vital signs, electrocardiograms (especially QT), laboratory 
parameters (hematology, serum chemistry, urinalysis, serum pregnancy test), physical 
examination results. 
 
 
10.4 
EXPLORATORY ENDPOINTS 
 
1) To evaluate the utility of detection of KRAS G12C mutations in plasma ctDNA to identify the 
study population. 
2) To explore the association between baseline tumor biomarkers, gene alterations and clinical 
activity. 
3) To identify known and possibly new markers of resistance to KRAS G12C inhibition in 
baseline tumor tissue (if available) including phosphorylated ERK and S6 kinase. 
4) To examine mutations in RAS and other tumor genes potentially implicated in the resistance to 
sotorasib using ctDNA. 
 
11 STATISTICAL CONSIDERATIONS 
 
11.1 STUDY DESIGN 
 
Study CTO # 103048 is a potentially multicenter, non-randomized, single cohort phase IB trial 
evaluating the safety and efficacy of tarloxotinib in combination with sotorasib in NSLC patients 
with KRAS G12C mutation who have progressed on any small molecule KRAS G12C inhibitor. 
 
Safety lead-in 
A minimum of 6 patients and as many as 18 patients will be enrolled in a safety lead-in cohort to 
evaluate the safety of the combination of tarloxotinib and sotorasib. Sotorasib will be held at a 
fixed dose of 960 mg QD (the approved dose) while the starting dose of tarloxotinib will be the 
monotherapy RP2D equal to 150mg/m2 QW (dose level 1 [DL1]). Following a 3+3 algorithm, an 
initial 3 patients will be enrolled at DL1. If 0 or 1 of 3 patients experience a DLT, an additional 3 
patients will be enrolled to DL1. DL1 will be declared the combination RP2D (RP2Dc) if at most 
1 of 6 patients treated at DL1 experience a DLT. Alternatively, if there are 2 or more DLTs 
observed at DL1, 3 patients will be enrolled at DL -1 and the 3+3 rules repeated for safety 
evaluation. The RP2Dc will be the highest DL at which at most 1 patient of 6 experiences a DLT. 
If DL -2 is considered too toxic, additional dose levels below DL -2 to be determined may be 
considered for safety. 

CTO # 103048 
Protocol version November 3, 2022 
35 
 
 
Dose expansion 
Once the tarloxotinib RP2Dc is reached, an expansion cohort of up to 12 patients will be enrolled 
to evaluate the safety of the combination of tarloxotinib and sotorasib. Eligible safety lead-in 
patients treated at the RP2Dc will be included in the expansion cohort. 
 
The combination of tarloxotinib and sotorasib will not be considered promising if there is weak 
evidence the true objective response rate (ORR) exceeds 20%. Specifically, the trial will be 
declared negative if Prob (true ORR > 20% | observed no. of responses) < 20%, equivalent to 
observing at most 1 response in 12 patients. We assume the true ORR follows a beta (0.5, 0.5) 
prior distribution and, conditional on the true ORR, the number of responses follows a binomial 
distribution. If at least 2 responses in 12 patients are observed, the combination may be 
considered promising. Given 1 response in 12 patients, the probability the true ORR exceeds 
20% is approximately 16%. Given 2 responses in 12 patients, the probability the true ORR 
exceeds 20% is approximately 42%. 
11.1.1 SAMPLE SIZE DETERMINATION 
 
The sample size of 6 patients in the safety lead-in and 12 patients in the expansion cohort will 
allow for preliminary assessment of safety and anti-tumor activity at the RP2Dc. For primary 
safety outcomes, the table below shows the probability of observing at least one DLT/DLT- 
equivalent (DLT-E) for true DLT/DLT-E rates ranging from 10% to 40% for group sample sizes 
of 6 (safety lead-in cohort) and 12 (expansion cohort). (A DLT-equivalent is any safety event 
that would have qualified as a DLT had that patient been enrolled in the safety lead-in portion of 
the study.) 
 
 
Probability of observing at least 1 DLT/DLT-equivalent events for n = 6 or 12. 
 
Probability of observing ≥1 DLT/DLT-Es 
True DLT/DLT-E rate 
n=6 
n=12 
0.05 
0.26 
0.46 
0.10 
0.47 
0.72 
0.15 
0.62 
0.86 
0.20 
0.74 
0.93 
0.25 
0.82 
0.97 
0.30 
0.88 
0.99 
 
For the 12 patients in the expansion cohort, example incidence rates and corresponding exact 
95% binomial confidence intervals (CIs) summarizing safety (e.g., AE or DLT-E rates) or 
response (e.g., ORR or DCR) are shown in the table below. The values are provided as a 
reference for estimation rather than as a basis for any decision criteria. The RP2Dc may be 
revised based on accumulated safety data obtained in expansion. 
 
