A Randomized Phase 2 Study of Ompenaclid Versus Placebo in Combination With FOLFIRI Plus Bevacizumab in Patients With Previously Treated RAS Mutant Advanced or Metastatic Colorectal Cancer
Phase: PHASE2
Conditions: Colorectal Cancer, Metastatic Colon Cancer
Sponsor: Inspirna, Inc.

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Title Page 
Protocol Title: 
A randomized Phase 2 study of ompenaclid versus placebo in 
combination with FOLFIRI plus bevacizumab in patients with 
previously treated RAS mutant advanced or metastatic 
colorectal cancer 
Brief Title: 
A study to investigate response to ompenaclid combined with 
FOLFIRI plus bevacizumab in patients with advanced or 
metastatic colorectal cancer 
Compound: 
Ompenaclid (RGX-202-01) 
Indication: 
RAS mutant advanced or metastatic colorectal cancer 
Study Sponsor: 
Inspirna, Inc. 
310 East 67th Street 
Suite 1-12 
New York, NY 10065 
Telephone: 646-590-9064 
Protocol Number: 
RGX-202-002 
Study Phase: 
Phase 2 
Regulatory Agency 
Identifying 
Numbers: 
Version: 
Approval Date: 
IND 138812 
EU CT No. 2023-503356-27-00 
UTN U1111-1287-0704
NCT05983367 
Version 2.0 
Final, 20 November 2023 

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Contact Information for the Sponsor and Medical Monitor are provided separately. 
 
 

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Table of Contents 
TITLE PAGE ................................................................................................................................ 1 
PROTOCOL APPROVAL SIGNATURE .................................................................................. 2 
DOCUMENT HISTORY ............................................................................................................. 4 
TABLE OF CONTENTS ............................................................................................................. 5 
LIST OF TABLES ........................................................................................................................ 9 
LIST OF FIGURES ...................................................................................................................... 9 
ABBREVIATIONS AND DEFINITIONS ................................................................................ 10 
1 
PROTOCOL SUMMARY ................................................................................................... 13 
1.1 
Synopsis .............................................................................................................................. 13 
1.2 
Schema ............................................................................................................................... 20 
1.3 
Schedule of Activities (SoA) .............................................................................................. 21 
2 
INTRODUCTION ................................................................................................................ 26 
2.1 
Study Rationale .................................................................................................................. 26 
2.2 
Background......................................................................................................................... 26 
2.2.1 
Summary of Findings from Non-clinical Studies with Potential Clinical Relevance .... 27 
2.2.1.1 
Pharmacokinetics ........................................................................................................ 27 
2.2.1.2 
Safety Pharmacology .................................................................................................. 27 
2.2.1.3 
Toxicology .................................................................................................................. 27 
2.2.2 
Summary of Findings from Clinical Studies .................................................................. 28 
2.3 
Benefit/Risk Assessment .................................................................................................... 30 
2.3.1 
Risk Assessment ............................................................................................................. 30 
2.3.2 
Benefit Assessment ......................................................................................................... 30 
2.3.3 
Overall Benefit/Risk Conclusion .................................................................................... 30 
3 
OBJECTIVES AND ENDPOINTS ..................................................................................... 31 
4 
STUDY DESIGN .................................................................................................................. 31 
4.1 
Overall Design .................................................................................................................... 31 
4.2 
Scientific Rationale for Study Design ................................................................................ 33 
4.3 
Justification for Dose .......................................................................................................... 33 
4.4 
End-of-Study Definition ..................................................................................................... 34 
5 
STUDY POPULATION ....................................................................................................... 34 
5.1 
Inclusion Criteria ................................................................................................................ 34 

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5.2 
Exclusion Criteria ............................................................................................................... 36 
5.3 
Lifestyle Considerations ..................................................................................................... 38 
5.4 
Screen Failures ................................................................................................................... 38 
5.4.1 
Screening and Enrollment Log and Participant Identification Numbers ........................ 38 
5.5 
Criteria for Temporarily Delaying Administration of Study Drug ..................................... 38 
6 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY ............................... 39 
6.1 
Study Interventions Administered ...................................................................................... 39 
6.2 
Preparation, Handling, Storage, and Accountability .......................................................... 40 
6.3 
Assignment to Study Intervention ...................................................................................... 41 
6.4 
Blinding .............................................................................................................................. 41 
6.5 
Study Drug Compliance ..................................................................................................... 41 
6.6 
Dose Modification .............................................................................................................. 41 
6.6.1 
Dose Modifications for Study Drug ............................................................................... 42 
6.6.2 
Dose Modifications of FOLFIRI for Treatment Related Toxicity .................................. 43 
6.6.3 
Dose Modifications of Bevacizumab for Treatment Related Toxicity ........................... 44 
6.7 
Continued Access to Study Drug After the End of the Study ............................................ 45 
6.8 
Treatment of Overdose ....................................................................................................... 45 
6.9 
Prior and Concomitant Therapy ......................................................................................... 46 
7 
DISCONTINUATION OF STUDY DRUG AND PARTICIPANT 
DISCONTINUATION .......................................................................................................... 46 
7.1 
Discontinuation of Study Drug ........................................................................................... 46 
7.1.1 
Temporary Discontinuation ............................................................................................ 48 
7.2 
Participant Discontinuation/Withdrawal from the Study ................................................... 48 
7.3 
Lost to Follow-Up .............................................................................................................. 48 
8 
STUDY ASSESSMENTS AND PROCEDURES ............................................................... 49 
8.1 
Administrative and Baseline Procedures ............................................................................ 51 
8.2 
Efficacy Assessments ......................................................................................................... 51 
8.2.1 
General Considerations .................................................................................................. 51 
8.2.2 
Evaluation of Antitumor Response ................................................................................. 52 
8.3 
Safety Assessments ............................................................................................................. 55 
8.3.1 
Height and Weight .......................................................................................................... 55 
8.3.2 
Physical Examinations .................................................................................................... 55 
8.3.3 
Standard 12-lead Electrocardiograms ............................................................................. 56 
8.3.4 
Vital Signs ...................................................................................................................... 56 

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8.3.5 
Clinical Safety Laboratory Tests .................................................................................... 56 
8.3.6 
Pregnancy Testing ........................................................................................................... 57 
8.4 
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Safety Reporting ..... 57 
8.4.1 
Time Period and Frequency for Collecting AE and SAE Information ........................... 57 
8.4.2 
Method of Detecting AEs and SAEs .............................................................................. 58 
8.4.3 
Follow-up of AEs and SAEs ........................................................................................... 58 
8.4.4 
Regulatory Reporting Requirements for SAE ................................................................ 58 
8.4.5 
Pregnancy ....................................................................................................................... 59 
8.4.6 
Disease-related Events and/or Disease-related Outcomes Not Qualifying as AEs or 
SAEs ............................................................................................................................... 60 
8.5 
Pharmacokinetics ................................................................................................................ 60 
8.6 
Pharmacodynamics ............................................................................................................. 60 
8.7 
Genetics .............................................................................................................................. 61 
8.8 
Biomarkers ......................................................................................................................... 61 
8.9 
Immunogenicity Assessments ............................................................................................ 61 
9 
STATISTICAL CONSIDERATIONS ................................................................................ 61 
9.1 
Statistical Hypotheses ......................................................................................................... 61 
9.1.1 
Multiplicity Adjustment .................................................................................................. 62 
9.2 
Analysis Sets ...................................................................................................................... 62 
9.3 
Statistical Analyses ............................................................................................................. 62 
9.3.1 
General Considerations .................................................................................................. 62 
9.3.2 
Primary Endpoint Analysis ............................................................................................. 63 
9.3.2.1 
Definition of Endpoint ................................................................................................ 63 
9.3.2.2 
Main Analytical Approach .......................................................................................... 63 
9.3.3 
Secondary Endpoints Analysis ....................................................................................... 63 
9.3.3.1 
Progression-free Survival (Key Secondary Endpoint)................................................ 63 
9.3.3.2 
Overall Survival .......................................................................................................... 63 
9.3.3.3 
Duration of Response.................................................................................................. 64 
9.3.3.4 
Disease Control Rate .................................................................................................. 64 
9.3.4 
Safety and Population Analyses ..................................................................................... 64 
9.3.4.1 
Adverse Events ........................................................................................................... 64 
9.3.4.2 
Laboratory Parameters ................................................................................................ 65 
9.3.4.3 
Vital Signs ................................................................................................................... 65 
9.3.4.4 
ECOG Performance Status ......................................................................................... 65 
9.3.4.5 
Physical Examination ................................................................................................. 65 
9.3.4.6 
Electrocardiograms ..................................................................................................... 65 

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9.3.5 
Steady State Pharmacokinetics Analysis ........................................................................ 65 
9.3.6 
Population Data .............................................................................................................. 66 
9.3.7 
Other Analyses ................................................................................................................ 66 
9.4 
Interim Analysis.................................................................................................................. 66 
9.5 
Sample Size Determination ................................................................................................ 66 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .. 68 
10.1 Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ............................ 68 
10.1.1 
Regulatory and Ethical Considerations .......................................................................... 68 
10.1.2 
Financial Disclosure ....................................................................................................... 69 
10.1.3 
Informed Consent Process .............................................................................................. 69 
10.1.4 
Data Protection ............................................................................................................... 70 
10.1.4.1 
Data Monitoring Committee ....................................................................................... 70 
10.1.5 
Dissemination of Clinical Study Data ............................................................................ 70 
10.1.6 
Data Quality Assurance .................................................................................................. 71 
10.1.7 
Source Documents .......................................................................................................... 72 
10.1.8 
Study and Site Start and Closure .................................................................................... 72 
10.1.9 
Publication Policy ........................................................................................................... 73 
10.1.10 Protocol Approval and Amendment ............................................................................... 74 
10.1.11 Liability and Insurance ................................................................................................... 74 
10.1.12 Access to Source Data .................................................................................................... 74 
10.2 Appendix 2: Clinical Laboratory Tests ............................................................................... 76 
10.3 Appendix 3: AEs and SAEs: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ................................................................................................... 77 
10.3.1 
Definition of AE ............................................................................................................. 77 
10.3.2 
Definition of SAE ........................................................................................................... 78 
10.3.3 
Recording and Follow-up of AE and SAE ..................................................................... 79 
10.3.4 
Reporting of SAE ........................................................................................................... 81 
10.4 Appendix 4: Contraceptive and Barrier Guidance ............................................................. 83 
10.4.1 
Woman of Childbearing Potential .................................................................................. 83 
10.4.2 
Acceptable Methods of Contraception ........................................................................... 83 
11 REFERENCES ..................................................................................................................... 85 
INVESTIGATOR AGREEMENT PAGE ................................................................................ 86 
 
 

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List of Tables 
Table 1-1 
Schedule of Activities (SoA) ................................................................................ 21 
Table 3-1 
Objectives and Endpoints ..................................................................................... 31 
Table 6-1 
Study Interventions Administered......................................................................... 39 
Table 6-2 
Dose Modifications for Study Drug-Related Toxicities ....................................... 42 
Table 6-3 
Dose Modifications for FOLFIRI-Related Toxicity ............................................. 43 
Table 6-4 
FOLFIRI Component Dose Levels ....................................................................... 44 
Table 6-5 
Dose Modifications for Bevacizumab-Related Toxicity ...................................... 44 
Table 8-1 
Approximate Total Amount of Blood for Each Patient ......................................... 50 
Table 8-2 
Derivation of Overall Response ............................................................................ 54 
Table 10-1 
Protocol-required Safety Laboratory Tests ........................................................... 76 
 
List of Figures 
Figure 1–1 
Study Design ......................................................................................................... 20 
 
 
 

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1 Protocol Summary 
1.1 Synopsis 
Protocol Title: A randomized Phase 2 study of ompenaclid versus placebo in combination with 
FOLFIRI plus bevacizumab in patients with previously treated RAS mutant advanced or 
metastatic colorectal cancer 
Brief Title: A study to investigate response to ompenaclid combined with FOLFIRI plus 
bevacizumab in patients with RAS mutant advanced or metastatic colorectal cancer 
Sponsor Protocol No.: RGX-202-002 
Study Phase: Phase 2 
Sponsor: Inspirna, Inc.  
Regulatory Agency Identifier Numbers: IND No. 138812, EU CT No. 2023-503356-27-00, 
UTN U1111-1287-0704 
Rationale: 
Inspirna is developing ompenaclid (the hemi-succinate salt of RGX-202, 
 
 an orally bioavailable, small 
molecule inhibitor of the creatine transporter, SLC6a8, for the treatment of patients with 
gastrointestinal malignancies. 
 
