A Phase II Study Evaluating Safety and Efficacy of Telatinib in Combination With Keytruda in Subjects With Advanced Stomach and Gastroesophageal Junction Cancers or Hepatocellular Carcinoma
Phase: PHASE2
Conditions: Gastric Cancer, Hepatocellular Carcinoma
Sponsor: Andrew Hendifar, MD

 
CONFIDENTIAL  
This material is the property of Cedars-Sinai Medical Center. Do not disclose or use except as authorized in writing by the study 
sponsor. 
 
 
 
 
IIT2020-11-Hendifar-TELAT  
 
A Phase II Study Evaluating Safety and Efficacy of 
Telatinib in Combination with Keytruda in 
Subjects with Advanced Stomach and 
Gastroesophageal Junction Cancers or 
Hepatocellular Carcinoma 
 
 
Principal Investigator:  
Andrew Hendifar, MD, MPH 
 
 
 
 
Cedars-Sinai Medical Center 
 
 
 
 
8700 Beverly Blvd, Los Angeles, CA 90048 
 
Site
Sub-Investigator(s) 
CS Cancer at the Samuel Oschin Cancer 
Center 
Jun Gong, MD* ** 
Arsen Osipov, MD 
Ju Dong Yang, MD** 
Kamya Sankar, MD 
CS Cancer Beverly Hills 
David Hoffman, MD 
Jeremy Lorber, MD* 
Kevin Scher, MD 
CS Cancer at The Angeles Clinic and 
Research Institute 
Vi Chiu, MD* 
Cathie Chung, MD, PhD 
 Inderjit Mehmi, MD 
Omid Hamid, MD 
Michelle Offner, NP 
Kristopher Wentzel, MD 
*Lead co-investigators, AGC cohort: Vi Chiu, MD, Jeremy Lorber, MD, Jun Gong, MD 
**Lead co-investigators, HCC cohort: Ju Dong Yang, MD and Jun Gong, MD 
 
 
 
 
 
Biostatistician: 
Mourad Tighiouart, PhD 
 
FDA Status:  
 
 
IND Required 
 
IND Number: 
 
 
154515 
 
IND Holder Name: 
 
Andrew Hendifar, MD, MPH 
 
Funding Source:  
EOC Pharma 
 
ClincialTrials.gov Reg:  
Required 
 
NCT Number:   
 
Pending 
 
ClincialTrials.gov Reporting: Required 

 
CONFIDENTIAL  
This material is the property of Cedars-Sinai Medical Center. Do not disclose or use except as authorized in writing by the study 
sponsor. 
 
 
Current Version: 
 
Protocol Version 4 dated 15MAR2023 
 
Initial version:  
 
N/A 
 
 

 
CONFIDENTIAL  
This material is the property of Cedars-Sinai Medical Center. Do not disclose or use except as authorized in writing by the study 
sponsor. 
 
 
 
 
 
IIT2020-11-Hendifar-TELAT 
Protocol Version 4: Dated 15MAR2023 
 
Signature Page 
 
 
The signature below constitutes the approval of this protocol and the attachments, and provides the 
necessary assurances that this trial will be conducted according to all stipulations of the protocol, 
including all statements regarding confidentiality, and according to local legal and regulatory requirements 
and applicable U.S. federal regulations and ICH guidelines. 
 
 
 
 
______________________________________________ 
 
 
_________________ 
Principal Investigator (PI) Signature    
 
 
 
 
Date 
 
 

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TABLE OF CONTENTS  
 
LIST OF ABBREVIATIONS............................................................................................................. 1 
STUDY SCHEMA ............................................................................................................................ 2 
STUDY SUMMARY ......................................................................................................................... 3 
1.0 
BACKGROUND AND RATIONALE ................................................................................... 4 
2.0 
STUDY OBJECTIVES ...................................................................................................... 12 
3.0 
STUDY DESIGN ............................................................................................................... 13 
4.0 
PATIENT ELIGIBILITY ..................................................................................................... 13 
5.0 
TREATMENT PLAN ......................................................................................................... 16 
6.0 
STUDY PROCEDURES.................................................................................................... 19 
7.0 
ADVERSE EVENTS (AE) ................................................................................................. 24 
8.0 
CORRELATIVES/SPECIAL STUDIES ............................................................................. 28 
9.0 
STATISTICAL CONSIDERATIONS ................................................................................. 29 
10.0 
STUDY MANAGEMENT ................................................................................................... 31 
11.0 
REFERENCES .................................................................................................................. 36 
12.0 
APPENDICES ................................................................................................................... 38 

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LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ANC 
Absolute neutrophil count 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate Aminotransferase 
CBC 
Complete Blood Count 
CMP 
Comprehensive Metabolic Panel 
CR 
Complete Response 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DARF 
Drug Accountability Review Form 
DCR 
Disease control rate 
DLT 
Dose Limiting Toxicity 
DSMC 
Data and Safety Monitoring Committee 
ECG 
Electrocardiogram  
ECOG 
Eastern Cooperative Oncology Group 
HCC 
Hepatocellular carcinoma 
HRPP 
Human Research Protections Program 
INR 
International normalized ratio 
IV (or iv) 
Intravenously 
MTD 
Maximum Tolerated Dose 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PBMCs 
Peripheral Blood Mononuclear Cells 
PD 
Progressive Disease 
PFS 
Progression Free Survival 
PO 
per os/by mouth/orally 
PR 
Partial Response 
PT 
Prothrombin time 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
ULN 
Upper limit of normal 
WBC 
White Blood Cells 
WOCBP 
Women of childbearing potential 
 
 
 
 
 
 
 
 
 
 
 
 

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STUDY SCHEMA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AGC cohort (n=21) 
Telatinib 900mg PO BID + 
Keytruda 200mg IV Q3W 
Until disease progression, intolerable 
toxicities, or withdrawal of consent 
HCC cohort (n=24) 
Telatinib 900mg PO BID + 
Keytruda 200mg IV Q3W 
Until disease progression, intolerable 
toxicities, or withdrawal of consent 
Screening and Enrollment 
Enrollment will follow the safety stopping rules 
Primary endpoint: Progression Free Survival (PFS) 
Secondary endpoints: Overall response rate (ORR), Disease Control Rate (DCR), Overall survival 
(OS), and Safety 

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STUDY SUMMARY 
Title 
A Phase II Study Evaluating Safety and Efficacy of Telatinib in 
Combination with Keytruda in Subjects with Advanced Stomach and 
Gastroesophageal Junction Cancers or Hepatocellular Carcinoma 
Protocol Number 
IIT2020-11-Hendifar-TELAT 
Phase 
Phase II  
Methodology 
Single arm, open label study with two parallel cohorts  
Study Duration 
Approximately 30 months (anticipated accrual duration 12 months, with 
up to an estimated 12 months on-treatment and up to an estimated 6 
months follow-up) 
Stopping rules for safety will be followed. 
Study Center 
Cedars-Sinai Medical Center and affiliates 
Objectives 
Primary: 
The primary objective is to assess progression-free survival (PFS) in 
subjects with advanced gastric cancer or HCC receiving telatinib 900 
mg BID in combination with Keytruda.  
Secondary: 
The secondary objectives are to assess: 
Overall response rate (ORR), Disease Control Rate (DCR), Overall 
survival (OS), and Safety 
Exploratory: 
Time to Progression (TTP) 
Change in inflammatory cytokines 
Change in plasma metabolites 
Change in immune cell profile 
Change in stool microbiome 
Change in stool metabolites 
Number of Subjects 
21 subjects with advanced gastric cancer 
24 subjects with advanced hepatocellular carcinoma 
Diagnosis and Main 
Inclusion Criteria 
Adult subjects with advanced gastric cancer or HCC who are indicated for 
Keytruda 
Study Product(s), Dose, 
Route, Regimen 
Telatinib 900 mg (3 x 300 mg tablets) will be administered orally, 
twice daily. 
Keytruda will be administered IV 200 mg every 3 weeks. 
Duration of administration 
Until disease progression, intolerable toxicities, or withdrawal of consent 
Statistical Methodology 
Gastric cancer: PFS will be compared to KEYNOTE-059 with a primary 
endpoint of improvement in PFS from 2.0 months to 4 months.  
HCC: PFS will be compared to KEYNOTE-224 with a primary endpoint 
of improvement in PFS from 4.9 months to 10 months.  
 

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1.0 
BACKGROUND AND RATIONALE 
1.1 
Disease Background 
1.1.1 
Gastric Cancer 
Gastric cancer is the 5th most common cancer and remains the world’s third leading cause of 
cancer mortality [1]. Surgery is the mainstay of curative treatment in stage I to III gastric cancers. 
However, more than half of the patients at diagnosis are already too advanced for curative 
resection. Even for those who are resectable upfront, the recurrence rate is still high at around 40–
80% [2, 3]. First-line then second-line palliative chemotherapy is the standard of treatment in 
patients with advanced/metastatic gastric cancer. A Cochrane review and meta-analysis performed 
by Wagner demonstrated that chemotherapy extended overall survival (OS) by approximately 6.7 
months more than best supportive care [4]. Standard front-line therapy includes chemotherapy 
using fluorouracil (5FU) and platinum agents, with the option of adding anthracycline or taxane 
group agents. In human epidermal growth factor receptor 2 (Her2) positive advanced gastric 
cancer, adding trastuzumab to platinum-based chemotherapy (cisplatin/carboplatin + 5FU) showed 
superior efficacy compared with chemotherapy alone (OS: 13.8 versus 11.1months, HR 0.74; 95% 
CI 0.60–0.91; p = 0.0046) [5]. Several systematic reviews and meta-analyses had confirmed 
survival advantage of second-line chemotherapy when compared with BSC alone [6-8]. In Kim and 
colleagues’ meta-analysis, which involved 410 patients, second-line chemotherapy significantly 
reduced the risk of death when compared with BSC [7].  Standard second-line therapies include 
irinotecan-based and taxane-based (docetaxel or paclitaxel) chemotherapy. Ramucirumab, a 
vascular endothelial growth factor receptor (VEGFR) monoclonal antibody, has also been 
established as monotherapy or in combination with paclitaxel in the second-line setting. Several 
network meta-analyses have been published to compare these second-line regimes. Combination 
of paclitaxel plus ramucirumab showed superior efficacy in prolonging OS when compared with 
single-agent chemotherapy or ramucirumab [9-11]. 
 
With the development of new chemotherapies or targeted agents which are potentially more 
effective and less toxic, many patients can still maintain a good general condition after failing 
second-line therapies. According to previous studies, around 20–90% patients were able to 
continue active third-line or further lines of treatment. Established third-line therapies include 
chemotherapies: irinotecan, taxane and TAS-102, tyrosine kinase inhibitors: apatinib and 
regorafenib, and immune-checkpoint inhibitors (CPIs): nivolumab and pembrolizumab. Given the 
expanding options for third-line therapies, there is an unmet need for clinicians to individualize 
treatment.  
 
Pembrolizumab is a humanized anti-PD-1 monoclonal antibody. In the KEYNOTE-059 Cohort 1, a 
multicenter, open-label, single-arm phase II trial conducted at 67 sites in 17 countries, 259 patients 
(after failing two or more lines of chemotherapy including cisplatin and 5FU; patients with Her-2 
positive tumors must have received treatment with trastuzumab) received a fixed dose of 200mg 
pembrolizumab in a 3-weekly cycle [12]. Pembrolizumab showed an objective response rate of 
11.6% (95% CI 8.0–16.1%), with complete response of 2.3% (95% CI 0.9–5.0%). The response 
rate was higher in the patients with PD-L1 positive tumors (PD-L1-positive versus PD-L1-negative: 
15.5% versus 6.4%). A total of seven (4%) tumors were microsatellite instable (MSI)-high (H) and 
the response rates were higher, with an overall response rate of 57.1%. Median PFS was 2.0 
months and median OS was 5.6 months. Based on this result, the Food and Drug Administration 
(FDA) has approved pembrolizumab as the third line treatment for PD-L1-positive gastric 
adenocarcinoma. Adverse events (AE) of any grade was reported in 60.2% of patients receiving 
pembrolizumab. The most common any-grade AEs were fatigue, pruritis, rash, hypothyroidism, 
decreased appetite, anemia, nausea, diarrhea and arthralgia. Grade ≥3 treatment-related AEs 
occurred in 17.8% patients, with more common AEs including anemia, fatigue and diarrhea. Overall, 
17.8% of patients experienced at least one immune-mediated AE of any grade; the most common 
were hypothyroidism (8.9%), hyperthyroidism (3.5%) and colitis (2.3%). 
 

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This study aims to explore the clinical safety and efficacy of combination of Telatinib, a potent oral 
inhibitor of VEGFR2 tyrosine kinase, and Pembrolizumab within the 3rd line and after treatment of 
locally advanced and metastatic gastric cancer 
1.1.2 
Hepatocellular carcinoma (HCC) 
 
Hepatocellular cancer is the sixth most common cancer and the second leading cause of cancer 
mortality worldwide [13]. Heterogeneity of clinical conditions contributes to the complex 
management of care for patients with advanced HCC. Recently, the treatment landscape for 
advanced HCC has expanded rapidly, with the additional FDA approvals of several oral tyrosine 
kinase inhibitors (lenvatinib, regorafenib, and cabozantinib), as well as immunotherapies such as 
immune check point inhibitors (nivolumab and pembrolizumab) and the monoclonal IgG1 antibody, 
ramucirumab.  
 