 
Estimated incidence rate and exact binomial 95% CI for n = 12. 
 
95% CI 
No. of Cases 
Estimated Rate 
Lower Limit 
Upper Limit 
0 
0 
0 
0.26 

CTO # 103048 
Protocol version November 3, 2022 
36 
 
 
 
1 
0.08 
0.00 
0.38 
2 
0.17 
0.02 
0.48 
3 
0.25 
0.05 
0.57 
4 
0.33 
0.10 
0.65 
5 
0.42 
0.15 
0.72 
6 
0.5 
0.21 
0.79 
 
11.1.2 POPULATIONS FOR ANALYSES 
 
The following analysis sets will be defined for this study. 
 
The safety analysis set comprises all enrolled patients who receive any quantity of study 
treatment, regardless of eligibility. The safety evaluation will be performed based on the first 
dose of study treatment a patient receives, regardless of the patient’s cohort assignment. The 
safety analysis set will be used for all dosing/exposure and safety analyses. 
 
The DLT-evaluable population (safety lead-in only) comprises patients who have either 
completed the DLT-observation period (1 cycle, 28 days) and received at least 75% of planned 
doses of the tarloxotinib and sotorasib combination in cycle 1 or have discontinued study 
treatment or study participation before completing cycle 1 due to a DLT. 
 
The intention to treat (ITT) analysis set comprises all patients in the safety analysis set eligible 
for study inclusion and who meet the inclusion criteria for dose expansion, including eligible 
safety lead-in patients treated at the RP2Dc. This analysis set will be used for all efficacy 
analyses. 
 
11.2 
STATISTICAL ANALYSES 
 
11.2.1 GENERAL APPROACH 
Frequencies and percentages will be used to summarize the distributions of categorical variables. 
Mean, median, range, inter-quartile range and standard deviation will be used to summarize 
distributions of continuous variables. 
 
11.2.1.1 Participant Disposition 
A detailed description of participant disposition will be provided at the end of the study, 
including a summary of the number and percentage of patients entered into the study, enrolled in 
the study, and treated, as well as the number and percentage of patients completing the study or 
discontinuing (overall and by reason for discontinuation). 
 
11.2.1.2 Participant Characteristics 
A summary of baseline patient and disease characteristics, historical diagnoses, pre-existing 
conditions, and prior therapies will be reported using descriptive statistics. 
 
11.2.1.3 Concomitant Therapy 
A summary of prior and concomitant medications by dose level (safety lead-in) and cohort (lead- 
in versus expansion) will be reported. 

CTO # 103048 
Protocol version November 3, 2022 
37 
 
 
 
11.2.1.4 Treatment Compliance 
Study treatment compliance will be assessed as the proportion of treatment actually taken 
relative to what is expected, after accounting for protocol-defined dose adjustments. For oral 
medications, study treatment taken will be derived from the difference between the total number 
of capsules/tablets dispensed and returned over the course of the patient’s treatment. The number 
of cycles received, dose omissions, dose reductions, dose delays, and dose intensity will be 
summarized for all treated patients by dose level (safety lead-in) and cohort (lead-in versus 
expansion). 
 
11.2.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
 
Objective response rate (ORR), defined as the proportion of patients who achieve a best 
overall response of CR or PR, is the primary efficacy endpoint. Tumor response will be 
measured and recorded using RECIST 1.1 guidelines (Eisenhauer et al. 2009). All lesions should 
be radiologically evaluated using the same method used for baseline evaluation. Any CR or PR 
will require confirmation at least 4 weeks following initial response observation. Objective 
response rate will be summarized for the ITT population using frequencies and proportions. A 
95% CI for the ORR will be constructed using exact binomial (Clopper-Pearson) methods. 
 
11.2.3 ANALYSIS OF THE SECONDARY EFFICACY ENDPOINT(S) 
 
Disease control rate (DCR) is defined as the proportion of patients who achieve a CR or PR or 
SD for at least 2 cycles. DCR will be summarized for the ITT population using frequencies and 
proportions. A 95% CI for the DCR will be constructed using exact binomial (Clopper-Pearson) 
methods. 
 
Best overall response (BOR) will be determined from a sequence of responses assessed. Two 
objective status determinations of CR before progression are required for a BOR of CR. Two 
determinations of PR or better before progression, but not qualifying for a CR, are required for a 
BOR of PR. A minimum timeframe of 8 weeks is required for a BOR of SD. BOR will be 
summarized for the ITT population using frequencies and proportions. A 95% CI for BORs of 
CR, PR, SD or PD will be constructed using exact binomial (Clopper-Pearson) methods. 
 