Metastatic colon cancer cells activate the creatine pathway by upregulating 
SLC6a8 and creatine kinase B (CKB) to fuel survival and metastatic progression. In animal 
models of colon cancer, knockdown of SLC6a8 or CKB suppresses metastatic colonization to the 
liver, while overexpression of CKB enhances metastatic colonization. Ompenaclid interferes 
with this pathway by inhibiting the SLC6a8 creatine transporter and thus reducing intracellular 
creatine and adenosine triphosphate (ATP) levels in cancer cells.  
In an ongoing study (RGX-202-001), multiple oral doses of ompenaclid as a single agent or in 
combination with irinotecan, leucovorin, and 5-fluorouracil (5-FU) (FOLFIRI) ± bevacizumab 
have been evaluated in patients with unresectable or metastatic gastrointestinal tumors. Among 
the patients with previously treated colorectal cancer (CRC) harboring RAS mutations, the 
overall response rate (ORR) indicated a treatment benefit and 3000 mg twice daily (BID) of 
ompenaclid was determined to be optimal for achieving efficacious systemic exposure.  
 

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• The primary efficacy endpoint of the study is ORR. The secondary efficacy endpoints are 
PFS, OS, DoR, and DCR. Steady state PK will be evaluated. Safety will be monitored 
throughout the study. 
• An independent Data Monitoring Committee (DMC) will conduct unblinded interim analyses 
of safety approximately every 6 months following randomization of the first patient. 
Additionally, the DMC will conduct unblinded interim analyses of efficacy, the timing and 
scope of which will be outlined in the DMC Charter. 
Brief Summary: 
The purpose of this study is to measure tumor response to treatment with ompenaclid in patients 
with previously treated RAS mutant advanced or metastatic CRC. All patients will receive 
treatment with FOLFIRI and bevacizumab. In addition, patients will be randomized to receive 
either ompenaclid 3000 mg BID or matching placebo (herein referred to as Study Drug). Each 
treatment cycle is 28 days in duration. 
Each patient will continue with their assigned study treatment until progressive disease (PD), or 
another discontinuation criterion is met.  
Patients will be required to attend the clinic for screening evaluations prior to randomization. 
During each 28-day treatment cycle, patients will have visits on Days 1 and 15 for study 
procedures including the FOLFIRI and bevacizumab infusions. Patients will return to the clinic 
on Days 3 and 17 to disconnect from the 5-FU infusion unless a home-based nursing service or 
other local care has been arranged. Follow-up to determine post-treatment safety and survival 
will be conducted by telephone. 
Number of Participants: 
Approximately 70 patients are planned to be randomized 1:1 to Study Drug (ompenaclid or 
placebo) treatment. 
Study Arms and Duration: 
Patients will attend a screening visit between 28 days (Day -28) and 1 day (Day -1) prior to 
randomization. The 28-day treatment cycle will start on Cycle 1 Day 1. Treatment cycles will 
continue until PD, or another discontinuation criterion is met, including unacceptable toxicity, 
voluntary withdrawal from treatment, or closure of the study by the Sponsor; no maximum 
duration of therapy has been set. An end of treatment (EOT) assessment will be performed 
within 21 days following the last dose of Study Drug and a safety follow-up phone call will 

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occur 30 days (±3 business days) after the last dose of Study Drug. Thereafter, patients should be 
contacted approximately every 90 days (±14 days) for up to 2 years from last subject enrolled, or 
until withdrawal of consent, loss to follow-up, death, or study closure, whichever occurs first. 
Data to be collected during this extended follow-up includes the patients’ survival status, disease 
status, and anticancer treatment. If the patient discontinued for a reason other than radiographic 
PD, additional scan data may also be collected, if possible, until documented radiographic PD, 
initiation of new anticancer treatment, or study closure, whichever occurs first. In patients who 
become candidates for surgery or radiation with curative intent during the study, post-EOT 
follow-up may include tumor measurements and disease response assessments, and documenting 
any anti-cancer therapies until development of radiographic or clinical PD. 
An independent DMC has been appointed for this study. It is comprised of a group of 
independent experts who are appointed to monitor the safety and scientific integrity of a human 
research intervention, and to make recommendations to the Sponsor regarding the stopping of a 
study for efficacy, for harm, or for futility. The composition of the committee is dependent upon 
the scientific skills and knowledge required for monitoring this particular study. 
Inclusion and Exclusion Criteria 
To be randomized in this study, patients must meet the following criteria during the screening 
period: 
1. Advanced disease, defined as cancer that is either metastatic or locally advanced and 
unresectable and for which additional radiation therapy or other locoregional therapies 
are not considered feasible. 
2. Progression of disease after receiving only 1 prior regimen considered standard of care 
for CRC in the advanced/metastatic setting, and it must have been an 
oxaliplatin-containing regimen. Patients who have mismatch repair deficiency/ high 
microsatellite instability (dMMR/MSI-H) CRC must have also received prior treatment 
with pembrolizumab or a Food and Drug Administration (FDA)/European Union (EU)-
approved programmed cell death protein 1 (PD-1)/ programmed death-ligand 1 (PD-L1) 
inhibitor. Patients may have received prior treatment with bevacizumab or an European 
Medicines Agency (EMA)-approved biosimilar. Patients who developed metastatic CRC 
within 12 months of completion of adjuvant oxaliplatin and 5-FU based therapy are also 
eligible. 
3. Histologic or cytologic evidence of a malignant colorectal tumor of adenocarcinoma or 
poorly differentiated histology that is laboratory-confirmed to be RAS mutant. 
Confirmation of RAS mutant status by liquid biopsy is acceptable only if the tumor 

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sample is not available and the liquid biopsy was performed before initiation of the 
patient’s prior treatment regimen. Patients who convert to RAS mutant status after 
initially having documented wild-type histology are not eligible. 
4. Disease that is measurable by standard imaging techniques by Response Evaluation 
Criteria in Solid Tumors (RECIST) version 1.1. For patients with prior radiation therapy, 
measurable lesions must be outside of any prior radiation field(s), unless disease 
progression has been documented at that disease site subsequent to radiation. 
5. At least 18 years old. 
6. ECOG performance score ≤ 1. 
7. Adequate baseline organ function, as demonstrated by the following: 
a. Calculated creatinine clearance > 60 mL/min per institutional standard. 
b. Serum albumin ≥ 2.5 g/dL. 
c. Bilirubin ≤ 1.5 × institutional upper limit of normal range (ULN).  
d. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × 
institutional ULN; patients with hepatic metastases may have AST and ALT ≤ 5 × 
institutional ULN. 
e. Absolute neutrophil count (ANC) ≥1.5×109/L.  
f. Hemoglobin ≥ 8 g/dL and no red blood cell (RBC) transfusions during the prior 
14 days.  
g. Platelet count ≥ 100×109/L and no platelet transfusions during the prior 14 days. 
8. If not taking warfarin (or similar vitamin K inhibitor) the following values are required: 
international normalized ratio (INR) ≤ 1.5 or prothrombin time (PT) ≤ 1.5 × ULN and 
either partial thromboplastin time or activated partial thromboplastin time (PTT or aPTT) 
≤ 1.5 × ULN. Patients on warfarin (or similar vitamin K inhibitor) may be included if on 
a stable dose with a therapeutic INR < 3.5.   
9. Left ventricular ejection fraction (LVEF) ≥ 45% as determined by either 
echocardiography (ECHO) or multigated acquisition (MUGA) scanning. 
10. Woman of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test within 2 weeks prior to treatment. 

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11. Men and WOCBP must agree to use acceptable contraceptive methods for the duration of 
time on the study and continue to use acceptable contraceptive methods for at least 
6 months from the last dose of bevacizumab or 2 months after the last dose of 
ompenaclid, whichever is longer. 
12. Provides signed informed consent prior to initiation of any study-specific procedures or 
treatment. 
13. Able to adhere to the study visit schedule and other protocol requirements, including 
follow-up for survival assessment. 
Potential patients who meet any of the following criteria at screening will be excluded from the 
study: 
1. Persistent clinically significant toxicities (Grade ≥ 2) from previous anticancer therapy. 
Excluded are Grade 2 chemotherapy-related neuropathy and alopecia which are permitted 
and Grade 2 laboratory abnormalities if they are not associated with symptoms, are not 
considered clinically significant by the Investigator, or can be managed with available 
medical therapies.  
2. CRC with histology (or component of histology) consistent with small cell, 
neuroendocrine, or squamous carcinoma, or lymphoma. 
3. Received treatment with chemotherapy, external-beam radiation, or other systemic 
anticancer therapy within 14 days prior to study therapy administration (42 days for prior 
nitrosourea or mitomycin-C). 
4. Received treatment with an investigational systemic anticancer agent within 5 half-lives 
of the investigational systemic therapy or within 28 days, whichever is shorter prior to 
Study Drug administration.  
5. Has an additional active malignancy that may confound the assessment of the study 
endpoints. Patients with a past cancer history with substantial potential for recurrence 
must be discussed with the Medical Monitor before study entry. Patients with the 
following concomitant neoplastic diagnoses are eligible: non-melanoma skin cancer, 
carcinoma in situ (including transitional cell carcinoma, cervical intraepithelial neoplasia, 
and melanoma in situ), organ-confined prostate cancer with no evidence of progressive 
disease. 