In 2007, the FDA approved sorafenib, an oral TKI targeting–among others–vascular endothelial 
growth factor (VEGF), the key mediator of angiogenesis, for the first-line treatment of advanced 
HCC in light of positive results from the Sorafenib Hepatocellular Carcinoma Assessment 
Randomized Protocol (SHARP) study [14]. This was a multicenter, phase III, double-blind, placebo-
controlled trial in treatment-naïve patients with advanced HCC that demonstrated a 2.8-month 
median overall survival (OS) benefit for sorafenib compared to placebo (10.7 vs. 7.9 months; 
hazard ratio (HR), 0.69) [14]. A second phase III trial done in the Asia-Pacific region further 
demonstrated that sorafenib improved median OS compared to placebo (6.5 vs. 4.2 months; HR, 
0.68) [15]. Notably, both trials confirmed the antitumor activity of sorafenib in patients with well-
preserved liver function (Child–Pugh A) not amenable for surgery or loco-regional therapies. 
 
Pembrolizumab is an IgG4 anti-PD-1 cancer therapeutic that was tested in the KEYNOTE-224 non-
randomized, multicenter, open-label, phase II trial [16]. This study aimed to assess the efficacy and 
safety of pembrolizumab in advanced HCC patients who had progression on or intolerance to 
sorafenib. The primary endpoint was ORR and from the 104 patients that were treated, 18 (17%) 
achieved the ORR and 46 (44%) patients had stable disease. Among the 18 patients who 
responded to pembrolizumab, there was 1 complete response and 17 partial responses. Grade ≥3 
treatment-related adverse events occurred in 26% of the patients; the most common adverse 
events were elevated levels of aspartate aminotransferase (7%), elevated levels of alanine 
aminotransferase (4%), and fatigue (4%). The efficacy data from the KEYNOTE-224 trial led to the 
accelerated FDA approval of pembrolizumab as a second-line agent for the treatment of patients 
with advanced HCC who have previously received sorafenib. However, recent results of the 
confirmatory phase III trial, KEYNOTE-240, revealed that statistically significant improvement of the 
co-primary endpoints, OS and PFS, was not achieved [17]. Subsequently, many are left with 
uncertainty regarding the future of single agent PD-1 immune checkpoint inhibitors in the treatment 
landscape of advanced HCC. 
1.2 
Study Agent(s) Background and Associated Known Toxicities 
1.2.1 
Preclinical Data  
 
Telatinib is an orally bioavailable potent inhibitor of vascular endothelial growth factor receptor 2 
(VEGFR2) tyrosine kinase activity with an IC50 of 6 nM when measured in a biochemical assay. It 
also inhibited platelet-derived growth factor receptor (PDGFR) tyrosine kinase activity with an IC50 
of 15 nM. These 2 receptors play key roles in the angiogenic process involving the stimulation of 
endothelial cells forming the vessel, and PDGFR-expressing pericytes supporting the newly formed 
vessels. Telatinib is the most selective known VEGFR inhibitor under development and is unique in 
its ability to discriminate the above targets from other kinase enzymes. As an oral agent, patients 
can achieve sustained and prolonged inhibition of the intended targets. 
 
The drug product proposed for marketing is formulated as immediate-release tablets of telatinib 
mesylate for oral dosing. The tablets contain 300 mg of micronized telatinib mesylate (the dose 

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refers to the free base). Telatinib is administered under a continuous (uninterrupted) dosing 
regimen. 
 
The pharmacology of telatinib has been extensively characterized in a series of in vitro 
receptor binding and functional assays and in vivo efficacy studies assessing the effects of 
telatinib alone and in combination with standard chemotherapeutic agents. To support the 
safety in humans, the nonclinical toxicology of telatinib has been evaluated in a series of 
single and repeat dose studies in mice, rats, rabbits, and dogs involving the oral route of 
administration. Complementing the toxicology studies, a series of in vitro and in vivo safety 
pharmacology studies, the latter in rats and dogs, were also conducted to evaluate the effects of 
telatinib upon central nervous, respiratory, cardiovascular, gastrointestinal, and renal systems. 
1.2.2 
Clinical Data 
In company-sponsored studies, 185 subjects have been exposed to telatinib as a single agent. In 
addition, 120 subjects have been exposed to telatinib in combination with other chemotherapeutic 
or biologic agents in company-sponsored studies. Most subjects received 900 mg bi-daily (bid) dose 
continuously without interruption. Single agent antitumor activity has been demonstrated in a variety 
of tumor types including renal, colorectal, hepatocellular and gastric cancer. In an ongoing Phase II 
study of telatinib in combination with capecitabine (X) and cisplatin (P), >65% of patients have 
achieved a partial response (>30% reduction in tumor), which is double the expected objective 
response rate (ORR) from an XP combination. These responses appear durable. 
 
The recommended Phase II dose for single agent telatinib studies is 900 mg bid administered 
continuously based on biologic effect (decreased serum soluble VEGFR2 levels and PK). The most 
common adverse events (AEs) at 900 mg bid are gastrointestinal (diarrhea, nausea, hypertension 
and fatigue). Drug-related AEs of CTCAE Grade 3-4 in subjects treated at a dose level of 900 mg 
bid continuous were hypertension and diarrhea. In an ongoing Phase II study of telatinib in 
combination with capecitabine (X) and cisplatin (P), preliminary results indicate the 900 mg bid dose 
is well tolerated without additive toxicity. 
 
Based on the clinical studies to date, telatinib has the potential as a cancer therapeutic, in 
particular because of the non-overlapping toxicity profile with fluoropyrimidine, platinum, 
topoisomerase inhibitors and taxanes. Telatinib has a low incidence of hand-foot syndrome 
and myelosuppression, attributed to the selectivity of the target. Clinical results to date 
indicate that the 900 mg bid dose given continuously has side effects that are predictable, reversible 
and manageable. 
1.2.3 
Clinical Pharmacokinetics 
 
After oral administration of 14C-labeled telatinib to rats, the absorption of radioactivity from the GI 
tract was almost complete. In dogs, the mean absorption was 35% and showed high inter-individual 
variability. Bioavailability was high in rats (about 100%) and low in dogs (2-11%). The low 
bioavailability in dogs was due to pronounced first-pass metabolism and limited absorption. The PK 
of telatinib was characterized by low variability in rats. In dogs, however, high variability of the 
plasma concentration vs. time profiles of telatinib was observed, especially after oral administration. 
PK of telatinib was almost linear in rats after oral administration in terms of AUC (dose range: 
0.075-50 mg/kg). Cmax increased less than dose proportionally. In dogs, an over- proportional 
increase in AUC was observed after iv infusion of 1 and 3 mg/kg. The Cmax and AUC values 
increased less than dose proportionally after oral administration in the 
investigated dose range of 1-500 mg/kg. A pronounced decrease in exposure was observed after 
repeated oral administration of high doses in rats and dogs. The blood clearance was very low in 
rats (0.2 L/kg*h) but moderate in dogs (1.1 L/kg*h). The Vss was moderate in both species (0.5-0.8 
L/kg). 
 
The terminal plasma elimination half-lives of telatinib were between 2.1 and 3.4 h after oral 
administration (interval: up to 31 h) in rats. In dogs, the corresponding terminal half-life was 
about 1 h and was recorded in the interval up to 8 h after administration. Protein binding of telatinib 
was high and species dependent. The fractions unbound to plasma proteins ranged from 0.2-1.6% 

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in all investigated species (mouse, rat, rabbit, dog, Rhesus monkey, and human). Albumin was 
identified as important binding site in human plasma. There was no saturation of plasma protein 
binding in the investigated concentration range of 1-100 mg/L. 
 
The radioactivity was homogeneously distributed to organs and tissues of rats after intravenous and 
oral administrations of 14C-labeled telatinib. The CEQmax and the AUC of radioactivity was similar 
to blood in most of the organs and tissues. Moderate penetration across the blood/brain barrier was 
observed. Considerable higher radioactivity exposure than in blood was determined in liver, 
adrenals, and kidneys. The radioactivity concentrations were more than 100 times higher in the eye-
wall of the pigmented rats in comparison with the albino rats. This reflects the affinity of radioactivity 
to melanin-containing tissues. After 7 days, elimination was virtually complete. With the exception of 
the enrichments of radioactivity in melanin-containing tissues in the pigmented rat, there was no 
evidence of irreversible binding or retention of radioactivity in organs and tissues of rats. 
 
Incubation of telatinib with liver microsomes of different species revealed Rhesus monkey and 
Wistar rat as most human-like animals regarding oxidative Phase I biotransformation reactions 
(Table 9). New Zealand rabbit, Beagle dog, CD-1 mouse, and NMRI mouse were also regarded 
human-like animals. Hydroxylation of the N-methyl group, leading to metabolite M-1, was 
distinguished as major primary Phase I reaction followed by N-demethylation leading to M-2. The 
cleavage of the ether bond leading to metabolite M-3 was found to a minor extent. 
 
 
 
 
Upon incubation of 14C-labeled telatinib with rat hepatocytes, M-2 was detected as a most 
important metabolite. In addition, metabolite M-1 was found in low amounts. Incubation with dog 
hepatocytes led to metabolites M-1, M-2, and M-3 in small concentrations and M-7 and M-9 as the 2 
major metabolites. The latter were identified as sulfates formed by hydroxylation of the p-
chlorophenyl moiety followed by sulfate conjugation. The metabolic profile in human hepatocytes 
showed 2 N-glucuronides, M-4 and M-5, as major metabolites, whereas metabolites M-1, M-2, and 
M-3 were present in only low concentrations. 
 

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Thus, the in vitro data indicated that direct drug glucuronidation may play an important role in the 
metabolism of telatinib in man. This hypothesis was confirmed after evaluation of the human mass 
balance study using 14C-labeled telatinib in healthy volunteers. 
 
1.3 
Rationale of Combining Telatinib and Pembrolizumab 
1.3.1 
Telatinib 
Telatinib, a potent oral inhibitor of VEGFR2 tyrosine kinase, targets the multi-faceted roles of 
VEGF/VEGFR signaling in immune suppression, including within tumor microenvironment stopping 
or blocking angiogenesis and hypoxia process, regarding Treg, stopping or blocking Treg 
proliferation, regarding MDSC, stopping or blocking recruitment and proliferation of MDSC, also 
regarding cytotoxic T-cells, promoting cytotoxic T-cells recruitment, effector function and trafficking, 
et al. 
1.3.2 
Pembrolizumab 
Pembrolizumab, as an IgG4 subclass antibody, is preferred over other subclasses as it only induces 
weakly the complement and cell activation due to low affinity to C1q and Fc receptors. It binds with 
high affinity to the cell surface receptor programmed cell death protein 1 (PD-1) and it antagonizes 
its interaction with its known ligands PD-L1 and PD-L2. In normal circumstances, the binding of the 
ligands of PD-1 to the receptor inhibits the TCR-mediated T cell proliferation and cytokine 
production. This inhibitory signal seems to be essential for self-tolerance, collateral damage 
minimizing after immune response against a pathogen and maternal tolerance to fetal tissue. 
Therefore, the binding of pembrolizumab to PD-1 prevents the inhibitory pathway causing a 
physiological shift to immune reactivity and enhancing tumor immunosurveillance and anti-tumor 
immune response. 
1.3.3 
Preclinical data of Telatinib combined with Pembrolizumab  
Preclinical data is consistent with excellent synergy with the addition of Telatinib to check point 
inhibitors. The combination of Telatinib and Keytruda was more active than either agent alone in a 
humanized MC38 tumor model. 

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Combination of EOC315 and hPD-1 Ab (Keytruda) on humanized MC38 tumor model 
 
This synergistic effect was also seen in experiments adding Opdivo to Telatinib. 
 
Combination of EOC315 and hPD-1 Ab (Opdivo) on humanized MC38 tumor model 
 
Several in vitro models evaluating the combination of checkpoint inhibition to Telatinib also showed 
a dose response benefit. The combo regimen anti-m PD-1 1mg/kg and Telatinib with different 
dosage (2mg/kg, 6mg/kg and 20mg/kg) compared with single drug (anti-m PD1), which 
demonstrated that the combo regimen had better suppressed efficacy for tumor growth according to 
EOC315 dose escalation. 
 

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Combination of PD-1 blockage with different dose of EOC315 on MC38 tumor model 
 
The benefit of this combinatorial regimen extended to varying cell-lines and doses of checkpoint 
inhibition.  In the anti-m PD-1 3mg/kg dosage, the tumor model shown tumor growth was inhibited. 
In the Telatinib 20mg/kg dosage, the tumor model shown tumor growth was inhibited. The combo 
regimen (anti-m PD-1 3mg/kg and EOC315 20mg/kg) compared with single drug (anti-m PD-1 or 
EOC315), demonstrated that the combo regimen had better suppression efficacy for CT26 tumor 
growth. 
 