Duration of response (DOR) will be evaluated only for responders. Duration of response is 
measured from the date of first confirmed response (CR or PR) to date of first disease 
progression (taking as reference for progressive disease the smallest measurements recorded 
since the treatment started) or death. DOR will be summarized graphically using Kaplan-Meier 
curves. Median DOR and corresponding 95% CI will be reported. For patients who are not 
known to have died or to have had a progression of disease as of the data-inclusion cut-off date, 
DOR will be censored at the date of last objective response assessment prior to the date of any 
subsequent systemic anticancer therapy. 
 
Progression free survival (PFS) is defined as the time from the date of start of treatment to the 
first date of radiologically documented progressive disease or the date of death due to any cause, 
whichever occurs first. PFS will be summarized graphically using Kaplan-Meier curves. Median 

CTO # 103048 
Protocol version November 3, 2022 
38 
 
 
PFS and corresponding 95% CI will be reported. For patients who are not known to have died or 
progressed as of the data-inclusion cut-off date, PFS time will be censored at the date of the last 
objective progression-free disease assessment prior to the date of any subsequent systemic 
anticancer therapy. 
 
Overall survival (OS) is defined as the time from the date of start of treatment to the date of 
death due to any cause. OS will be summarized graphically using Kaplan-Meier curves. Median 
OS and corresponding 95% CI will be reported. For patients who are alive, lost to follow-up, or 
withdrawn from the study at the time of analysis, OS will be censored at the last date the patient 
is known to be alive. 
 
11.2.4 SAFETY ANALYSES 
 
All patients in the safety analysis set will be evaluated for safety and toxicity. Adverse events, 
SAEs and TEAEs will be summarized by System Organ Class (SOC) and by decreasing 
frequency of Preferred Term within SOC. Safety analyses will include the following summaries: 
• AEs, including severity and possible relationship to study drug 
• SAEs, including possible relationship to study drug 
• AEs leading to dose adjustments 
• DLTs and DLT-E events 
• Discontinuations from study treatment due to AEs or death 
• Treatment-emergent abnormal changes in laboratory values 
• Treatment-emergent abnormal changes in vital signs and ECGs 
 
AEs should be reported for 28 days after the last dose of tarloxotinib and/or sotorasib. 
 
11.2.5 EXPLORATORY ANALYSES 
 
The frequency and proportion of patients with specific mutations and alterations will be 
summarized. Corresponding exact binomial (Clopper-Pearson) 95% confidence intervals will be 
constructed. The association of specific mutations and alterations with clinical activity will be 
evaluated using Fisher’s exact test for categorical efficacy endpoints and using Cox proportional 
hazards regression models for time-to-event efficacy endpoints. 
 
11.3 
INTERIM ANALYSES 
Safety lead-in 
Safety and tolerability data will be reviewed on a cohort-by-cohort basis during safety lead-in to 
determine if an additional cohort of patients should be enrolled at the current DL, if de-escalation 
is warranted, or if the protocol should be amended to evaluate additional intermediate or lower 
DLs. The final determination of the RP2Dc will be based on the totality of data including, but not 
limited to, safety and early signs of anti-tumor activity. 
 
Dose expansion 

CTO # 103048 
Protocol version November 3, 2022 
39 
 
 
Interim futility analysis. Given the limited sample size, there will be no futility interim analysis 
in the dose expansion cohort. 
 
Continuous safety monitoring. Bayesian toxicity monitoring will be used to perform continuous 
safety monitoring of patients enrolled in the expansion cohort. Specifically, patients enrolled in 
the expansion cohort will be monitored for incidence of DLT-equivalent (DLT-E) events, 
defined as any safety event that would have qualified as a DLT had that patient been enrolled in 
the safety lead-in portion of the study. We assume the true DLT-E rate follows a beta (0.5, 0.5) 
prior distribution and, conditional on the true DLT-E rate, the number of patients who experience 
a DLT-E follows a binomial distribution. If Prob (DLT-E rate > 33% | observed no. DLT-Es) > 
50%, trial enrollment will be paused. (Note: The observed number of DLT-Es will include DLTs 
from eligible safety lead-in patients treated at the RP2Dc who are included in the expansion 
cohort. Bayesian toxicity monitoring parameters were selected to calibrate with the 3+3 de- 
escalation rules used in the safety lead-in.) If the trial is paused, the safety review committee will 
review the totality of the safety data and determine whether to continue patient enrollment at the 
current RP2Dc, introduce intermediate or lower dose levels for evaluation, or close the trial to 
accrual and declare the combination of tarloxotinib and sotorasib too toxic. This monitoring rule 
has a 13% and 95% probability of pausing if the true DLT-E rate is 10% or 50%, respectively. 
The table below specifies safety monitoring thresholds. 
 