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6. Clinically significant cardiovascular disease: e.g., uncontrolled or any New York Heart 
Association Class 3 or 4 congestive heart failure, uncontrolled angina, history of 
myocardial infarction, unstable angina or stroke within 6 months prior to study entry, 
uncontrolled hypertension (defined as systolic blood pressure [SBP] > 160 or diastolic 
blood pressure [DBP] > 90), or clinically significant arrhythmias not controlled by 
medication. 
7. Known active or suspected brain or leptomeningeal metastases. Central nervous system 
(CNS) imaging is not required prior to study entry unless there is a clinical suspicion of 
CNS involvement.  
8. Uncontrolled intercurrent illness including, but not limited to, uncontrolled infection, 
disseminated intravascular coagulation, or psychiatric illness/social situations that would 
limit compliance with study requirements. 
9. Pregnant or breast feeding. 
10. Evidence of muscular dystrophies or ongoing muscle pathology. 
11. Oxygen-support requirements. 
12. QTc > 470 msec. 
13. Physical abnormality or medical condition that limits swallowing multiple pills or has a 
history of non-adherence to oral therapies. 
14. A gastrointestinal (GI) condition that may significantly alter absorption. 
15. Clinically significant ascites (i.e., requiring paracentesis within the preceding 28 days or 
treatment with pain medication). 
16. Any medical condition which, in the opinion of the Investigator, places the patient at an 
unacceptably high risk for toxicities. 
17. Known dihydropyrimidine dehydrogenase (DPD) deficiency or is on treatment with DPD 
inhibitors, including sorivudine or its chemically related analogues such as brivudine, 
within 4 weeks prior to the start of FOLFIRI treatment. 
18. Requires treatment with strong CYP3A4 inhibitors or strong UGT1A1 inhibitors. 
19. Previously received FOLFIRI or other irinotecan containing treatment regimens. 

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20. Marked proteinuria (≥ 2 g/24 hours) and/or nephrotic syndrome. Patients with a 
proteinuria 2+ or greater urine dipstick reading should undergo further assessment, e.g., a 
24-hour urine collection. 
21. History of acute or subacute intestinal occlusion, unless such an event occurred only 
around the time of initial diagnosis or development of metastatic disease, or from chronic 
inflammatory bowel disease or chronic diarrhea. 
22. Severe, non-healing wounds, ulcers, or bone fractures. 
23. History of hemodynamically significant pulmonary embolism within 6 months prior to 
inclusion in the study. 
24. History of hemorrhagic diathesis or tendency towards thrombosis that is not optimally 
managed, with the exception of tumor bleeding before tumor resection surgery. 
1.2 Schema 
Figure 1–1 
Study Design 
 
FOLFIRI = irinotecan, leucovorin, and 5-fluorouracil 
 

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d. Coagulation tests at Screening and Cycle 1 Day 1 only. Either PT or INR may be measured, depending on institutional standards. PT/INR should be checked 
weekly for patients on warfarin (or similar vitamin K inhibitor) or per standard of care. It is recommended that the smallest appropriate sampling tubes be 
used to curtail blood loss due to phlebotomy.  
e. 
Tumor measurements and disease response assessments also are to be performed at the EOT visit unless radiographic PD was previously documented. In 
patients who become candidates for surgery or radiation with curative intent during the study, post-EOT follow-up may include tumor measurements and 
disease response assessments and documenting any anti-cancer therapies until development of radiographic or clinical PD. 
f. 
Patients will return to clinic on Days 3 and 17 to disconnect from the 5-FU infusion unless a home-based nursing service or other local care close to the 
patient’s home has been arranged. 
 
 
 

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2 Introduction 
Ompenaclid (the hemi-succinate salt of RGX-202, 
 
 is an orally bioavailable, small molecule inhibitor of the 
creatine transporter, SLC6a8, for the treatment of patients with gastrointestinal malignancies. 
 
2.1 Study Rationale 
Metastatic colon cancer cells activate the creatine pathway by upregulating SLC6a8 and CKB to 
fuel survival and metastatic progression (Loo 2015). In animal models of colon cancer, 
knockdown of SLC6a8 or CKB suppresses metastatic colonization to the liver, while 
overexpression of CKB enhances metastatic colonization (Loo 2015). Ompenaclid interferes 
with this pathway by inhibiting the SLC6a8 creatine transporter and thus reducing intracellular 
creatine and ATP levels in cancer cells. 
RAS mutations, which are found in ~45% of CRCs, can induce significant metabolic 
dysregulation in cancer cells. In an ongoing study (RGX-202-001), multiple oral doses of 
ompenaclid as a single agent or in combination with FOLFIRI ± bevacizumab have been 
evaluated in patients with unresectable or metastatic gastrointestinal tumors. Among the patients 
with previously treated CRC harboring RAS mutations, the ORR indicated a treatment benefit 
and 3000 mg BID of ompenaclid was determined to be optimal for achieving efficacious 
systemic exposure.  
2.2 Background 
Metastatic CRC that is resistant to the currently approved methods of treatment is recognized as 
a serious threat to public health worldwide. Research efforts in recent years have become 
increasingly geared towards discovering and developing new treatment regimens with modes of 
action distinct from those of established agents and with the ability to target subclasses of CRC, 
such as those associated with RAS mutations.  
Ompenaclid (the hemi-succinate salt of RGX-202, 
 
, is an orally bioavailable, small molecule inhibitor of the 
creatine transporter, SLC6a8, for the treatment of patients with gastrointestinal malignancies. 
  
In an ongoing study (RGX-202-001), 3000 mg BID of ompenaclid was determined to be optimal 
for achieving efficacious systemic exposure and demonstrated the potential for clinical benefit to 
the patients with previously treated RAS mutant advanced or metastatic CRC.  

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A detailed description of the chemistry, pharmacology, efficacy, and safety of ompenaclid is 
provided in the Investigator’s Brochure. 
2.2.1 
Summary of Findings from Non-clinical Studies with Potential Clinical 
Relevance 
2.2.1.1 
Pharmacokinetics 
Ompenaclid is not a substrate of the efflux transporters P-gp or breast cancer resistance protein 
(BCRP) in MDCKII cells or vesicles expressing P-gp or BCRP; however, there was evidence 
suggesting that ompenaclid is a substrate of an uptake transporter that is endogenously expressed 
in the MDCKII cell line. 
Metabolism does not appear to be a major clearance mechanism for this compound as 
ompenaclid does not appear to interact with cytochrome P450 (CYP) enzymes and is not 
metabolized by liver hepatocytes in any species tested, nor is it an inhibitor of the common 
human ATP-binding cassette or solute carrier transporters. 
Since ompenaclid does not appear to be metabolized, therefore excretion of the parent unchanged 
is likely the main clearance mechanism. In the dose regimen finding studies in the rat and dog, 
significant amounts of ompenaclid were found in the urine, indicating that renal excretion is a 
likely clearance mechanism for this compound.   
2.2.1.2 
Safety Pharmacology 
Ompenaclid inhibited human ether-a-go-go related gene (hERG) current by 1.0% at 100 µM and 
3.8% at 1000 µM and was not statistically significant when compared to vehicle control values. 
As inhibition greater than 50% was not observed, the IC50 for the inhibitory effect of ompenaclid 
on hERG potassium current was not calculated but was estimated to be greater than 1000 µM.   
2.2.1.3 
Toxicology 
Nonclinical studies were conducted in vitro and in vivo in Sprague-Dawley rats and Beagle dogs 
to evaluate the potential toxicity of ompenaclid. Ompenaclid was given via oral gavage 
administration, which is the route proposed for use in the initial clinical study. 
In the non-Good Laboratory Practices (GLP) single-dose escalation studies, the maximum 
tolerated dose (MTD) of ompenaclid via a single oral dose in rats and dogs was 1000 mg/kg. 
In the 7-day non-GLP range-finding study in rats and dogs, animals were given ompenaclid 
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tolerated and all animals survived until scheduled necropsy and test article-related effects were 
mainly observed in 300 and 1000 mg/kg/day groups. In rats, these effects included slightly 
decreased mean body weights, body weight gains and food consumptions, as well as minor 
changes in clinical chemistry and hematology parameters. In dogs, these effects included emesis, 
loose feces, minor changes in clinical chemistry parameters, as well as minimally increased liver 
weight. No target organs were identified in either species. 
A 4-week GLP rat toxicity study with a two-week recovery period was conducted at dose levels 
of 0, 100, 600, and 1330 mg/kg/day, and also included evaluation of the central nervous and 
respiratory systems. There were no test article-related mortalities, clinical signs or abnormal 
ophthalmology findings Target organs identified microscopically at doses ≥ 600 mg/kg/day 
included the liver (minimal hypertrophy) and male reproductive system at doses 
≥ 100 mg/kg/day. Delayed spermiation was considered adverse at all dose levels of ompenaclid. 
At recovery sacrifice in animals administered 1330 mg/kg/day, minimally to mildly delayed 
spermiation, mild tubular dilatation, minimal epididymal cellular debris and/or epididymal 
atrophy was observed. These findings were consistent with a partial reversal of testicular changes 
during the recovery period. There were no treatment-related deaths at oral doses up to 
1330 mg/kg/day ompenaclid in Sprague-Dawley rats, thus the STD10 is considered to be at least 
1330 mg/kg/day. Based on the adverse effects of delayed spermiation in male rats given 
≥ 100 mg/kg/day, the no-observed-adverse-effect-level (NOAEL) is undetermined in males and 
is 1330 mg/kg/day in female rats. 
A 4-week GLP dog toxicity study with a 2-week recovery period was conducted at dose levels of 
0, 100, 600, and 1330 mg/kg/day, and also included evaluation of the cardiovascular system. 
There were no test article-related mortalities, or changes in food consumption, body temperature, 
blood pressure, electrocardiogram (ECG), hematology, coagulation, or urinalysis parameters. 
Target organs identified microscopically were limited to the liver (dose-related increased 
hepatocellular rarefaction) at doses ≥ 100 mg/kg/day. This microscopic observation was 
morphologically indistinguishable from glycogen deposition; however, other subcellular 
alterations were also possible. None of the hepatic changes was considered adverse. All the 
changes at terminal sacrifice had fully or partially recovered during the 2-week recovery period. 
The NOAEL was considered to be 1330 mg/kg/day. 
2.2.2 
Summary of Findings from Clinical Studies 
Ompenaclid is being studied in RGX-202-001, a Phase 1, first-in-human, two stage (dose 
escalation and expansion) study evaluating multiple doses of orally administered ompenaclid as a 
single agent and in combination with FOLFIRI ± bevacizumab in patients with advanced 
gastrointestinal tumors (i.e., locally advanced and unresectable, or metastatic) who have had PD 