0
3
6
9
12
15
18
0
1000
2000
3000
4000
5000
6000
Days Post Treatment
Tumor size(mm3)
Vehicle
anti-m-PD1, 3mg/kg, i.v.,biw
EOC315, 20mg/kg, PO, QD
anti-m-PD1, 3mg/kg, i.v.,biw + EOC315, 20mg/kg, PO, QD
 
Combination of EOC315 and PD-1 blockage on CT26 tumor model 
 
The addition of telatinib in addition to checkpoint inhibition also increased t-cell infiltration in tumor 
models. Comparing EOC315 and combination regimen, T cell infiltration ratio was significantly 
increased in the tumor model(mouse) that received the combination regimen (EOC315 20mg/kg 
and anti-m PD1 1mg/kg) vs EOC315 alone. 
 
 

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Control
Anti-PD1
EOC315
EOC315+Anti-PD1
0
10
20
30
T cells in Tumor
The percentage of CD3+ T cells (%)
*
**
 
T cell infiltration in tumors treated with Anti-PD-1, EOC315 and combo 
 
 
Micro-vessel density in tumor was significantly altered when challenged with EOC315. However, 
checkpoint inhibition had minimal effect on tumor vasculature. There was a substantial increase in 
CD-8 infiltration in patients with checkpoint inhibitors. The combination of EOC315 20mg/kg and 
anti-m PD1 1mg/kg compared with single drug (anti-PD-1 or EOC315), resulted in a significant 
decrease in micro-vessel density. Consequently, the combination regimen had a synergetic effect.  
 
Control
Anti-PD1
EOC315
EOC315+Anti-PD1
0
1
2
3
4
5
 Micro-Vessel Density in Tumor
CD31+ positive tissue (%)
**
*
 
Micro-vessel density in tumors treated with Anti-PD-1, EOC315 and combo 
 
 
Pre-clinical data suggests that the addition of checkpoint inhibition to Telatinib will provide 
synergistic improvement in efficacy.  This effect is dose responsive with escalating doses of 
telatinib. The combination regimen improves CD8 T-cell infiltration into the tumor.  The combination 
also reduces tumor micro-vessel density.   
 
1.4 
Correlative Studies 
Previous studies have demonstrated potential toward the use of plasma biomarkers for 
prognostic and predictive applications in advanced gastric cancer and HCC. Pro-
inflammatory cytokines have been shown to correlate with the development and 
progression of gastric cancer and HCC tumors [18-20]. It is of interest to determine if 
telatinib in combination with Keytruda has an impact on inflammatory cytokines associated 
with advanced gastric cancer or HCC. Plasma metabolites have been studied as potential 

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biomarkers for gastric cancer and HCC [21-24]. Changes in immune cell profiles have been 
shown to correlate with treatment response [25-28]. A blood sample will be collected from 
the patient at the start of each odd cycle of treatment and at the end of the study. 
Inflammatory cytokines, metabolites, and immune cell profiles as potential biomarkers and 
prognostic indicators will be measured in the plasma. 
 
Recent evidence suggests that the gut microbiome is associated with cancer progression. 
This has been demonstrated for both gastric cancer and HCC [29-33]. Stool samples 
collected at baseline and cycle three, will allow microbiome changes to be investigated. 
Correlations with favorable treatment responses using telatinib in combination with 
Keytruda will be further interrogated. Recent studies have begun to look at fecal 
metabolites as a potential biomarker in cancer [34-36]. We will also investigate the potential 
for stool metabolites as a biomarker in gastric cancer and HCC. Furthermore, associations 
of inflammatory cytokines, metabolites, and microbiome changes will provide insight on the 
mechanistic action of the combination of telatinib and Keytruda. 
2.0 
STUDY OBJECTIVES 
Response will be assessed using RECIST 1.1 criteria. Upon initial radiographic evidence of 
progression, treatment may continue until repeat imaging is performed 4-8 weeks later (see Section 
5.3). 
2.1 
Primary Objective 
The primary objective is to assess progression-free survival (PFS) in subjects with advanced 
gastric cancer or HCC receiving telatinib in combination with Keytruda.   
2.2 
Secondary Objectives  
2.2.1 
Overall response rate (ORR) 
2.2.2 
Disease control rate (DCR) (CR+PR+SD) 
2.2.3 
Overall survival (OS) 
2.2.4 
Safety 
2.3 
Exploratory Objectives 
2.3.1 
Time to progression (TTP) 
2.3.2 
Change in inflammatory cytokines 
2.3.3 
Change in plasma metabolites 
2.3.4 
Change in immune cell profile 
2.3.5 
Change in stool microbiome 
2.3.6 
Change in stool metabolites 
2.4 
Endpoints 
2.4.1 
Primary Efficacy Endpoint 
 
PFS: Length of time from the start of treatment until the date of first 
observed disease progression (radiological or clinical, whichever is earlier), 
or the date of death due to any cause, whichever occurs first 

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2.4.2 
Secondary Efficacy Endpoints 
 
ORR: Percentage of patients who have a best overall response of partial 
response (PR) or complete response (CR) 
 
DCR: Percentage of patients who have achieved complete response, 
partial response, or stable disease 
 
OS: Length of time from the start of treatment until death due to any cause 
2.4.3 
Safety Evaluations 
 
Incidence and severity of adverse events by CTCAE V5 
2.4.4 
Exploratory Endpoints 
 
 
TTP: Length of time from the start of treatment until the date of first 
observed disease progression (radiological or clinical, whichever is earlier) 
 
The effect of immune modulation will be assessed by inflammatory 
cytokines in subject plasma samples 
 
Plasma metabolite changes from baseline/C1D1 and over time with 
treatment 
 
Immune cell profile (ex. T-cells) from baseline/C1D1 and over time with 
treatment 
 
Stool microbiome changes from baseline and over time with treatment, 
compared to samples collected from subjects on SOC Keytruda through 
the GI-Bank protocol (IRB# Pro00054363) 
 
Stool metabolite changes from baseline/C1D1 and over time with 
treatment, compared to samples collected from subjects on SOC Keytruda 
through the GI-Bank protocol (IRB# Pro00054363) 
 
3.0 
STUDY DESIGN 
This is a phase II, single arm, open-label study of two parallel cohorts (AGC and HCC), evaluating 
the effects of telatinib in combination with Keytruda on progression-free survival.  
 
4.0 
PATIENT ELIGIBILITY  
Enrollment will follow the safety stopping rules described in Section 9.4, with interim looks after 
completion of the first cycle of treatment for the 6th subject in each cohort, and again after 
completion of the first cycle of treatment for the 15th subject in each cohort. Any enrollment holds 
deemed necessary for the evaluation of stopping rules will be at the discretion of the PI.  

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4.1 
Inclusion Criteria  
4.1.1 
Diagnosis: 
4.1.1.1 
Histologically confirmed gastric/esophagealgastric adenocarcinoma, recurrent, 
locally advanced or metastatic, PD-L1-positive disease (CPS ≥1), progressed on 
at least two prior lines of therapy and/or discontinued second line therapy for 
intolerance, indicated for Keytruda therapy.  
OR  
4.1.1.2 
Hepatocellular carcinoma, with diagnosis confirmed by histologic or cytologic 
analysis or clinical features according to the American Association for the Study 
of Liver Diseases criteria for patients with cirrhosis, unresectable disease not 
amenable to locoregional therapy with disease progression after at least one 
prior line of systemic therapy or discontinued first line therapy for intolerance. 
4.1.2 
At least 1 measurable metastatic lesion that has not been irradiated. The lesion will be 
measured according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1), and be 
documented by radiological evaluation within 28 days prior to registration. For subjects 
with locally advanced disease: at least one measurable lesion that has not been 
irradiated, documented by radiological evaluation within 28 days prior to registration. 
4.1.3 
Any prior radiation therapy must be completed at least 28 days prior to C1D1. 
4.1.4 
Eighteen years of age or older. 
4.1.5 
Eastern Cooperative Oncology Group (ECOG) performance score of 0, 1, or 2. 
4.1.6 
Adequate bone marrow, liver, and renal function as assessed by: 
4.1.6.1 
Hemoglobin ≥ 9.0 g/dL 
4.1.6.2 
Absolute neutrophil count (ANC) ≥1500/mcL  
4.1.6.3 
Total bilirubin ≤ 3.0 times the upper limit of normal (ULN) 
4.1.6.4 
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 5.0 x 
ULN in the presence of liver metastasis; ALT and AST 3.0 x ULN in the 
absence of liver metastasis 
4.1.6.5 
International normalized ratio for prothrombin time (PT/INR)  1.5 and activated 
partial thromboplastin time (aPTT)  1.5 x ULN. The use of full-dose oral or 
parenteral anticoagulants is permitted as long as the INR or aPTT is within 
therapeutic limits (according to the medical standard in the institution) and the 
subject has been on a stable dose of anticoagulants for at least two weeks before 
C1D1. 
4.1.6.6 
Serum creatinine  1.5 times the ULN 
 
 
 
AND/OR 
Calculated creatinine clearance ≥ 60 mL/min using the Cockcroft-Gault formula. 
Subjects with a calculated creatinine clearance below 60 mL/min may be eligible 
if a measured creatinine clearance (based on 24-hour urine collection or per 
institutional standards) is ≥ 60 mL/min. 
 
Calculated Creatinine Clearance = ((140 – Age in years) / (serum creatinine)) * 
(Weight in kg / 72) * 0.85 (if female) 

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4.1.7 
Negative urine or serum pregnancy test for women of childbearing potential. 
4.1.8 
Women of childbearing potential and men must agree to use adequate contraception 
(examples include condom, intrauterine device (IUD), oral contraceptive, double-barrier 
method, etc.), prior to registration, for the duration of study participation and until 4 months 
after the last study drug dosing. 
4.1.9 
Able and willing to sign a written informed consent. A signed informed consent must be 
appropriately obtained prior to any study specific procedures. 
4.1.10 Able to comply with study procedures and other protocol requirements and, receive 
outpatient treatment, laboratory monitoring and follow-up examinations at the institute that 
administers the study drug. 
4.1.11 Able to swallow and agree to take the prescribed tablets twice daily. 
 
4.2 
Exclusion Criteria 
4.2.1 
Clinical or radiographic evidence of current brain metastasis. History of treated brain 
metastases is allowable. 
4.2.2 
Cardiac disease defined by: 
a) Congestive heart failure > class II New York Heart Association (NYHA), or 
b) Unstable angina (anginal symptoms at rest), or new-onset angina (began within the last 
12 months), or myocardial infarction within the 12 months prior to registration, or 
c) Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy or  
d) Atrial fibrillation or atrioventricular heart block 
4.2.3 Uncontrolled hypertension (defined as persistent elevation of systolic blood pressure >150 
mmHg or diastolic pressure > 100 mmHg; if screening BP measurement exceeds these 
parameters, BP measurement must be repeated at least one day later during the screening 
period; if repeat BP measurement exceeds these parameters, the subject should be 
excluded; if repeat measurement does not exceed these parameters, the subject is not 
excluded.)  
4.2.4 Any (including pulmonary) hemorrhage/bleeding event Grade 3 or greater by National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) V5 within 
28 days prior to C1D1. 
4.2.5 Major surgery, open biopsy, or significant traumatic injury within 42 days prior to C1D1. 
4.2.6 Current serious, nonhealing wound, ulcer, or bone fracture within 42 days prior to C1D1. 
4.2.7 History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 
months prior to C1D1. 
4.2.8 Presence of an uncontrolled infection or infection that required IV antibiotics, antifungals, or 
antivirals within 14 days of C1D1. 
4.2.9 Known human immunodeficiency virus (HIV) infection. HIV-infected subjects on effective 
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months of screening (based on medical chart review) is negative. The safety of telatinib in 
this subject population has not been studied. 
4.2.10 Known chronic hepatitis B, unless receiving antiviral treatment. 
4.2.11 Known Child-Pugh Score B or C liver cirrhosis. 
4.2.12 Diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of 
immunosuppressive therapy within 7 days prior to the first dose of study treatment or has 
been diagnosed with an autoimmune disease that has required systemic treatment in the 
past 2 years (i.e., with use of disease modifying agents, corticosteroids, or 
immunosuppressive drugs). Patients that require replacement therapy (e.g., thyroxine [T4], 
insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary 
insufficiency, etc.) may be enrolled. 
4.2.13 History of (non-infectious) pneumonitis that required steroids, or current pneumonitis, or has 
a history of interstitial lung disease. 
4.2.14 Has received a live-virus vaccination within 30 days of planned treatment start. 
4.2.15 Known history of proteinuria > 1gr/24 hours.  
4.2.16 Previous or concurrent cancer that is distinct in primary site or histology from the current 
stomach or liver cancer. Subjects with cervical cancer in-situ, treated basal cell carcinoma, 
superficial bladder tumors (Ta and Tis) or any cancer curatively treated are not excluded. 
4.2.17 Anti-cancer therapy (chemotherapy, hormonal therapy, radiation therapy, surgery, 
immunotherapy, biologic therapy, or tumor embolization) or investigational agent within 28 
days prior to C1D1. 
4.2.18 Known or suspected allergy to any component of telatinib or Keytruda 
4.2.19 Prior or current history of substance abuse, or medical, psychological, or social condition 
that in the opinion of the investigator may interfere with the subject’s participation in the 
study or evaluation of the study result. 
4.2.20 Women who are pregnant or breastfeeding. 
4.2.21 Prior history of thromboembolic disease, e.g., deep vein thrombosis (DVT), pulmonary 
emboli (PE), within 6 months of C1D1 that has required continued medical intervention. 
4.2.22 Baseline peripheral neuropathy of Grade 2 or greater. 
 