Bayesian toxicity monitoring boundaries 
No. of patients 
No. of DLT-Es to pause study 
Observed DLT-E rate 
6 
≥2 
≥0.33 
7-9 
≥3 
≥0.33 
10-11 
≥4 
≥0.36 
12 – expansion cohort fully accrued 
 
 
 
12 CORRELATIVE STUDIES 
 
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 
expression of specific mutations and biomarkers in consenting patients. 
 
Blood samples will be collected for biomarker analysis at Cycle 1 Day 1, Cycle 2 Day 1, and end 
of treatment. Whole blood samples will be collected in two 10 mL cell-free DNA BCT (Streck) 
blood collection tubes and two 10 mL BD Vacutainer EDTA tubes with total volume of 
collection no more than 40 mL. Tumor tissue will be collected for retrospective concordance 
mutation testing and correlation with biomarkers. 
 
 
 
13 ADVERSE EVENT REPORTING REQUIREMENTS 

CTO # 103048 
Protocol version November 3, 2022 
40 
 
 
13.1 
PURPOSE 
 
AE data collection and reporting, which are required as part of every clinical trial, are done to 
ensure the safety of patients enrolled in the studies as well as those who will enroll in future 
studies using similar agents. AE are reported in a routine manner at scheduled times during a 
trial. Additionally, certain AEs must be reported in an expedited manner to allow for more timely 
monitoring of patient safety and care. The following guidelines prescribe routine and expedited 
AEs reporting for this protocol. 
 
Throughout the study, the Investigator will be required to provide appropriate information 
concerning any findings that suggest significant hazards, contraindications, side effects, or 
precautions pertinent to the safety of the drug under investigation. 
 
Note: All deaths on study require both routine and expedited reporting regardless of causality. 
Attribution to treatment or other cause must be provided. 
13.2 
DEFINITION OF ADVERSE EVENT 
 
An AE is defined as any illness, sign or symptom which has appeared or worsened during the 
course of the study, regardless of causal relationship to the drug under study, experienced by a 
patient. 
 
 
All adverse events should be recorded and described in the adverse event database in REDCap. 
Adverse events also include Grade 3 or 4 abnormal laboratory test results that were not noted in 
the Screening Phase. 
 
Pre-existing diseases or conditions will not be considered AEs unless there is an increase in the 
frequency, duration or severity, or a change in the quality, of the disease or condition. Only 
grade 3 or 4 abnormal lab values that were not noted during the Screening Phase should be 
recorded; however, any clinical consequences of the abnormality, regardless of grade should be 
reported as AEs. Hospitalization for elective surgery or routine clinical procedures that are not 
the result of an AE (e.g., surgical insertion of central line) need not be considered AEs and 
should not be recorded as an AE. Progression of cancer also will not be considered an AE. 
 
Death should only be entered as the outcome for an AE when the patient’s death is at least 
probably related to the AE (Note: the causal relationship of the AE to the test article is not to be 
considered in making this decision). If more than 1 AE is possibly related to the patient's death, 
the outcome of death should be indicated for each such AE. 
 
13.3 
DEFINITION OF SERIOUS ADVERSE EVENT 
 
An SAE is defined by regulatory agencies as one that suggests a significant hazard or side effect, 
regardless of the investigator or sponsor’s opinion on the relationship to investigational product. 
This includes, but may not be limited events that result in the following outcomes: 

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• Death 
• Life-threatening. Patient was at substantial risk of dying at the time of the event or use or 
continued use of the medical product may have resulted in the death of the patient. 
• Hospitalization (initial or prolonged). Report hospital admissions or prolongation of 
hospitalization. Emergency room visits that do not result in admission should be 
evaluated for one of the other serious outcomes. 
• Disability or Permanent Damage. Report is the adverse event resulted in a substantial 
disruption of a person’s ability to conducts normal life functions. 
• Congenital anomaly/birth defect. Report if it is suspected that the exposure to the 
medical product prior to conception or during pregnancy may have resulted in an adverse 
outcome for the child. 
• Other Serious or important medical events. If the event does not fit other outcomes, but 
may jeopardize the patient and may require intervention to prevent one of the other 
outcomes. 
 