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on available standard systemic therapies or for which there are no standard systemic therapies of 
relevant clinical impact.  
Based on the assessment of preliminary results from study RGX-202-001 obtained as of 
05 June 2023 ompenaclid 3000 mg BID has the potential to optimize the likelihood of 
consistently achieving efficacious systemic exposure and pharmacodynamic biomarkers 
associated with target management with an acceptable safety profile when combined with 
FOLIFIRI and bevacizumab. The efficacy results also provide a rationale to enroll patients with 
previously treated CRC harboring RAS mutations. In summary: 
• The dose escalation cohorts with single agent ompenaclid or in combination with FOLFIRI ± 
bevacizumab did not reach an MTD and no dose-limiting toxicities were observed. 
• The most common treatment-emergent adverse events (TEAEs) observed with single agent 
ompenaclid treatment (n = 17 patients) were nausea (8 patients, 47%), vomiting (7 patients, 
41%), fatigue (5 patients, 29%), diarrhea (4 patients, 24%), and decreased appetite 
(4 patients, 24%). Grade ≥ 3 TEAEs were observed in 8 patients with the most frequent being 
hypertension (n = 2, 12%), nausea (n = 1, 6%), and vomiting (n = 1, 6%). 
• The most common TEAEs observed with ompenaclid 2400 mg BID or 3000 mg BID in 
combination with FOLFIRI and bevacizumab (n = 38) were nausea (18 patients, 47%), 
fatigue (10 patients, 26%), diarrhea (10 patients, 26%), neutropenia/neutrophil count 
decreased (6 patients, 16%), constipation (6 patients, 16%), vomiting (5 patients, 13%), 
decreased appetite (5 patients, 13%), and abdominal pain (5 patients, 13%). 
• Grade ≥ 3 TEAEs were observed in 22 patients with the most frequent being neutropenia or 
neutrophil count decreased (5 patients, 13%), diarrhea (4 patients, 11%), fatigue (4 patients, 
11%), nausea (3 patients, 8%), small intestine obstruction (3 patients, 8%), 
hyperbilirubinemia or blood bilirubin increased (3 patients, 8%), hypertension (2 patients, 
5%), pulmonary embolism (2 patients, 5%), and anemia (2 patients, 5%). 
• The most common Grade 3-4 TEAEs considered related to ompenaclid were nausea (8%), 
neutropenia/neutrophil count decreased (6%), diarrhea (6%), and vomiting (5%). 
• The GI events and neutropenia in the dose escalation and expansion stages are consistent 
with those reported for the standard of care therapy with FOLFIRI and bevacizumab in the 
second line treatment of CRC. Additionally, the overall safety profile of ompenaclid 2400 mg 
BID or 3000 mg BID in combination with FOLFIRI and bevacizumab showed an acceptable 
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• Among 28 patients with advanced (unresectable or metastatic) CRC harboring RAS 
mutations treated with ompenaclid 2400 mg BID or 3000 mg BID in combination with 
FOLFIRI and bevacizumab as second line therapy, the ORR was 28.6% (8 partial responses 
[PRs]), or 40.0% among the 20 best response evaluable patients in this subset; with an 
estimated median PFS of 11.8 months. 
2.3 Benefit/Risk Assessment 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of ompenaclid may be found in the Investigator’s Brochure. 
2.3.1 
Risk Assessment 
Gastrointestinal disorders (including nausea, vomiting, and diarrhea) and fatigue are the most 
frequently reported AEs attributed to ompenaclid as a single agent or in combination with 
FOLFIRI ± bevacizumab. The safety concerns identified to date are summarized in Section 
2.2.2. 
Please refer to the Investigational Brochure for additional information regarding potential risks.  
2.3.2 
Benefit Assessment 
Assessments of the benefits of treatment with ompenaclid are ongoing. It is intended to 
demonstrate that treatment with ompenaclid in combination with FOLFIRI + bevacizumab will 
provide a safe, effective treatment for patients with previously treated RAS mutant advanced or 
metastatic CRC. 
2.3.3 
Overall Benefit/Risk Conclusion 
Taking into account favorable pre-clinical and clinical safety data generated to date and the 
measures outlined in this clinical study protocol in Section 6.6 to mitigate toxicities to 
participants in the study should they occur, the potential risks associated with ompenaclid 
treatment identified in clinical studies to date are justified by the anticipated benefits that may be 
afforded to participants with previously treated RAS mutant advanced or metastatic CRC. 
 

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Written informed consent must be obtained prior to initiating any screening activities, except 
where patients have agreed to the use of previously available tests completed within 28 days of 
the planned first dose of Study Drug, e.g., computed tomography (CT)/magnetic resonance 
imaging (MRI) scans. Screening for study eligibility must be completed within 28 days prior to 
first dose of Study Drug. Patients who are determined to be eligible, based on Screening 
assessments, will be randomized in the study.  Patients will receive their first dose of Study Drug 
on Cycle 1, Day 1. A treatment cycle is 28 days in duration. Patients will be randomized in a 1:1 
ratio to receive oral administration of the five 600-mg tablets BID of ompenaclid or matching 
placebo (Study Drug). The intravenous FOLFIRI dose and schedule will be administered 
according to institutional standard practice; irinotecan 180 mg/m2 over 60-90 minutes (in patients 
with UGT1A1*28 or UGT1A1*6 homozygosity, one level dose reduction may be considered 
[Karas 2022]) concurrently with leucovorin 400 mg/m2, followed by 5-FU 2400 mg/m2 over 
46 hours, on Days 1 and 15 of each 28-day cycle. Sites may discuss alternative 5-FU 
administration regimens with the study Medical Monitor, e.g., bolus dosing. The bevacizumab 
dose of 5 mg/kg will be administered intravenously on Days 1 and 15 of each 28-day cycle. 
During the study, patients will attend study center visits and have study evaluations performed as 
detailed in the Schedule of Activities (Table 1-1). All routine study visits are to be conducted on 
an outpatient basis. 
Patients may continue to receive Study Drug until the development of PD, or another 
discontinuation criterion is met, including unacceptable toxicity, voluntary withdrawal from 
treatment, or closure of the study by the Sponsor; no maximum duration of therapy has been set. 
After discontinuation of the Study Drug, patients will complete an EOT visit within 21 days after 
their last dose of Study Drug to complete procedures as outlined in the Schedule of Activities. In 
the event a patient is unable to return to the clinic for EOT assessments due to death, 
hospitalization, or admittance to hospice care, results from outside assessments may be entered 
in the EDC or the visit may be marked as “not done” and all efforts should focus on obtaining 
any further safety follow-up related to new or ongoing Study Drug-related AEs and SAEs.  
An additional Safety Follow-up is to be conducted by telephone 30 days (± 3 business days) after 
their last dose of Study Drug. Thereafter, patients should be contacted approximately every 
90 days (±14 days) for up to 2 years from last subject enrolled, or until withdrawal of consent, 
loss to follow-up, death, or study closure, whichever occurs first. Data to be collected during this 
extended follow-up includes the patients’ survival status, disease status, and anticancer 
treatment. If applicable, sites may also use public records as a source of information to document 
patient survival status. If the patient discontinued for a reason other than radiographic PD, 

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additional scan data may also be collected, if possible, until documented PD, initiation of new 
anticancer treatment, or study closure, whichever occurs first. As applicable, safety information 
associated with study drug-related SAEs may also be collected during these follow-up contacts.  
All patients must have pre-randomization (prior to Study Drug dosing) imaging (CT scan of 
chest/abdomen/pelvis or MRI, if indicated) and historical tumor biopsy with confirmation that 
archival tissue is available for submission to a central lab as soon as feasible. Since archival 
tissue may need to be obtained from an outside institution, randomization may proceed prior to 
submission of the sample with the understanding that the site will make every effort to obtain 
and submit the tumor sample in a timely manner.   
The time window for screening activities is within 28 days prior to their first Study Drug dose 
and will differ for radiographic imaging, laboratory assessments, and physical exam and are 
detailed in Table 1-1. Patients with skin, subcutaneous, or lymph node metastases may also have 
tumor evaluations (including measurements with a ruler) by means of physical examination.  
Tumor measurements and disease response assessments also are to be performed approximately 
8 weeks (+/- 5 business days) after randomization, and approximately every 8 weeks (+/- 5 
business days) thereafter until development of radiographic PD (or other discontinuation 
criterion).  
4.2 Scientific Rationale for Study Design 
The design of this study follows the recommendations for the analysis of treatment benefit for 
patients with metastatic CRC who have been refractory to first-line treatment. The sample size is 
specified to detect a difference in ORR between the treatment groups (see Section 9.5). 
4.3 Justification for Dose 
The dose of 3000 mg BID was identified in Study RGX-202-001 to optimize the likelihood of 
consistently achieving efficacious systemic exposure (see Section 2.2.2). 
Study Drug dose modifications within a treatment cycle are to be discussed with the Medical 
Monitor prior to implementation in order to determine if a lower dose is expected to be tolerated 
more favorably by the patient, based upon collective safety data from patients treated on the 
original dose and on lower doses. See Section 6.6. 

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4.4 End-of-Study Definition 
The End of Study for a given patient is defined as the date of the last extended follow-up 
disease/survival status, or until death, withdrawal of consent, loss to follow-up, or study closure, 
whichever occurs first. 
The study is considered complete when sufficient information is available to enable assessment 
of the primary endpoint and key secondary endpoint. In the weeks subsequent to a determination 
that sufficient information is available for these assessments, a date for database lock will be 
assigned, and any outstanding inquiries concerning data elements will be resolved. The Study 
Completion date will be the date beyond which study data are no longer entered into the primary 
database (this study completion date generally precedes the date on which the database lock 
occurs by several weeks/months). 
5 Study Population 
5.1 Inclusion Criteria 
To be randomized in this study, patients must meet the following criteria during the screening 
period: 
1. Advanced disease, defined as cancer that is either metastatic or locally advanced and 
unresectable and for which additional radiation therapy or other locoregional therapies 
are not considered feasible. 
2. Progression of disease after receiving only 1 prior regimen considered standard of care 
for CRC in the advanced/metastatic setting, and it must have been an 
oxaliplatin-containing regimen. Patients who have dMMR/MSI-H CRC must have also 
received prior treatment with pembrolizumab or an FDA/EU-approved PD-1/PD-L1 
inhibitor. Patients may have received prior treatment with bevacizumab or an 
EMA-approved biosimilar. Patients who developed metastatic CRC within 12 months of 
completion of adjuvant oxaliplatin and 5-FU based therapy are also eligible. 
3. Histologic or cytologic evidence of a malignant colorectal tumor of adenocarcinoma or 
poorly differentiated histology that is laboratory-confirmed to be RAS mutant. 
Confirmation of RAS mutant status by liquid biopsy is acceptable only if the tumor 
sample is not available and the liquid biopsy was performed before initiation of the 
patient’s prior treatment regimen. Patients who convert to RAS mutant status after 
initially having documented wild-type histology are not eligible. 