 
5.0 
TREATMENT PLAN 
5.1 
Treatment Dosage and Administration 
 
Telatinib will be self-administered orally twice daily. Subjects will complete a dosing diary 
throughout the study treatment period. Oral compliance will be determined through review of the 
DARF. Oral compliance for Telatinib is 50%. Less than 50% compliance is considered a deviation 
reportable to the IRB.  
 
Pembrolizumab will be administered at a dose of 200mg as a 30 minute IV infusion Q3W. Effort 
should be made to target infusion timing to be as close to 30 minutes as possible. However, given 

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the variability of infusion pumps, a window of -5 minutes and +10 minutes is permitted (i.e., infusion 
time is 30 minutes: -5 min/+10 min). 
 
Drug 
Dose/Potency 
Dose/ 
Frequency
Route of 
Administration
Regimen/ Treatment 
Period
Telatinib 
900 mg 
BID 
Orally 
Daily (each cycle = 3 
weeks) 
Pembrolizumab 
200 mg 
Q3W 
IV infusion 
Day 1 of each 3-week 
cycle 
 
5.2 
Toxicities and Dosing Delays/Dose Modifications  
 
Telatinib known toxicities include: 
 
Nausea, vomiting, and diarrhea: Antiemetics and antidiarrheal agents may be 
administered to prevent or control symptoms. 
 
Hypertension 
 
Fatigue 
 
Liver injury 
 
Proteinuria/renal injury 
 
Hand and foot syndrome: Symptomatic therapy may be provided if necessary. 
 
Hypokalemia: Potassium treatment should be given in the event of hypokalemia. 
 
Hemorrhage  
 
Gastrointestinal perforation 
 
Cardiac function abnormality 
 
 
Please refer to the telatinib IB for more details.  
 
Toxicities may be treated symptomatically per standard of care/investigator discretion. 
Telatinib administration may be held at the investigator’s discretion for any reason. Dose 
modifications are permitted. Any dose holds or modifications will be documented in the 
research record. 
 
Dose Modifications and Delays for Telatinib  
General dose reductions for telatinib are outlined in the following table.  
 
Dose Level
0
-1
-2 
Telatinib
900 mg BID 
(3 tablets twice a day)
600 mg BID 
(2 tablets twice a day)
300 mg BID 
(1 tablet twice a day)
 
If a dose reduction of telatinib is required and the toxicity resolves and no additional  
toxicities are seen after 6 weeks of treatment at the reduced dose (2 cycles), then telatinib 
may be increased to the dose prior to the reduction, not to exceed the original dose of 
900mg (3 tablets) BID.  
 
Any clinical event that requires dose reduction must be recorded as an AE and recorded in 
the CRF. For any dose that is not administered according to the protocol, the reason for the 
omission must be recorded in the CRF. 
 
Suggested Dose Modifications for Telatinib-Associated Toxicities 
Toxicity 
Non-hematologic 
Hematologic 
Grade 1  
 
Continue at the same dose level  
 
Continue at the same dose level 
Grade 2  
 
Continue at the same dose level  
 
Continue at the same dose level  
Grade 3*  
 
Withhold dose until toxicity is 
grade ≤2, then resume treatment 
at the same dose level.  
 
Continue at the same dose level  

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 
If subject experiences a second 
grade 3 toxicity, withhold dose 
until toxicity is grade <1, then 
reduce 1 dose level and resume 
treatment  
Grade 4** 
 
 
Withhold dose until toxicity is 
grade ≤2, then reduce 1 dose 
level and resume treatment, or 
discontinue at the discretion of 
Investigator  
 
Withhold dose until toxicity is 
grade ≤2, then reduce 1 dose 
level and resume treatment, or 
discontinue at the discretion 
Investigator 
*Subjects who develop grade 3 fever/chills, grade 3 elevation of hepatic transaminases with 
ALT and AST <10X ULN, grade 3 hyperlipasemia or hyperamylasemia without clinical or 
other evidence of pancreatitis, grade 3 hypophosphatemia, grade 3 leukopenia, or grade 3 
lymphopenia may continue telatinib without interruption at the discretion of the Investigator. 
NOTE: Refer to CTCAE v 5.0 for grade definitions.  
**Subjects with grade 3 or 4 allergic reactions to telatinib should be removed from 
treatment. Subjects with grade 2 allergic reactions should be carefully assessed for 
potential risk of serious or life-threatening reactions following re-exposure to telatinib. 
 
Pembrolizumab 
Pembrolizumab toxicities and dosing delays/dose modifications will be managed per 
standard of care, the package insert, and investigator discretion. Pembrolizumab is 
associated with immune-related adverse events and infusion reactions. Please refer to the 
package insert for more details.  
 
In the event that pembrolizumab is discontinued, treatment with telatinib may continue.  
 
5.2.1 
Treatment-Related Serious Adverse Events 
Non-hematologic serious adverse events, graded 3 or 4 per CTCAE v5, deemed probably 
related or related to telatinib (alone or in combination), occurring within the first cycle of 
treatment, will be monitored throughout the study for safety stopping rules (see Section 
9.4). Serious adverse events deemed probably related or related to Keytruda alone will not 
count toward safety stopping rules.  
5.3 
Treatment Duration and Confirmation of Progression 
Subjects will continue treatment until disease progression, intolerable toxicities, or 
withdrawal of consent. 
 
In patients with initial disease progression substantiated by radiographic imaging per 
RECIST 1.1, study treatment may continue until repeat imaging is conducted, at least 4 
weeks and no later than 8 weeks later, under the following conditions: 
- 
No worsening of ECOG Performance Status 
- 
No clinically relevant increases in disease-related symptoms thought to be 
associated with disease progression 
- 
No requirement for intensified management of disease-related symptoms exists, 
including increased analgesia, radiotherapy, or other palliative care.  
 
5.4 
Concomitant Medications/Treatments 
 
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards 
of medical care. All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications 
and fluids. If changes occur during the trial period, documentation of drug dosage, 
frequency, route, and date will also be included on the CRF. 

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No other anti-cancer therapy (chemotherapy, hormonal therapy, radiation therapy, surgery, 
immunotherapy, biologic therapy, or tumor embolization) or investigational agent may be 
used from 28 days days prior to C1D1 until study treatment discontinuation.  
5.5 
Duration of Study Participation  
The study duration per subject will be up to 28 days of screening, up to an estimated 12 
months on treatment (until disease progression, intolerable toxicities, or withdrawal of 
consent), and 30 days of follow-up. Survival follow-up will continue until death (estimated 
approximately 6 months). 
5.6 
Removal of Patients from Protocol  
Patients will be removed from the study when any of the criteria listed in Section 6.5 apply. 
Notify the Principal Investigator, and document the reason for study removal and the date 
the patient was removed on the Case Report Form. The patient should be followed-up per 
protocol.  
5.7 
Evaluable for toxicity 
 
Any patient who receives at least one dose of investigational product (telatinib) is evaluable 
for toxicity and will be included in the safety analysis. 
5.8 
Subject Replacement  
Subjects who withdraw from the study prior to starting study treatment (telatinib) will be 
replaced.   
 
6.0 
STUDY PROCEDURES 
6.1 
Screening/Baseline Procedures 
Assessments performed exclusively to determine eligibility for this study will be done only 
after obtaining informed consent. Assessments performed for clinical indications (not 
exclusively to determine study eligibility) may be used for baseline values even if the 
studies were done before informed consent was obtained. 
 
All screening procedures must be performed within 28 days prior to C1D1 unless otherwise 
stated. Baseline procedures not used for eligibility verification may occur on C1D1 of 
treatment. The screening/baseline procedures include: 
6.1.1 Informed Consent 
6.1.2 Medical history and record review 
Relevant medical history, including history of current disease and information 
regarding underlying diseases, will be recorded at Screening. 
6.1.3 Demographics 
Age, sex, race, ethnicity 

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6.1.4 Review subject eligibility criteria 
6.1.5 Physical exam including weight, height, vital signs, and ECOG Performance 
Status 
6.1.6 Adverse event assessment 
Baseline symptoms will be assessed at Screening. See section 7.0 for Adverse 
Event monitoring and reporting.  
 
Duration (start and stop dates and times), severity/grade, outcome, treatment and 
relation to study drug will be recorded on the case report form (CRF). 
6.1.7 Concomitant Medications Review 
6.1.8 Laboratory Evaluations 
 Hematology (Complete blood count (CBC) with differential) 
 Serum chemistries (Comprehensive metabolic panel (CMP)), including: glucose, 
sodium, potassium, chloride, carbon dioxide, anion gap, blood urea nitrogen, 
creatinine, calcium, total bilirubin, total protein, albumin, alkaline phosphatase, 
aspartate aminotransferase, alanine aminotransferase 
 Tumor markers 
o 
HCC: AFP, CA19-9 
o 
Gastric: CEA, CA19-9 
 Thyroid panel (T3 Free, T4 Free, thyroid stimulating hormone) 
 Coagulation (PT, INR, aPTT) 
 Urinalysis (including urine protein)  
6.1.9 Pregnancy Testing for WOCBP (urine or serum) 
6.1.10 Imaging (CT chest/abdomen/pelvis and/or MRI) (within 28 days prior to 
registration) 
6.1.11 ECG 
6.1.12 Research stool sample collection and completion of 24-hour food recall and 
stool survey 
May be collected up to 4 weeks prior to C1D1 or on C1D1. The 24-hour food recall 
and stool survey should be completed on the same day as the stool sample 
collection, if feasible (not required).  
6.2 
Procedures During Treatment 
6.2.1 
Prior to Each Treatment Cycle 
 Physical exam, weight, vital signs, ECOG Performance Status 
 Hematology 
 Serum chemistries  
 Urinalysis  
6.2.2 
Each Cycle Day 1 
 Pembrolizumab administration 
 Adverse events assessment 
 Concomitant medications review 
 Tumor markers 
 Thyroid panel (TSH with reflex to T3 and T4 if TSH is abnormal) (even cycles 
only) 

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 Fasting research blood collection (odd cycles only beginning with C1D1) 
(patients must fast for 8 hours prior to blood collection, water is allowed) 
 Research stool sample collection, completion of 24-hour food recall, and stool 
survey (C3D1 only). The 24-hour food recall and stool survey should be 
completed on the same day as the stool sample collection, if feasible (not 
required). 
6.2.3 
Throughout the treatment period 
 Telatinib self-administration and completion of dosing diary 
 Drug supply and dosing diary will be returned at the next Cycle Day 1 (or for the 
last cycle, at the end-of-treatment visit) for compliance diary review and pill 
count. 
 Imaging as per standard of care or every 9 weeks for response assessment 
(RECIST 1.1) 
o 
Upon initial radiographic disease progression per RECIST 1.1, treatment may 
continue until confirmation of progression at least 4 weeks and no later than 8 
weeks later (see Section 5.3). 
6.2.4 
30 days after treatment termination (+/- 7 days) 
 Physical exam, vital signs, weight, ECOG Performance Status 
 Hematology 
 Serum chemistries 
 Tumor markers 
 Adverse events assessment 
 Concomitant medications review 
 If indicated: Imaging (CT or MRI) with response assessment (RECIST 1.1) 
 Fasting research blood collection (patients must fast for 8 hours prior to blood 
collection) 
6.3 
Follow-up Procedures 
Patients will be followed every 12 weeks (+/- 14 days) after completion of (or early 
withdrawal from) study treatment until death for survival and progression assessment via 
medical record review, telephone contact, or in-clinic contact.  
 