13.4 
DEFINITION OF SEVERITY 
 
Adverse events will be graded according to the revised NCI Common Toxicity Criteria. If 
toxicities are not defined by the NCI Common Toxicity Criteria v. 4.0, the intensity of each 
adverse event should be graded as outlined below: 
 
GRADE 1 
MILD: Sign or symptom noticeable, but does not interfere with normal daily 
activities. 
 
GRADE 2 
MODERATE: Sign or symptom sufficient to interfere with normal daily 
activities. 
 
GRADE 3 
SEVERE: Sign or symptom is incapacitating, with inability to perform daily 
activities. 
 
GRADE 4 
LIFE-THREATENING: sign or symptom poses immediate risk of death to this 
patient. 
 
13.5 
DEFINITION OF RELATIONSHIP TO STUDY DRUG 
 
The categories for classifying the Investigator’s opinion regarding the relationship of an AE to 
the study drug are listed below. 
 
Definitely related: 
An adverse event occurring in a plausible time relationship to drug 
administration, and which cannot be explained by concurrent 
disease or other drugs or chemicals. The response to withdrawal of 
the drug should be clinically plausible. The event must be definite 
pharmacologically or phenomenologically, using a satisfactory 
rechallenge procedure if necessary and feasible. 

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Possibly related: 
An adverse event with a reasonable time sequence to administration 
of the drug, but which could also be explained by concurrent 
disease or other drugs or chemicals. Information on drug 
withdrawal may be lacking or unclear. 
Not related: 
An adverse event with a temporal relationship to drug 
administration which makes a causal relationship improbable, and 
in which other drugs, chemicals or underlying diseases provide 
plausible explanations. 
 
13.6 
DOCUMENTATION OF ADVERSE EVENTS 
 
The Investigator will monitor and/or ask about or evaluate AEs using non leading questions at 
each visit or evaluation. The occurrence of all AEs will be documented in the CRF with the 
following information, where appropriate: 
 
• AE name or term 
• When the AE first occurred (start date) 
• When the AE stopped (stop date), (or an indication of “ongoing”) 
• How long the AE persisted (optional) 
• Severity of the AE 
• Seriousness 
• Actions taken 
• Outcome 
• Investigator opinion regarding the relationship of AE to the study drug(s) 
 
13.7 
FOLLOW UP OF PATIENTS WITH ADVERSE EVENTS 
 
 
The Investigator will follow patients with AEs, even if the patient was withdrawn from the study 
due to the AE, until the adverse event has: 
• resolved 
• the patient has returned to baseline state of health, 
• the patient is lost to follow-up, 
• the event is otherwise explained, 
• the Investigator does not expect any further improvement or worsening of the adverse 
event. 
 
Medically significant AEs considered related to the investigational product by the investigator or 
the sponsor will be followed until resolved or considered stable. 

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14 DATA COLLECTION AND MANAGMENT 
 
Electronic and hard copy CRF’s will be provided for the recording of data. With the exception 
of hard copy case report forms utilized for expedited reporting requirements, such as the 
reporting of SAE’s, the remainder of patient data will be collected and submitted via electronic 
CRFs. All data should be substantiated by clinical source documents organized within a patient 
research record. ICH Good Clinical Practices are to be followed. 
 
Electronic data for on study and follow-up patient data is submitted via the electronic system 
called REDCap (Research Electronic Data Capture). REDCap is managed from the Medical 
University of South Carolina as a consortium partner under their CTSA. REDCap CRF is a 
secure, Web-based application designed to capture and manage research study data. 
 
The system has been reviewed for 21CFR Part 11 compliance and has been deemed “21CFR 11 
Capable.” Users of the REDCap system are limited to members of the IRB approved research 
team who are delegated data management responsibilities, typically the study coordinator and 
data manager. 
 
15 ETHICAL AND REGULATORY CONSIDERATIONS 
 
The following must be observed to comply with Food and Drug Administration regulations for 
the conduct and monitoring of clinical investigations; they also represent sound research 
practice: 
15.1 
INFORMED CONSENT 
 
The principles of informed consent are described by Federal Regulatory Guidelines (Federal 
Register Vol. 46, No. 17, January 27, 1981, part 50) and the Office for Protection from Research 
Risks Reports: Protection of Human Subjects (Code of Federal Regulations 45 CFR 46). They 
must be followed to comply with FDA regulations for the conduct and monitoring of clinical 
investigations. 
15.2 
INSTITUTIONAL REVIEW 
 
This study must be approved by an appropriate institutional review committee as defined by 
Federal Regulatory Guidelines (Ref. Federal Register Vol. 46, No. 17, January 27, 1981, part 56) 
and the Office for Protection from Research Risks Reports: Protection of Human Subjects (Code 
of Federal Regulations 45 CFR 46) 

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