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4. Disease that is measurable by standard imaging techniques by RECIST version 1.1. For 
patients with prior radiation therapy, measurable lesions must be outside of any prior 
radiation field(s), unless disease progression has been documented at that disease site 
subsequent to radiation. 
5. At least 18 years old. 
6. ECOG performance score ≤ 1. 
7. Adequate baseline organ function, as demonstrated by the following: 
a. Calculated creatinine clearance > 60 mL/min per institutional standard. 
b. Serum albumin ≥ 2.5 g/dL. 
c. Bilirubin ≤ 1.5 × institutional ULN.  
d. AST and ALT ≤ 2.5 × institutional ULN; patients with hepatic metastases may have 
AST and ALT ≤ 5 × institutional ULN. 
e. ANC ≥ 1.5×109/L.  
f. Hemoglobin ≥ 8 g/dL and no RBC transfusions during the prior 14 days.  
g. Platelet count ≥ 100×109/L and no platelet transfusions during the prior 14 days. 
8. If not taking warfarin (or similar vitamin K inhibitor) the following values are required: 
INR ≤ 1.5 or PT ≤ 1.5 × ULN and either PTT or aPTT ≤ 1.5 × ULN. Patients on warfarin 
(or similar vitamin K inhibitor) may be included if on a stable dose with a therapeutic 
INR < 3.5.   
9. LVEF ≥ 45% as determined by either ECHO or MUGA scanning. 
10. WOCBP must have a negative serum or urine pregnancy test within 2 weeks prior to 
treatment. 
11. Men and WOCBP must agree to use acceptable contraceptive methods for the duration of 
time on the study and continues to use acceptable contraceptive methods for at least 
6 months from the last dose of bevacizumab or 2 months after the last dose of 
ompenaclid, whichever is longer. 
12. Provides signed informed consent prior to initiation of any study-specific procedures or 
treatment. 

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13. Able to adhere to the study visit schedule and other protocol requirements, including 
follow-up for survival assessment. 
5.2 Exclusion Criteria 
Potential patients who meet any of the following criteria at screening will be excluded from the 
study: 
1. Persistent clinically significant toxicities (Grade ≥ 2) from previous anticancer therapy. 
Excluded are Grade 2 chemotherapy-related neuropathy and alopecia which are permitted 
and Grade 2 laboratory abnormalities if they are not associated with symptoms, are not 
considered clinically significant by the Investigator, or can be managed with available 
medical therapies.  
2. CRC with histology (or component of histology) consistent with small cell, 
neuroendocrine, or squamous carcinoma, or lymphoma. 
3. Received treatment with chemotherapy, external-beam radiation, or other systemic 
anticancer therapy within 14 days prior to study therapy administration (42 days for prior 
nitrosourea or mitomycin-C). 
4. Received treatment with an investigational systemic anticancer agent within 5 half-lives 
of the investigational systemic therapy or within 28 days, whichever is shorter prior to 
Study Drug administration.  
5. Has an additional active malignancy that may confound the assessment of the study 
endpoints. Patients with a past cancer history with substantial potential for recurrence 
must be discussed with the Medical Monitor before study entry. Patients with the 
following concomitant neoplastic diagnoses are eligible: non-melanoma skin cancer, 
carcinoma in situ (including transitional cell carcinoma, cervical intraepithelial neoplasia, 
and melanoma in situ), organ-confined prostate cancer with no evidence of progressive 
disease. 
6. Clinically significant cardiovascular disease: e.g., uncontrolled or any New York Heart 
Association Class 3 or 4 congestive heart failure, uncontrolled angina, history of 
myocardial infarction, unstable angina, or stroke within 6 months prior to study entry, 
uncontrolled hypertension (defined as SBP>160 or DBP>90), or clinically significant 
arrhythmias not controlled by medication. 

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7. Known active or suspected brain or leptomeningeal metastases. CNS imaging is not 
required prior to study entry unless there is a clinical suspicion of CNS involvement.  
8. Uncontrolled intercurrent illness including, but not limited to, uncontrolled infection, 
disseminated intravascular coagulation, or psychiatric illness/social situations that would 
limit compliance with study requirements. 
9. Pregnant or breast feeding. 
10. Evidence of muscular dystrophies or ongoing muscle pathology.   
11. Oxygen-support requirements. 
12. QTc > 470 msec. 
13. Physical abnormality or medical condition that limits swallowing multiple pills or has a 
history of non-adherence to oral therapies. 
14. A GI condition that may significantly alter absorption. 
15. Clinically significant ascites (i.e., requiring paracentesis within the preceding 28 days or 
treatment with pain medication). 
16. Any medical condition which, in the opinion of the Investigator, places the patient at an 
unacceptably high risk for toxicities. 
17. Known DPD deficiency or is on treatment with DPD inhibitors, including sorivudine or 
its chemically related analogues such as brivudine, within 4 weeks prior to the start of 
FOLFIRI treatment. 
18. Requires treatment with strong CYP3A4 inhibitors or strong UGT1A1 inhibitors. 
19. Previously received FOLFIRI or other irinotecan containing treatment regimens. 
20. Marked proteinuria (≥ 2 g/24 hours) and/or nephrotic syndrome. Patients with a 
proteinuria 2+ or greater urine dipstick reading should undergo further assessment, e.g., a 
24-hour urine collection. 
21. History of acute or subacute intestinal occlusion, unless such an event occurred only 
around the time of initial diagnosis or development of metastatic disease, or from chronic 
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22. Severe, non-healing wounds, ulcers, or bone fractures. 
23. History of hemodynamically significant pulmonary embolism within 6 months prior to 
inclusion in the study. 
24. History of hemorrhagic diathesis or tendency towards thrombosis that is not optimally 
managed, with the exception of tumor bleeding before tumor resection surgery. 
5.3 Lifestyle Considerations 
There are no lifestyle restrictions for the patients in this study. 
5.4 Screen Failures 
A screen failure occurs when a participant who has consented to participate in the clinical study 
is not subsequently assigned to Study Drug in the study.  
Individuals who do not meet the criteria for participation in this study may be rescreened. 
Rescreened participants should be assigned a new screening number if they are being rescreened 
after the initial 28-day screening period. Specific screening tests, e.g., safety labs, may be 
repeated within the initial screening period without the need for a new screening number.   
5.4.1 
Screening and Enrollment Log and Participant Identification Numbers 
The participant’s screening and randomization numbers will be obtained from Medidata 
Interactive Response Technology (IRT) and recorded in the Screening and Enrollment Log. 
Upon randomization, each participant will receive a unique participant identification number. 
Participant numbers must not be re-used for different participants. 
5.5 Criteria for Temporarily Delaying Administration of Study Drug 
Study Drug may be interrupted due to treatment-related toxicity for > 1 cycle (i.e., > 28 days). In 
cases of interruptions for reasons other than AEs and/or in the setting of sustained disease 
control, delays > 28 days may be acceptable and are to be discussed with the Medical Monitor. 

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For additional information on Study Drug handling including dispensing directions refer to the 
ompenaclid Pharmacy Manual. 
6.3 Assignment to Study Intervention 
All participants will be centrally randomized using IRT. Each participant will be assigned a 
unique number (randomization number) that encodes the participant’s assignment to one of the 
2 arms of the study, according to the randomization schedule generated by the Study Statistician 
using a validated computer program.  
Study Drug will be administered/dispensed at the study visits as summarized in the SoA 
(Table 1-1). Unscheduled drug dispensation visits may be used as required to ensure adequate 
supply of Study Drug is available to patients throughout the study. 
6.4 Blinding 
Participants will be randomly assigned in a 1:1 ratio to receive ompenaclid or placebo (Study 
Drug). Investigators will remain blinded to each participant’s assigned Study Drug throughout 
the course of the study. To maintain this blind a matching placebo will be provided. 
In the event of a quality assurance audit, auditors will be allowed access to unblinded Study 
Drug records at the sites to verify that randomization/dispensing has been conducted accurately. 
Pharmacovigilance staff may unblind the intervention assignment for any participant with an 
SAE. If the SAE requires that an expedited regulatory report be sent to one or more regulatory 
agencies, a copy of the report, identifying the participant’s intervention assignment, may be sent 
to Investigators in accordance with local regulations and/or Sponsor policy. 
6.5 Study Drug Compliance 
Dosing diaries will be provided to the patients for the purpose of recording Study Drug self-
administration. The diaries along with unused Study Drug tablets will be returned to the study 
center at the start of subsequent cycles of therapy to assess compliance. Partially used bottles of 
returned Study Drug should not be re-dispensed to the participants. Un-opened bottles may be re-
dispensed. Dosing diaries will be filed in the patient’s source documents. 
6.6 Dose Modification 
If there is a loss or gain of body weight of ≥ 10% from baseline, or per institutional standard for 
managing significant weight fluctuations, doses of FOLFIRI and bevacizumab should be 
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6.6.1 
Dose Modifications for Study Drug 
In the setting of specific toxicities, Study Drug should not be administered on a given day (i.e., 
doses may be held). Doses held because of AEs should not be made up on subsequent days 
within or following a cycle. Missed doses should under no circumstances be made-up on a day 
when the patient is already taking a planned dose (i.e., no “doubling-up” to account for missed 
doses). If a patient forgets to take a dose at the specified dosing time it may be taken up to 
2 hours later. However, if the delay is > 2 hours the dose should be skipped for that day. 
Additionally, if a patient vomits after taking a dose, the dose should not be re-administered. 
Dosing should continue the next day per the original schedule. 
If Study Drug treatment is interrupted or discontinued at any time, administration of FOLFIRI 
and bevacizumab may continue unless toxicities specific to FOLFIRI and/or bevacizumab have 
also been experienced, in which case FOLFIRI and/or bevacizumab should also be interrupted or 
discontinued. If the Study Drug dose is modified, administration of FOLFIRI and bevacizumab 
may continue at the original dose unless toxicities specific to FOLFIRI and/or bevacizumab have 
also been experienced.  If the dose of FOLFIRI treatment is modified, administration of Study 
Drug and bevacizumab may continue at the original dose unless toxicities specific to ompenaclid 
and/or bevacizumab have also been experienced. Likewise, if the dose of bevacizumab treatment 
is modified, administration of Study Drug and FOLFIRI may continue at the original dose unless 
toxicities specific to Study Drug and FOLFIRI have also been experienced. 
Dose modifications for Study Drug-related toxicities are summarized in Table 6-2. 
Table 6-2 
Dose Modifications for Study Drug-Related Toxicities 
CTCAE Grade 
Dose Adjustment 
Grade 1-2 
No dose adjustment for subsequent cycles; provide supportive 
measures per institutional or European Society for Medical 
Oncology guidelines 
Grade ≥3 
Hold dosing for up to 4 weeks until resolution to Grade ≤ 1 and 
resume Study Drug therapy at 2400 mg BID. 
If another Grade > 3 event occurs, then hold dosing for up to 
4 weeks until resolution to Grade ≤ 1 and resume Study Drug 
therapy at 1800 mg BID.  
If another > Grade 3 event occurs, permanently discontinue 
Study Drug. 
 
Adjustments of study drug doses lower than 2400 mg BID should not be made without approval 
of the Medical Monitor. Dose modifications above this threshold do not require approval by, but 
do require notification of, the Medical Monitor. 