 

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6.4 
Time and Events Table  
 
Procedure 
Screening/ 
Baseline (Within 
4 weeks of 
C1D1) 
Each Cycle Day 1  
(+/- 3 days) (each 
cycle = 3 weeks / 21 
days) 
End of Treatment 
Survival 
Follow-up 
30 days after drug 
discontinuation (+/- 7 
days) 
Every 12 Weeks 
(+/- 14 days) 
until death 
Informed Consent 
X 
 
 
 
Medical History 
and record review 
X 
 
 
 
Demographics 
X 
 
 
 
Review subject 
eligibility criteria 
X 
 
 
 
Physical Exam  
X 
X 
X 
 
Height (at 
screening only) 
and weight 
X 
X 
X 
 
Vital signs 
X 
X 
X 
 
ECOG 
Performance 
Status 
X 
X 
X 
 
Adverse Event 
Assessment 
X 
X 
X 
 
Concomitant 
Medications 
X 
X 
X 
 
Hematology 
X 
X 
X 
 
Chemistry 
X 
X 
X 
 
Tumor markers 
X 
X 
X 
 
Thyroid panel 
(TSH with reflex to 
T3 and T4 if TSH 
is abnormal) 
X 
X (even cycles only) 
 
 
Coagulation (PT, 
INR, aPTT) 
X 
 
 
 
Urine or serum 
pregnancy test 
X 
 
 
 
Urinalysis 
X 
X 
 
 
ECG 
X 
 
 
 
CT Scan (Chest, 
Abdomen, Pelvis) 
and/or MRI 
X1 
As per standard of care (or every 9 weeks for 
response assessment by RECIST 1.1)2  
 
Pembrolizumab 
Administration 
 
X 
 
 
Telatinib 
Administration and 
Dosing Diary 
completion  
 
X (continuous 
throughout treatment 
period)3 
 
 
Telatinib Dosing 
Diary Review and 
pill counts3 
 
X 
X 
 

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Procedure 
Screening/ 
Baseline (Within 
4 weeks of 
C1D1) 
Each Cycle Day 1  
(+/- 3 days) (each 
cycle = 3 weeks / 21 
days) 
End of Treatment 
Survival 
Follow-up 
30 days after drug 
discontinuation (+/- 7 
days) 
Every 12 Weeks 
(+/- 14 days) 
until death 
Research blood 
collection 
 
X4 
X 
 
Research stool 
sample collection, 
completion of 24-
hour food recall 
and stool survey5 
X5 
X5 
 
 
 
 
Survival and 
progression 
assessment (by 
medical record 
review, phone call, 
or clinic visit) 
 
 
 
X 
1  Screening/baseline imaging to be conducted within 28 days prior to registration. 
2  Upon initial radiographic disease progression, treatment may continue until repeat imaging is conducted 
4-8 weeks later (see Section 5.3). 
3  Subjects will be given a telatinib dosing diary at Cycle 1 Day 1, and at Day 1 of each subsequent cycle 
while taking telatinib. The completed diary and remaining drug supply will be collected at the next cycle 
Day 1 (or for the last cycle, at the end-of-treatment visit) for a pill count and diary review.  
4  Fasting research blood collection will occur every odd cycle beginning with C1D1 and at the end-of-
treatment visit. (patients must fast for 8 hours prior to blood collection, water is allowed) 
5  Research stool sample collection and completion of 24-hour food recall and stool survey will occur at 
screening/baseline (within 4 weeks of C1D1 or on C1D1) and C3D1 (to be collected +/- 3 days of cycle 
start). 
 
 

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6.5 
Removal of Subjects from Study 
Patients can be taken off the study treatment and/or study at any time at their own request, 
or they may be withdrawn at the discretion of the investigator for safety, behavioral or 
administrative reasons. The reason(s) for discontinuation will be documented and may 
include: 
6.5.1 
Patient voluntarily withdraws (follow-up permitted);  
6.5.2 
Patient withdraws consent (termination of treatment and follow-up); 
6.5.3 
Patient is unable to comply with protocol requirements; 
6.5.4 
Patient demonstrates disease progression (unless continued treatment with study 
drug is deemed appropriate at the discretion of the investigator); 
6.5.5 
Patient experiences toxicity that makes continuation in the protocol unsafe; 
6.5.6 
Treating physician determines continuation on the study would not be in the 
patient’s best interest; 
6.5.7 
Patient becomes pregnant (pregnancy to be reported along same timelines as a 
serious adverse event); 
6.5.8 
Development of second malignancy (except for basal cell carcinoma or squamous 
cell carcinoma of the skin) that requires treatment, which would interfere with this 
study; 
6.5.9 
Lost to follow-up. If a research subject cannot be located to document survival after 
a period of 1 year, the subject may be considered “lost to follow-up.” All attempts to 
contact the subject during the one year must be documented. This will be reviewed 
during an interim data monitoring visit. 
 
7.0 
ADVERSE EVENTS (AE) 
7.1 
Definitions 
7.1.1 Adverse Event 
An adverse event is any untoward medical occurrence associated with use of a 
drug in humans, whether or not considered drug related. 
 
7.1.1.1 Laboratory test abnormalities 
A laboratory test abnormality considered clinically relevant (e.g., causing the 
subject to withdraw from the study, requiring treatment or causing apparent clinical 
manifestations, result in a delay or dose modification of study treatment, or judged 
relevant by the investigator), is considered an adverse event.   
  
7.1.2 Serious Adverse Events (SAE) 
An adverse event is considered “serious” if, in the view of either the investigator or 
sponsor, it results in any of the following outcomes: 

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 
Death. 
 
A life-threatening adverse event. 
 
In-patient hospitalization or prolongation of existing hospitalization. 
 
A persistent or significant incapacity or substantial disruption of the ability 
to conduct normal life functions 
 
A congenital anomaly/birth defect. 
 
Important medical events that may not result in death, be life-threatening, 
or require hospitalization may be considered serious when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject 
and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room 
or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse. 
 
7.1.3 Unanticipated Problem Involving Risk to Subjects or Others (UPIRSO)  
UPIRSOs include any incident, experience, or outcome that meets all of the 
following criteria: 
• 
Unexpected (in terms of nature, severity, frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as 
the IRB-approved research protocol and informed consent document; and 
(b) the characteristics of the subject population being studied; 
• 
Related or possibly related to participation in the research (possibly related 
means there is a reasonable possibility that the incident, experience, or 
outcome may have been caused by the procedures involved in the 
research); and 
• 
Suggests that the research places subjects or others at a greater risk of 
harm (including physical, psychological, economic, or social harm) than 
was previously known to an individual or group of individuals (including 
research subjects, research staff, or others not directly involved in the 
research). 
7.1.4 Suspected Unexpected Serious Adverse Reaction (SUSAR) 
Suspected unexpected serious adverse reactions (SUSARs) include adverse 
events that are deemed unexpected, serious, and as having a reasonable 
possibility of a causal relationship with the study drug.  
7.2 
Principal Investigator Responsibilities for Safety Monitoring 
The investigator or designee is responsible for ensuring that adverse events (both serious 
and non-serious) observed by the clinical team or reported by the subject which occur from 
treatment administration on Cycle 1 Day 1 and until 30 days following the last dose of the 
study drug or until initiation of a new anticancer therapy (whichever occurs first), are fully 
recorded in the subject’s medical records. Source documentation must be available to 
support all adverse events.  
7.2.1 
AE Documentation  
A laboratory test abnormality considered clinically relevant (e.g., causing the 
subject to withdraw from the study, requiring treatment or causing apparent clinical 

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manifestations, result in a delay or dose modification of study treatment, or judged 
relevant by the investigator), should be reported as an adverse event.   
The investigator or sub-investigator (treating physician if applicable) will document the 
following for all adverse events (both serious and non-serious): 
 
Event term- according to the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 5. The CTCAE current version is available at 
http://ctep.cancer.gov/reporting/ctc.html 
 
Description of the event 
 
Date of onset and resolution 
 
Expectedness of the toxicity 
o 
Expected events are those that have been previously identified as resulting 
from administration of the agent. An adverse event is considered unexpected, 
for expedited reporting purposes only, when either the type of event or the 
severity of the event is not listed in: 
 the current known adverse events listed in this protocol; 
 the drug package insert; and/or 
 the current Investigator’s Brochure 
 
Grade of toxicity  
 
Attribution of relatedness to the investigational agent- (this must be assigned by an 
Investigator, sub-investigator, or treating physician) 
o 
Attribution categories are as follows: 
 Definite: 
The AE is clearly related to the study treatment. 
 Probable: 
The AE is likely related to the study treatment. 
 Possible:   
The AE may be related to the study treatment. 
 Unlikely: 
The AE is doubtfully related to the study treatment. 
 Unrelated: 
The AE is clearly NOT related to the study treatment. 
 
Action taken as a result of the event, including but not limited to; no changes, dose 
interrupted, reduced, discontinued, etc. or action taken with regard to the event, i.e. 
no action, received conmed or other intervention, etc. 
 
Outcome of event 
 
Source documentation must be available to support all AEs.  
 
7.2.2 Duration of AE monitoring  
All patients experiencing an adverse event, regardless of its relationship to study drug, will 
be monitored until:  
 
the AE resolves or the symptoms or signs that constitute the AE return to baseline 
 
any abnormal laboratory value deemed an AE as per section 7.1.1.1, has returned to 
baseline 
 
there is a satisfactory explanation other than the study drug for the changes observed 
 
death, or 
 
until 30 days following last dose of study drug or until initiation of a new anticancer 
therapy (whichever occurs first) 
 
7.2.3 Pembrolizumab 
As pembrolizumab is FDA-approved for this indication and used in accordance with 
the package insert, only events determined to be unexpected and at least possibly 
related to pembrolizumab will be recorded in the eCRF.  
 

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7.3 
Safety Reporting Requirements 
7.3.1.1 Reporting to the Principal Investigator 
The Principal Investigator must be notified by study staff or co-investigators within 
24 hours of learning of any serious adverse events, regardless of attribution, 
occurring during the study or within 30 days of the last administration of the study 
drug or until initiation of a new anticancer therapy (whichever occurs first).  
 
Contact for Expedited Reporting: 
Andrew Hendifar, MD, MPH 
310-423-2217; Andrew.Hendifar@cshs.org 
 
Alternate Contact for Expedited Reporting: 
Jun Gong, MD 
310-423-5776; Jun.Gong@cshs.org 
 
7.3.1.2 
Reporting to DSMC:  
Serious Adverse Events deemed to be related to the protocol and on-study 
deaths, including death of a research subject unless the death is expected (e.g. 
due to disease progression) are to be reported to the DSMC within 24 hours of 
awareness. Hardcopies or electronic versions of the MedWatch Form 3500A 
(Mandatory Reporting) or a narrative report, along with any other supporting 
documentation available, should be submitted to the DSMC Coordinator. The 
DSMC Coordinator will forward the information to the DSMC Chair, and/or 
medical monitor. The DSMC Chair will review all documentation upon receipt 
from the DSMC Coordinator and determination of whether the following actions 
are required: 1) takes action immediately, 2) convenes a special DSMC session 
(physical or electronic), or 3) defers the action until a regularly scheduled DSMC 
meeting. Reports to be emailed to the DSMC team at 
GroupSOCCICCTODSMCAdmin@cshs.org. 
7.3.1.3 
Reporting to the Institutional Review Board (IRB) 
As per the Cedars-Sinai IRB Reporting Possible Unanticipated Problems 
Involving Risks to Subject or Others (UPIRSO) Policy, the IRB must be notified of 
all UPIRSOs as soon as possible, but no later than 10 business days from when 
the study team learned of any of the following events:  Any serious event 
(injuries, side effects, deaths or other problems), which in the opinion of the 
Principal Investigator was unanticipated, involved risk to subjects or others, and 
was possibly related to the research procedures. 
 
Any internal AE, SAE or Research-Related Subject Injury (RRSI), which in 
the opinion of the Principal Investigator was unanticipated or unexpected, 
and has a reasonable possibility of relationship to the research. 
 
Any actionable external SAE, AE, SUSAR, development safety update 
report (DSUR), or FDA MEDWATCH report deemed to be a UPIRSO. An 
event is considered “actionable” if it warrants a change to the conduct of 
the study.  
 
Any accidental, unintentional protocol or consent/HIPAA related deviation 
that may impact subjects’ rights, safety, or welfare. See section 10.8.3. 
 
Any planned protocol exception or eligibility waiver. See sections 10.8.2 
and 10.8.3. 

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 
 Changes to the research or protocol deviations made without prior IRB 
approval in order to eliminate apparent immediate hazard to a research 
subject.(Note: These must be reported to the IRB within 5 business days.) 
 
Problems, events, unanticipated incidental findings, billing problems, or 
other events, outcomes, or new information related to the research (e.g., 
publication, safety monitoring report, interim findings, product labeling 
changes, findings generated from preclinical, animal studies) that may 
adversely affect the rights, safety, or welfare of the subjects or others, put 
subjects or others at increased risk, compromise the research data, or 
require/recommend changes to the study conduct. 
 
Any new information (e.g., publication, safety monitoring report, updated 
sponsor safety report), interim result or other finding that indicates an 
unexpected change to the risk/benefit ratio for the research. 
 
Breach or potential breach of confidential or sensitive information.  
 
Subject complaints or concerns that cannot be resolved by the research 
staff to the subject’s satisfaction. 
 
Incarceration of a subject who is enrolled in a study that is not approved by 
the IRB to include prisoners. 
7.3.1.4 
Reporting to the Food and Drug Administration 
The sponsor-investigator of the IND, or designee must submit all reported 
SUSARs to the FDA on FDA Form 3500A (MedWatch). 
The sponsor-investigator of the IND must notify the FDA as soon as possible but 
no later than: 
 
7 calendar days after the sponsor-investigator’s initial receipt of the 
information in a written IND safety report of any fatal or life-threatening 
SUSARs. 
 
15 calendar days after the sponsor-investigator’s initial receipt of the 
information in a written IND safety report of any non-fatal / non-life-
threatening SUSARs. 
 
Copies of IND Safety Reports will be kept in the Trial Master File in the 
SOCCI CCTO. 
7.3.1.5 
Reporting to EOC Pharma 
SUSARs reported to the FDA as per Section 7.4.2.4 will be sent to EOC Pharma 
within 3 days of awareness via the MedWatch FDA Form 3500A, and emailed to 
eoc.pv@eocpharma.com. 
8.0 
CORRELATIVES/SPECIAL STUDIES 
The effect of immune modulation will be assessed by inflammatory cytokines in subject plasma 
samples. Changes in metabolites and inflammatory biomarkers will also be assessed in plasma. 
Changes in the stool microbiome will be assessed by 16s and/or shotgun metagenomics analysis. 
Stool metabolites will also be measured by MS-based quantitation. Stool microbiome and 
metabolites will be compared to samples collected from subjects on SOC Keytruda collected 
through the GI-Bank protocol (IRB# Pro00054363). 
8.1 
Plasma and PBMC Collection / Specimen Banking 
Immune modulation will be assessed by FACS from PBMCs, inflammatory cytokines and 
metabolites will be assessed in the plasma. 
 