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6.6.2 
Dose Modifications of FOLFIRI for Treatment Related Toxicity 
Dose modifications for FOLFIRI-related toxicity are summarized in Table 6-3. Patients should 
return to pre-treatment bowel function without requiring antidiarrhea medications for at least 
24 hours before the next chemotherapy administration. A new cycle of therapy should not begin 
until the ANC has recovered to ≥ 1.5 × 109/L, and the platelet count has recovered to 
≥ 100 ×109/L, and treatment-related diarrhea is fully resolved. If the investigator wishes to wait 
for the ANC to be to ≥ 1.5 × 109/L in mid cycle treatment that would be acceptable. Treatment 
should be delayed 1 to 2 weeks to allow for recovery from treatment-related toxicities. If the 
patient has not recovered after a 2-week delay, consideration should be given to optimizing 
supportive care (i.e., growth factor support, additional anti emetic, anti-diarrheal agents etc.). If 
the investigator considers holding a component of the SOC chemotherapy (i.e., irinotecan) the 
patient may stay in the study as long as they continue to take the Study Drug. 
Table 6-3 
Dose Modifications for FOLFIRI-Related Toxicity 
Toxicity NCI CTC  
Grade (Value) 
Dose Adjustment During a Cycle of Therapy 
Dose Adjustment at the Start of 
Subsequent Cycles of Therapy 
Neutropenia 
Grade 1 (1.5 to 
1.999 x 109/L) 
Maintain dose level 
Maintain dose level 
Grade 2 (1.0 to 
1.499 x 109/L) 
↓ 1 dose level 
Maintain dose level 
Grade 3 (0.5 to 
0.999 x 109/L) 
Omit dose until resolved to ≤ Grade 2, then ↓ 1 dose level ↓ 1 dose level 
Grade 4 (< 0.5 x 
109/L) 
Omit dose until resolved to ≤ Grade 2, then ↓ 2 dose levels ↓ 2 dose levels 
Neutropenic fever 
Omit dose until resolved, then ↓ 2 dose levels 
Other hematologic 
toxicities 
Dose modifications for leukopenia or thrombocytopenia during a cycle of therapy and at the 
start of subsequent cycles of therapy are also based on NCI toxicity criteria and are the same 
as for neutropenia above. 
Diarrhea 
Grade 1 (2–3 
stools/day > pretx)  
Delay dose until resolved to baseline, then give same dose Maintain dose level 
Grade 2 (4–6 
stools/day > pretx) 
Omit dose until resolved to baseline, then ↓ 1 dose level 
Maintain dose level 
Grade 3 (7–9 
stools/day > pretx) 
Omit dose until resolved to baseline, then ↓ 1 dose level 
↓ 1 dose level 
Grade 4 (≥10 
stools/day > pretx) 
Omit dose until resolved to baseline, then ↓ 2 dose levels ↓ 2 dose levels 
Other 
nonhematologic 
toxicities 

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Toxicity NCI CTC  
Grade (Value) 
Dose Adjustment During a Cycle of Therapy 
Dose Adjustment at the Start of 
Subsequent Cycles of Therapy 
Grade 1 
Maintain dose level 
Maintain dose level 
Grade 2 
Omit dose until resolved to ≤ grade 1, then ↓ 1 dose level Maintain dose level 
Grade 3 
Omit dose until resolved to ≤ grade 2, then ↓ 1 dose level ↓ 1 dose level 
Grade 4 
Omit dose until resolved to ≤ grade 2, then ↓ 2 dose levels ↓ 2 dose levels 
For mucositis/stomatitis decrease only 5-FU, not 
irinotecan 
For mucositis/stomatitis decrease 
only 5-FU, not irinotecan. 
Dose levels of the components of FOLFIRI as a consequence of FOLFIRI-related toxicity are 
summarized in Table 6-4. 
Table 6-4 
FOLFIRI Component Dose Levels 
Drug 
Starting Dose 
mg/m2 
Dose Level -1 
mg/m2 
Dose Level -2 
mg/m2 
Irinotecan 
180 
150 
120 
Leucovorin Infusion 
400 
No change 
No change 
5-FU Infusion 
2400 
2000 
1600 
 
6.6.3 
Dose Modifications of Bevacizumab for Treatment Related Toxicity 
Dose modifications for bevacizumab-related toxicity are summarized in Table 6-5. 
Table 6-5 
Dose Modifications for Bevacizumab-Related Toxicity 
Adverse Reaction 
Severity 
Dosage Modification 
Gastrointestinal Perforations 
and Fistulae  
• 
Gastrointestinal perforation, any grade  
• 
Tracheoesophageal fistula, any grade  
• 
Fistula, Grade 4  
• 
Fistula formation involving any internal 
organ  
Discontinue Bevacizumab 
Wound Healing 
Complications  
• 
Wound healing complications requiring 
medical intervention  
• 
Necrotizing fasciitis  
Discontinue Bevacizumab 
Hemorrhage  
• 
Grade 3 or 4  
Discontinue Bevacizumab 
• 
Recent history of hemoptysis of ½ 
teaspoon (2.5 mL) or more  
Withhold Bevacizumab 
 
Thromboembolic Events  
• 
Arterial thromboembolism, severe  
Discontinue Bevacizumab 
• 
Venous thromboembolism, Grade 4  
Discontinue Bevacizumab 
Hypertension  
• 
Hypertensive crisis  
• 
Hypertensive encephalopathy  
Discontinue Bevacizumab 

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Adverse Reaction 
Severity 
Dosage Modification 
• 
Hypertension, severe 
Withhold Bevacizumab if not 
controlled with medical management; 
resume once controlled  
Posterior Reversible 
Encephalopathy Syndrome 
(PRES)  
• 
Any  
Discontinue Bevacizumab 
Renal Injury and Proteinuria  
• 
Nephrotic syndrome  
Discontinue Bevacizumab 
• 
Proteinuria greater than or equal to 2 
grams per 24 hours in absence of 
nephrotic syndrome  
Withhold Bevacizumab until 
proteinuria less than 2 grams per 24 
hours  
Infusion-Related Reactions  
• 
Severe  
Discontinue Bevacizumab 
• 
Clinically significant  
Interrupt infusion; resume at a 
decreased rate of infusion after 
symptoms resolve  
• 
Mild, clinically insignificant  
Decrease infusion rate  
Congestive Heart Failure  
• 
Any 
Discontinue Bevacizumab 
 
6.7 Continued Access to Study Drug After the End of the Study 
There is no planned intervention after the end of study as patients will continue treatment until 
PD. 
6.8 Treatment of Overdose 
For this study, any dose of Study Drug greater than 3000 mg BID within a 24-hour time period 
will be considered an overdose. 
In the event of an overdose, the Investigator should: 
• Evaluate the participant to determine, in consultation with the Medical Monitor, if 
possible, whether Study Drug should be interrupted or whether the dose should be 
reduced. 
• Closely monitor the participant for any AE/SAE and laboratory abnormalities as medically 
appropriate and at least until the next scheduled follow-up. 
• Document the quantity of the excess dose as well as the duration of the overdose. 
• Signs and symptoms of an overdose should be reported as AEs. Overdoses will not be 
considered SAEs unless the outcome of the overdose meets seriousness criteria (see 
Section 10.3.2). 

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6.9 Prior and Concomitant Therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, recreational 
drugs, vitamins, herbal supplements, other non-traditional medicines) must be recorded along 
with: 
• reason for use 
• dates of administration including start and end dates 
• dosage information including dose and frequency 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
Prior and Concomitant Medications Review 
The Investigator or qualified designee will review prior medication use and record prior 
medications taken by the participant within 1 month prior to screening. 
The Investigator or qualified designee will record medication, if any, taken by the participant 
during the study through the last visit. Concomitant medications will be recorded for 30 days 
after the last dose of Study Drug (or longer if related to an SAE). 
7 Discontinuation of Study Drug and Participant Discontinuation 
Discontinuation of specific sites or of the study as a whole are handled as part of the appendix on 
Governance, Appendix 1, Section 10.1.8. 
7.1 Discontinuation of Study Drug 
It may be necessary for a participant to permanently discontinue Study Drug. See the SoA 
(Table 1-1) for data to be collected at the time of discontinuation of Study Drug (EOT Visit) and 
follow-up and for any further evaluations that need to be completed for patients continuing in the 
follow-up portion of the study. 
Study Drug may be discontinued for any of the following reasons: 
• Radiographic progression of disease typically precludes further Study Drug as this 
will be considered a PD event. 
o After consultation with the Medical Monitor, Study Drug may be continued for a 
patient who has met the criteria for PD, but in the Investigator’s opinion presents 

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additional evidence of disease control or symptomatic improvement. In this case, 
the patient must meet the following criteria: 
 Absence of symptoms and signs indicating clinically significant 
progression of disease. 
 No decline in ECOG or Karnofsky performance status. 
 Absence of symptomatic rapid disease progression requiring urgent 
medical intervention (i.e., symptomatic pleural effusion, spinal cord 
compression). 
o Patients who meet the aforementioned criteria may continue to receive study 
therapy until subsequent scans show unequivocal progression by RECIST criteria. 
• Occurrence of an unacceptable AE, or clinical deterioration that interferes with 
activities of daily living. 
• Pregnancy. 
• Study Drug interruption due to treatment-related toxicity for > 1 cycle (i.e., > 28 
days). Interruptions for reasons other than AEs and/or in the setting of sustained 
disease control, delays > 28 days may be acceptable and are to be discussed with the 
Medical Monitor. 
• Patient requires use of a prohibited concomitant medication or therapy. 
• General or specific changes in the patient’s condition unacceptable for further 
treatment within the study parameters, in the judgment of the Investigator: 
- Non-compliance 
- Lost to follow-up 
- Patient withdrawal of consent 
- Sponsor request 
All study procedures outlined for the EOT visit are to be completed within 21 days of the last 
Study Drug dose. In the event a patient is unable to return to the clinic for EOT assessments due 
to death, hospitalization, or admittance to hospice care, results from outside assessments may be 
entered in EDC or the visit may be marked not done. The primary reason for Study Drug 
discontinuation is to be recorded in the electronic case report form (eCRF). 

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7.1.1 
Temporary Discontinuation 
See Section 6.6, Dose Modification, for discussion of Study Drug modifications that may lead to 
stopping and re-starting Study Drug treatment. FOLFIRI and bevacizumab treatment will 
continue in cases where intolerance is limited to the Study Drug. 
7.2 Participant Discontinuation/Withdrawal from the Study 
A patient may withdraw from the study at any time at the patient’s own request or for any reason 
(or without providing any reason). A patient may be withdrawn at any time at the discretion of 
the Investigator for safety or compliance reasons. The patient will be permanently discontinued 
from the Study Drug and the study at that time. 
If the patient withdraws consent for disclosure of future information, the Sponsor may retain and 
continue to use any data and samples collected before such a withdrawal of consent. 
If a patient withdraws from the study, the patient may request destruction of any samples taken 
and not tested, and the Investigator must document this in the site study records. 
7.3 Lost to Follow-Up 
A patient will be considered lost to follow-up if they repeatedly fail to return for scheduled visits 
and are unable to be contacted by the study site. 
The following actions must be taken if a patient fails to return to the clinic for a required study 
visit: 
• The site must attempt to contact the patient and reschedule the missed visit as soon as 
possible (and within the visit window, where one is defined), counsel the patient on the 
importance of maintaining the assigned visit schedule and ascertain whether the patient 
wishes to and/or should continue in the study. 
• In cases in which the patient is deemed lost to follow-up, the Investigator or designee must 
make every effort to regain contact with the patient. Contact attempts should be 
documented in the patient’s medical record/eCRF. 
• Where possible, contact attempts will include 3 telephone calls and, if necessary, a 
certified letter to the patient’s last known mailing address or local equivalent methods. 
• Should the patient continue to be unreachable, the patient will be considered to have 
withdrawn from the study. 