A fasting morning research plasma sample will be collected at odd cycles during the study 
and at the end-of-treatment visit. 
 
Samples will be processed in the CSMC CCTO lab or Biobank. 

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 
Samples will be stored indefinitely in Dr. Hendifar’s Biobank rental freezer.  
 
 
 
 
 
 
8.2 
Stool Specimen Collection / Banking 
8.2.1 
Materials/ Sample Collection 
 
A research stool sample will be collected at screening/baseline and C3D1. A stool 
collection kit will be given to the patient during the physical exam, where the patient will 
be advised to follow the instructions on the kit and bring their sample into laboratory 
within 4 weeks prior to Cycle1/Day1 or on Cycle 1 Day 1, and at C3D1 (+/- 3 days).  
Microbiome analysis will be measured from the collection of stool sample. 
8.2.2 
Process 
 
Patients will be advised to keep the stool sample frozen until transport to the clinic. 
Upon receipt of the sample at the investigator site, site personnel should verify that the 
collection date and subject ID is written on a paper in a biohazard bag with the stool 
container.  
8.2.3 
Storage of Stool Sample/ Specimen Banking 
 
The stool sample will be transported to the CCTO laboratory for short term storage.  
 
Samples will be stored indefinitely in Dr. Hendifar’s Biobank rental freezer. 
 
 
9.0 
STATISTICAL CONSIDERATIONS 
9.1 
Sample Size  
 
For the AGC cohort, the median PFS in the KEYNOTE-059 trial (Fuchs et al. 2020) is 2.0 
months. Assuming an accrual time of 12 months and 6 months follow-up, 21 patients are 
needed to improve median PFS from 2 months to 4 months or HR = 0.5 with 80% power 
using a two-sided one sample log-rank test at the 0.05 level of significance. Time to 
progression was assumed to follow an exponential distribution. 
 
For the HCC cohort, the median PFS in the KEYNOTE-224 trial (Zhu et al. 2018) is 4.9 
months. Assuming an accrual time of 12 months and 10 months follow-up, 24 patients are 
needed to improve median PFS from 4.9 months to 10 months or HR = 0.49 with 80% 
power using a two-sided one sample log-rank test at the 0.05 level of significance. Time to 
progression was assumed to follow an exponential distribution. 
9.2 
Data Sets Analyzed 
All eligible patients who receive at least one dose of telatinib (the Safety Population) will be 
included in the safety analysis. 
All patients who receive at least one dose of telatinib will be included in the efficacy 
analysis. Patients who drop before disease progression will be right censored. 
9.3 
Data Analyses/Study Endpoints 
9.3.1 
Efficacy Analysis 
The primary analysis will be based on an intention to treat approach and will include all 
subjects entered into the study at Cycle 1 Day 1.  

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The primary efficacy endpoint will be Progression-Free Survival. For each cohort, the log-
rank test will be used to test the null hypothesis that the median PFS is less than or equal to 
2 months for the AGC cohort and 4.9 months for the HCC cohort under exponential 
distribution assumption for time to progression. If this assumption is violated, bootstrap 
methods will be used to construct a 95% confident interval for the median. 
Kaplan-Meir (KM) curves with 95% confidence bands will be constructed for PFS of each 
cohort. For the secondary endpoints, exact 95% confidence intervals for ORR, DCR will be 
constructed and KM curves for OS will be reported. For the exploratory objectives, 95% 
confidence intervals for change in mean values of biomarkers such as inflammatory 
cytokines, plasma metabolites will be constructed. 
9.3.2 
Safety Analysis 
All subjects who receive at least one dose of telatinib will be included in the safety analysis. 
The frequencies of AEs by type, body system, severity and relationship to study drug will be 
summarized. SAEs (if any) will be described in detail. 
9.3.3 
Interim Analysis 
There will be no interim analysis for futility or early efficacy due to the small sample size in 
the AGC cohort and fast enrollment in the HCC cohort with hypothesized median PFS of 10 
months under the alternative hypothesis. 
9.4 
Stopping Rules 
 
Let PT be the true probability that a patient experiences a treatment-related SAE (as defined 
in Section 5.2.1) within the first cycle of treatment in the AGC cohort. The trial will stop if 
there is statistical evidence that PT exceeds 30%. We will use a Bayesian sequential design 
by checking whether PT exceeds this threshold value after 6, 15, and 21 patients are 
evaluable for SAEs. The decision rule is to stop the trial if the posterior probability that PT 
exceeds 0.30 is 0.97 or more; P(PT > 0.3 | data) > 0.97. A noninformative prior distribution 
for PT will be used.  
 
Table 1 gives the stopping rules for the design at each look and column 2 gives the 
maximum number of patients with treatment-related SAEs in order for the trial to proceed. 
For example, if 4 or more treatment-related SAEs are observed after enrolling 6 patients, 
the trial stops. The third column gives the probability of stopping the trial when in fact, the 
true PT = 0.30. This is the equivalent of the Bayesian type I error probability. The target type 
I error probability was set at 0.10.  
 
Number of 
Patients 
Number to
Continue 
Probability to 
Stop 
Cumulative Probability
to Stop 
6 
3 
0.070 
0.070 
15 
7 
0.028 
0.098 
21 
10 
0.006 
0.104 
Table 1.  Stopping rules based on three interim looks. Number to continue is the maximum number 
of treatment-related SAEs for not stopping the trial. 
 
 
Table 2 gives the design operating characteristics under selected values of the true probability PT. It 
gives the probability of stopping the trial under the alternative hypothesis, the expected sample size, 
and the average sample size given that the trial stopped. For example, if the true value of PT is 0.5, 
then there is an 63.6% chance that the trial is stopped early, and the average sample size is about 
14.5. On the other hand, there is a small chance of stopping the trial if PT is small; 1.9% chance of 
stopping the trial when in fact PT = 0.2. 
 
True Value
of PT 
Probability to 
Stop 
Expected
N 
Expected 
N given that we Stopped

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0.20 
0.0197 
20.73 
7.3 
0.30 
0.1043 
19.78 
9.2 
0.40 
0.3212 
17.66 
10.6 
0.50 
0.6362 
14.50 
10.8 
Table 2.  Design operating characteristics under different scenarios for the true probability of toxicity 
PT.  
 
Similar stopping rules are used for the HCC cohort with a target probability of treatment-related 
SAEs not to ne exceeded equal to 0.3. Tables 3 and 4 present the operating characteristics of this 
stopping rules for HCC arm. 
 
Number of 
Patients 
Number to
Continue 
Probability to 
Stop 
Cumulative Probability
to Stop 
6 
3 
0.070 
0.070 
15 
7 
0.028 
0.098 
24 
11 
0.010 
0.108 
Table 3.  Stopping rules based on three interim looks. Number to continue is the maximum number 
of treatment-related SAEs for not stopping the trial. 
 
True Value
of PT 
Probability to 
Stop 
Expected
N 
Expected 
N given that we Stopped
0.20 
0.0198 
23.67 
7.46 
0.30 
0.1087 
22.48 
10.03 
0.40 
0.3480 
19.79 
11.90 
0.50 
0.6866 
15.79 
12.05 
Table 4.  Design operating characteristics under different scenarios for the true probability of toxicity 
PT.  
 
 
10.0 
STUDY MANAGEMENT 
10.1 
Conflict of Interest 
Any reportable conflict of interest will be disclosed to the local IRB and will be outlined in 
the Informed Consent Form. 
10.2 
Institutional Review Board (IRB) Approval and Consent  
It is expected that the IRB will have the proper representation and function in accordance 
with federally mandated regulations. The IRB should approve the consent form and 
protocol. 
 
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s) and should adhere to Good Clinical Practice (GCP) 
and to ethical principles that have their origin in the Declaration of Helsinki. 
 
 
Before recruitment and enrollment onto this study, the patient will be given a full explanation 
of the study and will be given the opportunity to review the consent form. Each consent 
form must include all the relevant elements currently required by the FDA Regulations and 
local or state regulations. Once this essential information has been provided to the patient 
and the investigator is assured that the patient understands the implications of participating 
in the study, the patient will be asked to give consent to participate in the study by signing 
an IRB-approved consent form. 
 
Prior to a patient’s participation in the trial, the written informed consent form should be 
signed and personally dated by the patient and by the person who conducted the informed 
consent discussion. 

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10.3 
Registration Procedures 
 
All subjects that sign informed consent will be assigned a subject number sequentially by 
their date of consent.  Those subjects that do not pass the screening phase will be listed as 
screen failures on the master list of consented subjects.  Eligible subjects, as determined by 
screening procedures and verified by a treating investigator, will be registered on study at 
Cedars Sinai Medical Center by the Study Coordinator.   
 
Issues that would cause treatment delays after registration should be discussed with the 
Principal Investigator (PI). If a patient does not receive protocol therapy following 
registration, the patient’s registration on the study may be canceled.  The Study Coordinator 
should be notified of cancellations as soon as possible. 
 
Assignment of Subject ID: The study team will track all subjects who sign consent using 
OnCore. Subjects found to be ineligible will be recorded as screen failures. Subjects found 
to be eligible will be registered using a three-digit numeric ID that follows the standard 
SOCCI format (001, 002, etc.). 
 
A) 
Eligibility Verification 
 
Prior to registration, all subjects must undergo eligibility verification by the SOCCI Cancer 
Clinical Trials Office (CCTO) Quality Management Core (QMC). The following documents 
will be organized into an eligibility packet, scanned as a pdf, and emailed to 
GroupSOCCICROQMC@cshs.org for review: 
 
 
Registration form (or equivalent), if applicable 
 
Copy of applicable source documents 
 
QMC-approved eligibility checklist (signed by investigator and 2 members of the 
study team) 
 
Signed patient consent form with Subject’s Bill of Rights, HIPAA authorization form, 
consent progress note and any optional consent forms, as applicable 
 
B) 
Registration 
 
After eligibility is verified, registration is completed as follows: 
 
 
Assign a patient study number 
 
Assign the patient a dose as determined through communication with Biostatistics 
and the principal investigator, if applicable  
 
Enter the patient in OnCore 
 
Notify the investigational pharmacy and treating physicians that a subject has gone 
on study and anticipated treatment start date 
 
Oversight by the principal investigator is required throughout the entire registration process 
 
10.4 Data Management and Quality Control and Reporting 
The data will be entered into a HIPAA-compliant database. The Study Staff will be 
responsible for data processing, in accordance with procedural documentation. Database 
lock will occur once quality assurance procedures have been completed. 
 
All procedures for the handling and analysis of data will be conducted using good 
computing practices meeting FDA guidelines for the handling and analysis of data for 
clinical trials. 

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10.5 Data and Safety Monitoring 
 
10.5.1 Data Monitoring and Quality Assurance 
 
High Risk Monitoring 
Adherence to the protocol, Good Clinical Practices (GCP) and institutional policy will be 
monitored by the PI during the course of the study through routine Disease Research 
Group (DRG) meetings (or equivalent). In addition, the SOCCI Cancer Clinical Trials Office 
(CCTO) Quality Management Core (QMC) will conduct internal monitoring visits and audits 
for data quality and protocol adherence. QMC reports will be forwarded to the SOCCI Data 
and Safety Monitoring (DSMC). Refer to the DSMC Charter for more details. For any 
protocol, QMC has the authority to request more frequent reviews or focused safety 
monitoring if it is deemed appropriate for any reason. 
  
QMC will also conduct the following:  
1. Central eligibility verification for all subjects enrolled as described in protocol 
section 10.3.   
2. Central review by the SOCCI CCTO Medical Director or designee of all eligibility 
exception requests and waiver requests to assess appropriateness, to ensure 
quality data and subject safety protections for investigator-initiated research. 
  
 
10.5.2 Safety Monitoring 
High Risk Monitoring 
Oversight of the progress and safety of the study will be provided by the PI. The PI will 
maintain continuous safety monitoring for the duration of the study by reviewing 
subject/study data. Adverse events and unanticipated problems are not expected, but if 
they occur, they will be documented and reported according to CS-IRB policies and 
procedures. If the PI becomes aware of any new safety information that may place subjects 
at increased risk than what was previously known, the IRB will be promptly notified and if 
warranted, enrollment may be held until the PI determines whether a modification to the 
study is necessary and/or the informed consent documents are updated accordingly. It is 
the responsibility of the principal investigator to adhere to the Data Safety Monitoring Plan 
throughout the life of the study. 
 
In addition, this protocol will utilize the SOCCI Data and Safety Monitoring Committee to 
provide another layer of data and safety oversight. DSMC membership and responsibilities 
are governed by the committee charter. Every three (3) months the DSMC findings and 
recommendations will be reported in writing to the Principal Investigator as a summary 
letter which will be forwarded by the Principal Investigator or designee to the CS-IRB. The 
DSMC may increase or decrease the frequency of study review, at their discretion. Refer to 
the DSMC Charter for details of the DSMC review.  
 
10.6 
Record Retention 
 
Study documentation includes all Case Report Forms, data correction forms or queries, 
source documents, monitoring/auditing logs/letters, and regulatory documents (e.g., protocol 
and amendments, IRB correspondence and approval, signed patient consent forms). 
 
 
Source documents include all recordings of observations or notations of clinical activities and 
all reports and records necessary for the evaluation and reconstruction of the clinical 
research study. Government agency regulations and directives require that the study 
investigator must retain all study documentation pertaining to the conduct of a clinical trial. 
Study documents should be kept on file per local guidelines. 
 

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10.7 
Adherence to Protocol 
 
Except for an emergency situation in which proper care for the protection, safety, and well-
being of the study patient requires alternative treatment, or a protocol exception request 
approved by the SOCCI Medical Director and CSMC IRB, the study shall be conducted 
exactly as described in the approved protocol. 
10.7.1 Emergency Modifications 
Investigators may implement a deviation from, or a change of, the protocol to eliminate an 
immediate hazard(s) to trial subjects without prior IRB approval. For any such emergency 
modification implemented, the IRB must be notified as soon as possible, but no more than 
10 days from the investigator’s awareness of the event. 
10.7.2 Protocol Exceptions and Eligibility Waivers  
 
High Risk 
A protocol exception is an anticipated or planned deviation from the IRB-approved research 
protocol, as described in the IRB Policy, Reporting Possible Unanticipated Problems 
Involving Risks to Subject or Others (UPIRSO) Policy: Institutional Review Board/Research 
Compliance and Quality Improvement. A protocol exception most often involves a single 
subject and is not a permanent revision to the research protocol. Protocol exceptions that 
extend beyond a single subject should result in a protocol amendment to avoid serial 
violations.  
 
Planned exceptions to the protocol that are more than logistical in nature and/or impact an 
eligibility criterion, affect timing of study drug administration, or the investigator assesses 
the event may impact subject safety and/or study integrity, may not be implemented without 
prior approval from the SOCCI (CCTO) Medical Director and the IRB. The PI or her/his 
designee is responsible for submitting a protocol exception and its supporting documents to 
the SOCCI CCTO Medical Director for review and further instructions on IRB reporting.   
 
Study team should refer to the IRB Reporting Possible Unanticipated Problems Involving 
Risks to Subject or Others (UPIRSO) Policy: Institutional Review Board/Research 
Compliance and Quality Improvement guidelines to determine which deviations and 
exception requests meet reporting guidelines. Once approved by the medical director, the 
deviation or exception request must be submitted to the IRB for review and approval prior to 
implementation.   
 
Special considerations for Eligibility Waivers (EW) 
In general, subjects who do not meet the eligibility requirements should not be enrolled. In 
the rare event that it is appropriate for subject inclusion, the rationale/justification and 
subject case history should be forwarded to the SOCCI CCTO Medical Director for 
assessment prior to submission to the IRB for approval.  
 
The CCTO Medical Director will review the case and contact the investigator if additional 
information is needed or further discussion is warranted. The CCTO Medical Director will 
provide a written assessment/recommended course of action. The CCTO Medical Director’s 
assessment must be uploaded into CS-IRB with the waiver request for IRB review and 
consideration. The CCTO Medical Director may recommend future protocol changes.  
 
Eligibility Waiver and Exception Request Submission Process  
The PI and/or treating physician will provide a written request for an eligibility waiver 
including case history and justification for prospective deviation from the study design, to 
the SOCCI CCTO Medical Director. The “IIT Monitoring – Eligibility Waivers and Exception 
Requests (EW/ER) Form” must be completed then submitted, along with any applicable 
supporting documents, by email to QMC (GroupSOCCICROQMC@cshs.org) to request an 
eligibility exception or waiver request from the CCTO Medical Director. This is only a 
requirement for studies with a DSM category of moderate or high. An assessment from the 
CCTO Medical Director or designee must be done prior to submission to the IRB for review. 

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10.7.3 Other Protocol Deviations 
Logistical deviations from the protocol (e.g., minor changes to the study schedule for an 
individual subject) do not require prior IRB approval unless the deviation has the potential to 
affect the subject’s safety or study integrity. Such planned deviations that do meet this 
definition and do not affect the subject’s safety or study integrity should be noted in the 
subject’s research record or deviation log as described in the SOCCI CCTO’s Standard 
Operating Procedure 12: Deviation and Noncompliance Reporting. 
 
Unintentional deviations from the protocol that might affect subject safety or study integrity 
should be reported to the IRB within 10 days from when the investigator becomes aware 
that such a deviation has occurred, as outlined in the SOCCI CCTO’s Standard Operating 
Procedure 12: Deviation and Noncompliance Reporting. In this case, a Protocol Deviation 
report must be submitted in CS-IRB, per IRB policy, Reporting Possible Unanticipated 
Problems Involving Risks to Subject or Others (UPIRSO) Policy: Institutional Review 
Board/Research Compliance and Quality Improvement. All submissions should include a 
description of the plan to avoid similar deviations or exceptions in the future.   
 
10.7.4 Amendments to the Protocol  
Should amendments to the protocol be required, the amendments will be originated and 
documented by the Principal Investigator. It should also be noted that when an amendment 
to the protocol substantially alters the study design or the potential risk to the patient, a 
revised consent form might be required.  
 
The written amendment, and if required the amended consent form, must be sent to the 
IRB for approval prior to implementation. Repeat exceptions or deviations to the protocol 
may suggest a protocol amendment is needed. 
10.8 
Obligations of Investigators 
 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of 
Helsinki. The Principal Investigator is responsible for personally overseeing the treatment of 
all study patients. The Principal Investigator must assure that all study site personnel, 
including sub-investigators and other study staff members, adhere to the study protocol and 
all FDA/GCP/NCI regulations and guidelines regarding clinical trials both during and after 
study completion. 
 
 
The Principal Investigator will be responsible for assuring that all the required data will be 
collected and entered onto the Case Report Forms and/or into a HIPAA-compliant study 
database. Periodically, monitoring visits will be conducted and the Principal Investigator will 
provide access to his/her original records to permit verification of proper entry of data. At 
the completion of the study, all case report forms will be reviewed by the Principal 
Investigator and will require his/her final signature to verify the accuracy of the data. 
 

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11.0 
REFERENCES 
 
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Control, U.f.I.C. www.uicc.org.  [cited 2018; Available from: www.uicc.org. 
2. 
Gallo, A. and C. Cha, Updates on esophageal and gastric cancers. World J Gastroenterol, 2006. 
12(20): p. 3237-42. 
3. 
Gunderson, L.L., Gastric cancer--patterns of relapse after surgical resection. Semin Radiat Oncol, 
2002. 12(2): p. 150-61. 
4. 
Wagner, A.D., et al., Chemotherapy for advanced gastric cancer. Cochrane Database Syst Rev, 
2017. 8: p. CD004064. 
5. 
Bang, Y.J., et al., Trastuzumab in combination with chemotherapy versus chemotherapy alone for 
treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a 
phase 3, open-label, randomised controlled trial. Lancet, 2010. 376(9742): p. 687-97. 
6. 
Iacovelli, R., et al., Chemotherapy or targeted therapy as second-line treatment of advanced gastric 
cancer. A systematic review and meta-analysis of published studies. PLoS One, 2014. 9(9): p. 
e108940. 
7. 
Kim, H.S., et al., Second-line chemotherapy versus supportive cancer treatment in advanced gastric 
cancer: a meta-analysis. Ann Oncol, 2013. 24(11): p. 2850-4. 
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Liepa, A., Mitchell, S., Batson, S., et. al. Systematic review and meta-analysis of recommended 
second-line therapies for advanced gastric cancer (GC). in European Cancer Congress 
Conference. 2015. Vienna, Austria. 
9. 
Badiani, B., D. Maratea, and A. Messori, Second-line treatments for advanced gastric cancer: 
Interpreting outcomes by network meta-analysis. World J Clin Oncol, 2015. 6(4): p. 73-9. 
10. 
Harvey, R.C., Second-line Treatments for Advanced Gastric Cancer: A Network Meta-Analysis of 
Overall Survival Using Parametric Modelling Methods. Oncol Ther, 2017. 5(1): p. 53-67. 
11. 
Zhu, X., et al., A Bayesian network meta-analysis on second-line systemic therapy in advanced 
gastric cancer. Gastric Cancer, 2017. 20(4): p. 646-654. 
12. 
Fuchs, C.S., et al., Safety and Efficacy of Pembrolizumab Monotherapy in Patients With Previously 
Treated Advanced Gastric and Gastroesophageal Junction Cancer: Phase 2 Clinical KEYNOTE-
059 Trial. JAMA Oncol, 2018. 4(5): p. e180013. 
13. 
Bray, F., et al., Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality 
worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2018. 68(6): p. 394-424. 
14. 
Llovet, J.M., et al., Sorafenib in advanced hepatocellular carcinoma. N Engl J Med, 2008. 359(4): p. 
378-90. 
15. 
Cheng, A.L., et al., Efficacy and safety of sorafenib in patients in the Asia-Pacific region with 
advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. 
Lancet Oncol, 2009. 10(1): p. 25-34. 
16. 
Zhu, A.X., et al., Pembrolizumab in patients with advanced hepatocellular carcinoma previously 
treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol, 
2018. 19(7): p. 940-952. 
17. 
Finn, R.S., et al., Pembrolizumab As Second-Line Therapy in Patients With Advanced 
Hepatocellular Carcinoma in KEYNOTE-240: A Randomized, Double-Blind, Phase III Trial. J Clin 
Oncol, 2020. 38(3): p. 193-202. 
18. 
Sanchez-Zauco, N., et al., Circulating blood levels of IL-6, IFN-gamma, and IL-10 as potential 
diagnostic biomarkers in gastric cancer: a controlled study. BMC Cancer, 2017. 17(1): p. 384. 
19. 
Shao, Y.Y., et al., High plasma interleukin-6 levels associated with poor prognosis of patients with 
advanced hepatocellular carcinoma. Jpn J Clin Oncol, 2017. 47(10): p. 949-953. 
20. 
Zou, Z., et al., The plasma levels of 12 cytokines and growth factors in patients with gastric cancer. 
Medicine (Baltimore), 2018. 97(19): p. e0413. 
21. 
Chen, Y., et al., Revealing Different Lung Metastatic Potentials Induced Metabolic Alterations of 
Hepatocellular Carcinoma Cells via Proton Nuclear Magnetic Resonance Spectroscopy. J Cancer, 
2018. 9(24): p. 4696-4705. 
22. 
Chen, Y., et al., Plasma metabolomic analysis of human hepatocellular carcinoma: Diagnostic and 
therapeutic study. Oncotarget, 2016. 7(30): p. 47332-47342. 
23. 
Lario, S., et al., Plasma sample based analysis of gastric cancer progression using targeted 
metabolomics. Sci Rep, 2017. 7(1): p. 17774. 

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24. 
Lu, D., et al., A prognostic fingerprint in liver transplantation for hepatocellular carcinoma based on 
plasma metabolomics profiling. Eur J Surg Oncol, 2019. 45(12): p. 2347-2352. 
25. 
Buonaguro, L., et al., Immunotherapy in hepatocellular carcinoma. Ann Hepatol, 2019. 18(2): p. 
291-297. 
26. 
Peng, D., et al., Integrated Analysis Identifies an Immune-Based Prognostic Signature for the 
Mesenchymal Identity in Gastric Cancer. Biomed Res Int, 2020. 2020: p. 9780981. 
27. 
Rohr-Udilova, N., et al., Deviations of the immune cell landscape between healthy liver and 
hepatocellular carcinoma. Sci Rep, 2018. 8(1): p. 6220. 
28. 
Zhang, T., et al., Key Genes Associated with Prognosis and Tumor Infiltrating Immune Cells in 
Gastric Cancer Patients Identified by Cross-Database Analysis. Cancer Biother Radiopharm, 2020. 
29. 
Coker, O.O., et al., Mucosal microbiome dysbiosis in gastric carcinogenesis. Gut, 2018. 67(6): p. 
1024-1032. 
30. 
Engstrand, L. and D.Y. Graham, Microbiome and Gastric Cancer. Dig Dis Sci, 2020. 65(3): p. 865-
873. 
31. 
Rao, B.C., et al., Human microbiome is a diagnostic biomarker in hepatocellular carcinoma. 
Hepatobiliary Pancreat Dis Int, 2020. 19(2): p. 109-115. 
32. 
Ren, Z., et al., Gut microbiome analysis as a tool towards targeted non-invasive biomarkers for 
early hepatocellular carcinoma. Gut, 2019. 68(6): p. 1014-1023. 
33. 
Weng, M.T., et al., Microbiota and gastrointestinal cancer. J Formos Med Assoc, 2019. 118 Suppl 
1: p. S32-S41. 
34. 
Cao, H., et al., Fecal metabolome profiling of liver cirrhosis and hepatocellular carcinoma patients 
by ultra performance liquid chromatography-mass spectrometry. Anal Chim Acta, 2011. 691(1-2): p. 
68-75. 
35. 
Nomura, M., et al., Association of Short-Chain Fatty Acids in the Gut Microbiome With Clinical 
Response to Treatment With Nivolumab or Pembrolizumab in Patients With Solid Cancer Tumors. 
JAMA Netw Open, 2020. 3(4): p. e202895. 
36. 
Yachida, S., et al., Metagenomic and metabolomic analyses reveal distinct stage-specific 
phenotypes of the gut microbiota in colorectal cancer. Nat Med, 2019. 25(6): p. 968-976. 
 