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• Site personnel, or an independent third party, will attempt to collect the vital status of the 
patient within legal and ethical boundaries for all patients randomized. Reports from 
immediate family members and public sources may be searched for vital status 
information. If vital status is determined as deceased, this will be documented, and the 
participant will not be considered lost to follow-up. Sponsor personnel will not be 
involved in any attempts to collect vital status information. 
8 Study Assessments and Procedures 
Study procedures and their timing are summarized in the SoA (Table 1-1). Protocol waivers or 
exemptions are not allowed. 
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct. 
All screening evaluations must be completed and reviewed to confirm that potential participating 
patients meet all eligibility criteria. The Investigator will maintain a screening log to record 
details of all patients screened and to confirm eligibility or record reasons for screening failure, 
as applicable. 
Procedures conducted as part of the patient’s routine clinical management (e.g., blood count) and 
obtained before signing of the informed consent form (ICF) may be used for screening or 
baseline purposes provided the procedures met the protocol-specified criteria and were 
performed within the timeframe defined in the SoA. 
In the event of a significant study-continuity issue (e.g., caused by a pandemic), alternate 
strategies for patient visits, assessments, medication distribution, and monitoring may be 
implemented by the Sponsor or the Investigator, as per local health authority/ethics requirements. 
The maximum amount of blood collected from each patient over the duration of the study, 
including any extra assessments that may be required, will not exceed 18 mL per cycle 
(additional samples collected at Screening and in Cycles 1 and 2 for PK). The approximate blood 
volumes to be collected during the study are described in Table 8-1. 
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples. 

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8.1 Administrative and Baseline Procedures 
Medical History and Cancer History 
A medical history will be obtained by the Investigator or qualified designee. The medical history 
will collect all active conditions and any condition diagnosed within at least the prior 2 years that 
the Investigator considers to be clinically relevant. Details regarding the disease for which the 
participant has enrolled in this study will be recorded separately and not listed as medical history. 
The medical history is to include cancer history, including the patient’s primary tumor type, 
mutation/amplification statuses (e.g., RAS, BRAF, PDL-1, HER2 and other mutations), current 
disease stage, date of and disease stage at diagnosis, and all previous treatments, including 
systemic therapy, radiation therapy, and surgeries, as well as relevant documentation regarding 
radiological and/or clinical response to such treatment. 
Left Ventricular Ejection Fraction 
Left ventricular ejection fraction will be obtained using either ECHO or MUGA during 
Screening. 
8.2 Efficacy Assessments 
Planned timepoints for all efficacy assessments are provided in the SoA (Table 1-1). 
8.2.1 
General Considerations 
Imaging of the chest, abdomen, pelvis, and other anatomic areas relevant to the patient’s disease 
is required within 28 days prior to the first administration of Study Drug. CT or MRI are 
acceptable. Patients with skin, subcutaneous or lymph node metastases may also have tumor 
evaluations (including measurements, with a ruler) by means of physical examination. During 
Screening, patients must have disease that is measurable by standard imaging techniques, per 
RECIST version 1.1. For patients with prior radiation therapy, measurable lesions must be 
outside of any prior radiation field(s), unless disease progression has been documented at that 
disease site subsequent to radiation. 
Imaging at subsequent time points must include the chest, abdomen, and other anatomic areas 
relevant to the patient’s disease. In selected situations, combination of CT/MRI is acceptable 
(i.e., CT of chest, MRI of abdomen). It is strongly recommended that the same imaging 
modalities for each anatomic component be continued throughout the duration of the study. 
Imaging of extremities is also permitted and is required if significant metastases are present and 
are optimally evaluated via CT/MRI of an extremity.  

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Tumor measurements and disease response assessments also are to be performed approximately 
8 weeks (+/- 5 business days) after randomization, and then approximately every 8 weeks (+/- 5 
business days) thereafter until development of PD. Tumor measurements and disease response 
assessments are also to be performed at the EOT visit unless radiographic PD was previously 
documented.  
Anatomical measurements (summed across target lesions) will be documented. When possible, 
the same qualified physician will interpret results to reduce variability. Radiographic images will 
be maintained at the study center, and Investigator’s findings will be filed in the patient’s source 
documents. Additionally, all CT/MRI scans will be sent by the study center to an independent 
central imaging vendor for quality control review and possible central reading at a later date. 
8.2.2 
Evaluation of Antitumor Response 
Evaluation of antitumor response will be by RECIST version 1.1 (Eisenhauer 2009). The 
procedures are outlined below. 
Measurable 
Tumor lesions must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of:  
• 5 mm by CT scan (CT scan slice thickness no greater than 5 mm) 
• 10 mm caliper measurement by clinical exam (lesions that cannot be accurately measured 
with calipers should be recorded as non-measurable) 
Malignant lymph nodes must be ≥ 15 mm in the short axis when assessed by CT scan (CT scan 
slice thickness recommended to be no greater than 5 mm). At baseline and in follow-up, only the 
short axis will be measured and followed.  
Non-measurable 
Non-measurable lesions are 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 
or pericardial effusion, lymphangitic involvement of skin or lung, and abdominal 
masses/abdominal organomegaly identified by physical exam that is not measurable by 
reproducible imaging techniques.  
Special considerations regarding lesion measurability:  

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• Bone lesions: Bone scan, PET scan or plain films are not considered adequate imaging 
techniques to measure bone lesions. However, these techniques can be used to confirm 
the presence or disappearance of bone lesions. Lytic bone lesions or mixed lytic-blastic 
lesions with identifiable soft tissue components, that can be evaluated by cross sectional 
imaging techniques such as CT or MRI can be considered as measurable lesions if the 
soft tissue component meets the definition of measurability described above. Blastic 
bone lesions are non-measurable.   
• Cystic lesions: Lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-measurable) 
since they are, by definition, simple cysts. ‘Cystic lesions’ thought to represent cystic 
metastases can be considered as measurable lesions, if they meet the definition of 
measurability described above. However, if non-cystic lesions are present in the same 
patient, these are preferred for selection as target lesions.   
• Lesions with prior local treatment: Tumor lesions situated in a previously irradiated area, 
or in an area subjected to other loco-regional therapy, are usually not considered 
measurable unless there has been demonstrated progression in the lesion.  
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. Imaging-based evaluation should 
always be done rather than clinical examination unless the lesion(s) being followed cannot be 
imaged but is assessable by clinical exam.  
To assess objective response or future progression, it is necessary to estimate the overall tumor 
burden at baseline and use this as a comparator for subsequent measurements. Measurable 
disease is defined by the presence of at least one measurable lesion. When more than 
1 measurable lesion is present at baseline all lesions up to a maximum of 5 lesions total (and a 
maximum of 2 lesions per organ) representative of all involved organs should be identified as 
target lesions and will be recorded and measured at baseline (this means in instances where 
patients have only 1 or 2 organ sites involved a maximum of 2 and 4 lesions, respectively, will 
be recorded).  
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements.   
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 

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included in the sum, only the short axis is added into the sum. The baseline sum diameters will 
be used as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease.  
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline. Measurements are not required, and 
these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal 
progression.’  
Overall response is derived from time-point response assessments (based on tumor burden) as 
follows: 
• CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or 
non-target) must have reduction in short axis to < 10 mm.  
• PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference 
the baseline sum diameters.  
• PD: At least a 20% increase in the sum of diameters of target lesions, taking as reference 
the smallest sum on study (this includes the baseline sum if that is the smallest on study). 
In addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm. (Note: the appearance of one or more new lesions is also 
considered progression).  
• SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for 
PD, taking as reference the smallest sum diameters while on study.  
Details for derivation of overall response are summarized in Table 8-2. 
Table 8-2 
Derivation of Overall Response 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all e valuated 
No 
PR 
SD 
Non-PD or not all e valuated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or no 
PD 
Any 
PD 
Yes or no 
PD 
Any 
Any 
Yes 
PD 
CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease; NE 
= not evaluable 

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8.3 Safety Assessments 
Planned timepoints for all safety assessments are provided in the SoA (Table 1-1). Safety 
assessments may be performed up to 3 business days prior to the scheduled day. 
8.3.1 
Height and Weight 
Height will be measured and recorded at screening only. Body weight will be measured, 
documented in the source documents, and transcribed to the eCRF during screening and on 
Day 1 and Day 15 of each cycle. Except for Cycle 1 Day 1, this assessment may be performed up 
to 3 business days prior to the scheduled day. 
8.3.2 
Physical Examinations 
A complete physical examination is to be performed during screening and on Day 1 and Day 15 
of each cycle. Except for Cycle 1 Day 1, these assessments may be performed up to 3 business 
days prior to the scheduled day. Physical examinations are to be conducted by a physician or 
qualified health professional listed on the delegation log and licensed to perform physical 
examinations. The complete physical examination is to include assessment of the following: 
• General appearance 
• Head, eyes, ears, nose, and throat 
• Heart and lungs 
• Gastrointestinal system (abdomen) 
• Musculoskeletal system 
• Skin 
• Nervous system, includes questions regarding whether the patient is experiencing any 
numbness and/or pain as well as light touch, sharp touch (skin prick), and temperature, 
position (proprioception), and vibration sensation testing. Additional nervous assessments 
are to be performed as appropriate for the patient’s condition, at the Investigator’s 
discretion. 
It is preferred that all systems are examined; however, it is understood that some sites examine 
certain systems based on only clinical indication. Protocol violations will therefore not be 
incurred if certain systems are not examined. 
Abnormal physical examination findings that are considered by the Investigator to be clinically 
significant for a particular patient during Screening and before dosing of Study Drug on Cycle 1 
Day 1 are to be reported as part of the patient’s medical history. Abnormal, clinically significant 

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examination findings following initiation of dosing on Cycle 1 Day 1 are to be reported as an 
AE, if the finding represents a change from Baseline. 
Investigators should pay special attention to clinical signs related to previous serious illnesses. 
8.3.3 
Standard 12-lead Electrocardiograms 
Single 12-lead ECGs will be obtained as outlined in the SoA (Table 1-1) using an ECG machine 
that automatically calculates the heart rate and measures PR, QRS, QT, RR, and QTc intervals. 
The ECG results should be reviewed by the investigator or appropriately trained study staff. 
8.3.4 
Vital Signs 
Vital signs, including temperature, heart rate, respiration rate, and blood pressure, and weight are 
to be measured, documented in the source documents, and transcribed to the eCRF during 
screening and on Day 1 and Day 15 of each cycle. Except for Cycle 1 Day 1, these assessments 
may be performed up to 3 business days prior to the scheduled day. 
Temperature, pulse rate, respiratory rate, and blood pressure will be recorded (before blood 
collection for laboratory tests). 
Blood pressure and pulse measurements should be assessed in a consistent manner throughout 
the study. 
8.3.5 
Clinical Safety Laboratory Tests 
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and the SoA 
(Table 1-1) for the timing and frequency. 
The Investigator must review the laboratory results, document this review, and record any 
clinically significant changes occurring during the study as an AE. The laboratory results must 
be retained with source documents. 
Abnormal laboratory findings associated with the underlying disease are not considered 
clinically significant unless judged by the Investigator to be more severe than expected for the 
participant’s condition. 
• All protocol-required laboratory tests, as defined in Appendix 2, must be conducted in 
accordance with the laboratory manual and the SoA (Table 1-1). 
• Laboratory assessments will be performed at the laboratory affiliated with the study center. 