 
 

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12.0 
APPENDICES 

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12.1 
RESPONSE EVALUATION CRITERIA IN SOLID TUMORS (RECIST VERSION 1.1) 
Eligibility 
Only patients with measurable disease at baseline should be included in protocols where 
objective tumor response is the primary endpoint. 
 
— Measurable disease - the presence of at least one measurable lesion. If the measurable 
disease is restricted to a solitary lesion, its neoplastic nature should be confirmed by 
cytology/histology. 
 
— Measurable lesions - lesions that can be accurately measured in at least one dimension 
(longest diameter in the plane of measurement is to be recorded) with a minimum size of: 
 
o 10 mm by CT scan (CT scan slice thickness no greater than 5 mm) 
o 10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable) 
o 20 mm by chest X-ray. 
 
Malignant lymph nodes: to be considered pathologically enlarged and measurable, a lymph node must be ≥ 
15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater 
than 5 mm). At Baseline and follow-up, only the short axis will be measured and followed. 
 
— Non-measurable lesions - all other lesions, including small lesions (longest diameter <10 mm or 
pathological lymph nodes with ≥ 10 to <15 mm short axis) as well as truly non-measurable lesions. 
Lesions considered truly non-measurable include: leptomeningeal disease, ascites, pleural/pericardial 
effusion, inflammatory breast disease, lymphangitis cutis/pulmonis, abdominal masses/abdominal 
organomegaly identified by physical exam that is not measurable by reproducible imaging techniques. 
 
o For special considerations regarding lesion measurability for bone lesions, cystic lesions and 
lesions with prior local treatment, consult the RECIST 1.1 guidelines. 
o All measurements should be taken and recorded in metric notation using a ruler or calipers. 
All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before beginning of treatment. 
o The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. 
o 
Clinical lesions will only be considered measurable when they are superficial (e.g., skin nodules 
and palpable lymph nodes). For the case of skin lesions, either a CT scan or documentation by color 
photography, including a ruler to estimate the size of the lesion, is to be done. 

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Methods of Measurement 
 
• 
CT and MRI are the best currently available and reproducible methods to measure target lesions 
selected for response assessment. Conventional CT and MRI should be performed with cuts of 
10 mm or less in slice thickness contiguously. Spiral CT should be performed using a 5 mm 
contiguous reconstruction algorithm. This applies to tumors of the chest, abdomen and pelvis. 
Head and neck tumors and those of extremities usually require specific protocols. 
 
• 
Lesions on chest X-ray are acceptable as measurable lesions when they are clearly defined 
and surrounded by aerated lung. However, CT is preferable. 
 
• 
When the primary endpoint of the study is objective response evaluation, ultrasound (US) should 
not be used to measure tumor lesions. It is, however, a possible alternative to clinical 
measurements of superficial palpable lymph nodes, subcutaneous lesions and thyroid nodules. 
US might also be useful to confirm the complete disappearance of superficial lesions usually 
assessed by clinical examination. 
 
• 
The utilization of endoscopy and laparoscopy for objective tumor evaluation has not yet been fully 
and widely validated. Their uses in this specific context require sophisticated equipment and a high 
level of expertise that may only be available in some centers. Therefore, the utilization of such 
techniques for objective tumor response should be restricted to validation purposes in specialized 
centers. However, such techniques can be useful in confirming complete pathological response 
when biopsies are obtained. 
 
• 
Tumor markers alone cannot be used to assess response. If markers are initially above the 
upper normal limit, they must normalize for a patient to be considered in complete clinical 
response when all lesions have disappeared. 
 
• 
Cytology and histology can be used to differentiate between PR and CR in rare cases (e.g., after 
treatment to differentiate between residual benign lesions and residual malignant lesions in tumor 
types such as germ cell tumors). 
 
 
Baseline documentation of “Target” and “Non-Target” lesions 
— Target Lesions - all measurable lesions up to a maximum of 2 lesions per organ and 5 lesions 
in total, representative of all involved organs should be identified as target lesions and 
recorded and measured at baseline. 
 
o Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and their suitability for accurate repeated measurements (either by imaging 
techniques or clinically). 
o A sum of the longest diameter (LD) for all target lesions will be calculated and reported as the 
baseline sum LD. The baseline sum LD will be used as reference by which to characterize 
the objective tumor. 
 
— Non-target lesions - all other lesions (or sites of disease) should be identified as non-target 
lesions and should also be recorded at baseline. Measurements of these lesions are not 
required, but the presence or absence of each should be noted throughout follow-up. 
  
Response Criteria Evaluation of Target Lesions 
 

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Complete Response (CR): 
 
 
 
Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction in short 
axis to <10 mm). 
 
Partial Response (PR): 
At least a 30% decrease in the sum of the LD of target lesions, 
taking as reference the baseline sum LD 
Progressive Disease (PD): 
At least a 20% increase in the sum of the LD of target lesions 
from the smallest sum of the LD recorded since the treatment 
started; the sum must also demonstrate an absolute increase of 
at least 5 mm. The appearance of ≥1 new lesion is also 
considered progression. 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum 
LD since the treatment started 
 
Evaluation of non-target lesions 
 
Complete Response (CR): 
Disappearance of all non-target lesions and normalization of 
tumor marker level. All lymph nodes must be non- pathological in 
size (<10 mm short axis) 
Incomplete Response/ 
Stable Disease (SD): 
Persistence of one or more non-target lesion(s) or/and 
maintenance of tumor marker level above the normal limits 
 
Progressive Disease (PD): 
Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions* 
 
* Although a clear progression of “non target” lesions only is exceptional, in such circumstances, the 
opinion of the treating physician should prevail and the progression status should be confirmed later on 
by the review panel (or study chair). 
  
Evaluation of best overall response 
o The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for PD the smallest measurements 
recorded since the treatment started). In general, the patient's best response assignment will 
depend on the achievement of both measurement and confirmation criteria. 
 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Incomplete response/SD 
No 
PR 

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PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
o Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be classified as having 
“symptomatic deterioration”. Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
 
o In some circumstances it may be difficult to distinguish residual disease from normal 
tissue. When the evaluation of complete response depends on this determination, it is 
recommended that the residual lesion be investigated (fine needle aspirate/biopsy) to 
confirm the complete response status. 
 
Confirmation 
 
o The main goal of confirmation of objective response is to avoid overestimating the response 
rate observed. In cases where confirmation of response is not feasible, it should be made 
clear when reporting the outcome of such studies that the responses are not confirmed. 
 
o To be assigned a status of PR or CR, changes in tumor measurements must be confirmed by 
repeat assessments that should be performed no less than 4 weeks after the criteria for 
response are first met. Longer intervals as determined by the study protocol may also be 
appropriate. 
 
o In the case of SD, follow-up measurements must have met the SD criteria at least once 
after study entry at a minimum interval (in general, not less than 6-8 weeks) that is defined 
in the study protocol. 
  
Duration of overall response 
 
o The duration of overall response is measured from the time measurement criteria are met for 
CR or PR (whichever status is recorded first) until the first date that recurrence or PD is 
objectively documented, taking as reference for PD the smallest measurements recorded 
since the treatment started. 
 
Duration of stable disease 
 
o SD is measured from the start of the treatment until the criteria for disease progression are 
met, taking as reference the smallest measurements recorded since the treatment started. 
 
o The clinical relevance of the duration of SD varies for different tumor types and grades. 
Therefore, it is highly recommended that the protocol specify the minimal time interval 

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required between two measurements for determination of SD. This time interval should take 
into account the expected clinical benefit that such a status may bring to the population 
under study. 
 
Response review 
 
o For trials where the response rate is the primary endpoint it is strongly recommended that all 
responses be reviewed by (an) expert(s) independent of the study at the study’s completion. 
Simultaneous review of the patients’ files and radiological images is the best approach. 
 
Reporting of results 
 
o All patients included in the study must be assessed for response to treatment, even if there are 
major protocol treatment deviations or if they are ineligible. Each patient will be assigned one 
of the following categories: 1) complete response, 2) partial response, 3) stable disease, 4) 
progressive disease, 5) early death from malignant disease, 6) early death from toxicity, 7) 
early death because of other cause, or 8) unknown (not assessable, insufficient data). 
 
o All of the patients who met the eligibility criteria should be included in the main analysis of the 
response rate. Patients in response categories 4-8 should be considered as failing to respond 
to treatment (disease progression). Thus, an incorrect treatment schedule or drug 
administration does not result in exclusion from the analysis of the response rate. Precise 
definitions for categories 4-8 will be protocol specific. 
 
All conclusions should be based on all eligible patients. 
 
o Subanalyses may then be performed on the basis of a subset of patients, excluding those for 
whom major protocol deviations have been identified (e.g., early death due to other reasons, 
early discontinuation of treatment, major protocol violations, etc.). However, these 
subanalyses may not serve as the basis for drawing conclusions concerning treatment 
efficacy, and the reasons for excluding patients from the analysis should be clearly reported. 
 
o The 95% confidence intervals should be provided. 
 
 
Definition of CT tumor response by RECIST 1.1 criteria: 
The following table outlines the response categories by RECIST 1.1 criteria. 
 
Target Lesions  
Non-Target Lesions  
New Lesions  
Overall Response  
Complete Response  
(sum of diameters=0 mm) 
 
Complete response  
No  
Complete Response  
Complete Response  
Non-complete 
response, non-
progressive disease  
No  
 
 
 
 
 
Partial Response 
Complete Response 
Not evaluated 
No 

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Partial Response  
(decrease in sum of target 
lesions by ≥30%)  
Non-progressive       
disease OR  
Not evaluated  
No 
 
Stable Disease  
Non-progressive 
disease OR  
Not evaluated  
No  
Stable Disease  
Not all evaluated  
Non-progressive 
disease  
No  
Not Evaluable  
Progressive Disease 
(increase in sum of target 
lesions by ≥ 20% with an 
absolute increase in 
summed diameters by 
5mm)  
Any  
Yes or No  
 
 
 
 
Progressive Disease  
Any  
Progressive Disease 
Yes or No 
Any  
Any  
Yes 
 
 
 
 (Eisenhauer et al. 2009) 
 
 
 
 
 

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12.2 
ECOG Performance Status Scale 
 
 
 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity 
And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982. 
 
 

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12.3 Study Drug Dosing Diary: Attached as a separate document 
12.4 24-HR RECALL FORM: Attached as a separate document 
12.5 STOOL SURVEY: Attached as a separate document 
12.6 Instructions for Stool Collection: Attached as a separate document 
 
 
12.7 SUMMARY OF CHANGES 
Protocol version 2 dated 25AUG2021 
 
 
Addition of Kevin Scher, MD as a consenting Investigator 
 
Section 1.4, Correlative Studies: Update to timing of stool collection. Sample collection is required at 
baseline and the start of cycle 3. 
 
Section 4.1.1.2: Revise inclusion criteria to allow for intolerance to standard therapies  
 
Section 4.2.8: Revise HIV exclusion criteria to allow enrollment of patients who have an undetected viral 
load 
 
Section 4.2.9: Updated the Hepatitis B exclusion criterion to specify that patients with chronic hepatitis B are 
excluded unless they’re receiving antiviral treatment and HBV DNA test performed within six months of 
screening (based on medical chart review) is <2000 IU/mL. 
 
Section 4.2.10: Specified that patients with known Child-Pugh Score B or C liver cirrhosis are ineligible to 
participate 
 
Section 6.1.12 & 6.2.2: Clarified that the stool survey and 24-hour food recall should occur on the same day 
as the stool sample collection, if feasible 
 
Section 7.4.2.5: Clarified that SUSARs will be sent to EOC Pharma within 3 days of awareness 
 
Section 8.2.2: Clarified that the baseline stool sample should be collected 4 weeks prior to C1D1 or on 
C1D1. In addition a window (±3 days) was added for the C3D1 stool collection. This section was revised to 
be consistent with the Schedule of Events table. 
 
Removal of Appendix 12.2 Application of iRECIST 
 
Protocol version 3 dated 27JUL2022 
 
 
Section 4.0, Patient Eligibility: Clarified that enrollment holds deemed necessary for the evaluation of 
stopping rules is understood to be the responsibility of the PI. 
 
Section 4.1.6.6, Inclusion Criteria: Revised the creatine criterion to require either serum creatinine or CrCL 
(not both). 
 
Section 4.2.10, Exclusion Criteria: Corrected formatting error for HBV criterion. Removed requirement for 
HBV screening test results within 6 months and viral load threshold. 
 
Section 7.0, Adverse Events: Clarified that AE assessment occurs after the patient has started study 
treatment. 
 
Section 7.1, Adverse Event Monitoring: Clarified the timeframe for adverse event monitoring. Added a bullet 
to indicate that monitoring should occur “until 30 days following last dose of study drug or until initiation of a 
new anticancer therapy (whichever occurs first).” 
 
Protocol version 4 dated 02SEP2022 
 
 
Cover page: Updated sites and Investigators 
 
Sec 7.3.1.3: Updated IRB reporting requirements to indicate the AE is reportable if it “has a reasonable 
possibility of relationship,” per local guidelines.