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• If laboratory values from laboratory tests not specified in the protocol and performed at the 
institution’s local laboratory result in the need for a change in participant management or are 
considered clinically relevant by the Investigator (e.g., are considered to be an SAE or an AE 
or require dose modification), then the results must be recorded in the source document. 
• Laboratory abnormalities that are considered by the Investigator to be clinically significant 
for a particular patient during Screening and before Study Drug administration are to be 
reported as part of the patient’s medical history and as an AE after initiation of Study Drug, 
where the finding represents a change from Baseline. 
8.3.6 
Pregnancy Testing 
• Serum or urine samples for beta-human chorionic gonadotropin pregnancy testing are to be 
collected from WOCBP during Screening, within 2 weeks before the first scheduled study 
therapy dose on Cycle 1 Day 1. Pregnancy testing is to be performed in closer proximity to 
Cycle 1 Day 1 as required by local/institutional regulations. 
• Screening pregnancy test results must be reviewed and determined to be negative before 
administration of the first study therapy dose on Cycle 1 Day 1. 
• Pregnancy testing is to be repeated during the study at any time pregnancy is suspected. 
• All WOCBP will also have a pregnancy test at the EOT visit.  
8.4 Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Safety 
Reporting 
The definitions of AEs and SAEs can be found in Appendix 3. 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE and remain responsible for following 
up all AEs considered related to the Study Drug or the study, or that caused the participant to 
discontinue the Study Drug (see Section 7). This includes events reported by the patient (or, 
when appropriate, by a caregiver, surrogate, or the patient’s legal representative). 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3. 
8.4.1 
Time Period and Frequency for Collecting AE and SAE Information 
All AEs and SAEs will be collected from the signing of the ICF until 30 days after the last dose 
of Study Drug as specified in the SoA (Table 1-1). 

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Any clinically significant medical conditions observed after a participant signs the ICF, e.g., 
during screening are to be assessed by the investigator and recorded as medical history if present 
prior to signing the ICF and unchanged. Any new or worsening conditions noted following the 
ICF signature date should be recorded as an AE. 
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours of awareness, 
as indicated in Appendix 3. The Investigator will submit any updated SAE data within 24 hours 
of it being available. 
Investigators are not obliged to actively seek information on AEs or SAEs after the conclusion of 
study participation. However, if the Investigator learns of any SAE, including a death, at any 
time after a participant has been discharged from the study, and the Investigator considers the 
event to be reasonably related to the Study Drug or study participation, the Investigator must 
promptly notify the Sponsor or designee. 
8.4.2 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and non-
leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrence. 
8.4.3 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts through the 30-day Safety follow-up visit. Where 
possible, SAEs will be followed until resolution, stabilization, until the event is otherwise 
explained, or the participant is lost to follow-up (as defined in Section 7.3). Further information 
on follow-up procedures is given in Appendix 3. 
8.4.4 
Regulatory Reporting Requirements for SAE 
Prompt notification (within 24 hours, see Appendix 3) by the Investigator to the Sponsor or 
designee of an SAE is essential so that legal obligations and ethical responsibilities towards the 
safety of participants and the safety of a Study Drug under clinical investigation are met. 
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a Study Drug under clinical investigation. The Sponsor 
will comply with country-specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Board (IRB)/ Independent Ethics Committee (IEC), 
and Investigators. 

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An Investigator who receives an Investigator Safety Report describing an SAE or other specific 
safety information (e.g., summary or listing of SAEs) from the Sponsor will review and then file 
it along with the IB or state other documents and will notify the IRB/IEC, if appropriate 
according to local requirements. 
All SAEs that occur during the study, and all SAEs occurring up to 30 days after receiving the 
last dose of Study Drug, whether considered to be associated with the Study Drug or not, must be 
reported within 24 hours to the Parexel Safety Contact using the numbers in the List of Study 
Personnel. 
Investigator safety reports must be prepared and submitted for suspected unexpected serious 
adverse reactions (SUSARs) according to local regulatory requirements and Sponsor policy. 
Submission of blinded periodic line listings to Investigators will also be performed according to 
local requirements. 
8.4.5 
Pregnancy 
Details of all pregnancies in female participants and partners of male participants will be 
collected after the start of Study Drug and until 30 days after the last Study Drug dose. 
If a pregnancy is reported, the Investigator will record pregnancy information on the appropriate 
form and submit it to the Sponsor within 24 hours. Inspirna Clinical Safety and/or its 
collaborating Clinical Research Organization (CRO) will then forward the Exposure In Utero 
form to the Investigator for completion.  
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be reported as an AE or SAE. 
The Investigator will follow the patient/ patient’s partner until completion of the pregnancy and 
must notify the Medical Monitor of the outcome within 5 days. The Investigator will provide this 
information as a follow-up to the initial report. 
Abnormal pregnancy outcomes (e.g., maternal serious complications, therapeutic abortion, 
spontaneous abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are 
considered to be SAEs and will be reported as such. 
The participant/pregnant partner will be followed to determine the outcome of the pregnancy. 
The Investigator will collect follow-up information on the participant/pregnant partner and the 
neonate, and the information will be forwarded to the Sponsor. 

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Any post-study pregnancy-related SAE considered reasonably related to the Study Drug by the 
Investigator will be reported to the Sponsor as described in Section 8.4.4. While the Investigator 
is not obligated to actively seek this information in former study participants/pregnant partners, 
he or she may learn of an SAE through spontaneous reporting. 
Any female participant who becomes pregnant while participating in the study will discontinue 
Study Drug and be withdrawn from the study. The patient should be referred to an 
obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and 
counseling. 
8.4.6 
Disease-related Events and/or Disease-related Outcomes Not 
Qualifying as AEs or SAEs 
The following disease-related events (DREs) are common in participants with metastatic CRC 
and can be serious/life-threatening: 
• Clinical and/or Radiographic Disease Progression  
Because these events are typically associated with the disease under study, they will not be 
reported according to the standard process for expedited reporting of AEs/SAEs even though the 
event may meet the definition of a SAE. These DREs will be monitored by the DMC. See 
Section10.1.4.1. 
NOTE: However, if the following condition applies, then the event must be recorded and 
reported as an AE/SAE (instead of a DRE): 
• The Investigator considers that there is a reasonable possibility that the event was related 
to Study Drug. 
8.5 Pharmacokinetics 
Collection of blood samples for plasma concentrations of ompenaclid will be performed prior to 
the morning dose of Study Drug on Day 15 of Cycles 1 and 2. 
Detailed instructions for collecting, processing, storing, and shipping the PK samples are 
provided in the Laboratory Manual. 
8.6 Pharmacodynamics 
There are no pharmacodynamics assessments performed in this study. 

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8.7 Genetics 
Genetics are not evaluated as an outcome in this study.  
8.8 Biomarkers 
Tumor tissue (a minimum of 5 and up to 15 unstained formalin-fixed paraffin-embedded slides, 
or formalin-fixed paraffin-embedded block) obtained from an archival tissue sample is requested 
to be submitted to the central lab as soon as feasible during the study. If both a primary tumor 
and metastatic biopsy are available, both may be submitted. The tumor tissue will be evaluated 
for CKB immunohistochemistry expression and may be evaluated for other non-genetic 
biomarkers (e.g., markers related to the phosphocreatine transport pathway). 
Tissue samples collected at the respective treatment sites will be immediately shipped to the 
designated laboratory for analysis. Where archival tissue blocks are submitted, the central lab 
will prepare slides as soon as possible and the remaining block will be returned to the study 
center. 
8.9 Immunogenicity Assessments 
No immunogenicity evaluations will be performed in this study. 
9 Statistical Considerations 
The statistical analysis plan (SAP) will be finalized prior to the first DMC review of the study 
data, and it will include a more technical and detailed description of the statistical analyses 
described in this section. This section is a summary of the planned statistical analyses of the most 
important endpoints including primary and key secondary endpoints. Exploratory analyses will 
be described in the SAP. 
9.1 Statistical Hypotheses 
Primary Objective 
The primary objective is to demonstrate that ompenaclid is superior to placebo in achieving CR 
or PR (determined as ORR). The null hypothesis is that there is no difference in ORR between 
ompenaclid and placebo, while the alternative hypothesis is that there is a difference in ORR 
between treatment groups, with ompenaclid having a higher ORR. This hypothesis will be tested 
using a stratified analysis of the difference of two proportions as described in Section 9.3.2.2. 
 
 

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Key Secondary Objective 
The key secondary objective is to demonstrate that ompenaclid is superior to placebo in PFS 
time. This hypothesis will be tested using a stratified log-rank test as described in 
Section 9.3.3.1. 
Additional Secondary Objectives 
The additional secondary objectives are to demonstrate that ompenaclid is superior to placebo for 
OS, DoR, and DCR. These hypotheses will be tested using a stratified analyses described in 
Sections 9.3.3.2, 9.3.3.3, and 9.3.3.4. 
9.1.1 
Multiplicity Adjustment 
Given that this is a Phase 2 proof-of-concept study, there will be no attempt to preserve the 
overall type 1 error rate. All statistical tests will be performed at a one-sided significance level of 
5%. 
9.2 Analysis Sets 
Efficacy analyses will be performed in the intention-to-treat (ITT) population, consisting of all 
randomized patients. Patients will be allocated to treatment groups as randomized, and not by 
actual Study Drug received. 
Safety analyses will be performed in the safety population, consisting of all randomized patients 
who received any quantity of Study Drug, with patients grouped by actual treatment received. 
9.3 Statistical Analyses 
9.3.1 
General Considerations 
Baseline is defined as the last measurement for a variable prior to the first dose of Study Drug. 
Missing data will not be imputed. All data collected on the eCRF will be listed. Routine data 
listing or tabulation review during the study conduct will be performed in a blinded fashion to 
identify missing data, anomalies, outliers, etc. 
A complete description of data handling rules and planned statistical analyses will be detailed in 
the SAP. The SAP will supersede the protocol in the event of any difference between the two 
documents in the plans for data analysis. 
Further details of the analyses described below, including censoring conventions for the analysis 
of time-to event outcomes (PFS, OS, and DoR), will be provided in the SAP. 

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9.3.2 
Primary Endpoint Analysis 
9.3.2.1 
Definition of Endpoint 
The primary efficacy endpoint of this study is ORR, defined as the proportion of patients 
achieving a best response of CR or PR per the investigators using RECIST version 1.1. 
9.3.2.2 
Main Analytical Approach 
Comparison of ORR between treatment groups will be by a one-sided Mantel-Haenszel (MH) 
test of the difference in two proportions stratified by the randomization stratification factor using 
a type I error rate of 5%. The estimated MH ORR difference will be summarized along with the 
two-sided 90% confidence interval using MH stratum weights and Sato variance estimator. 
9.3.3 
Secondary Endpoints Analysis 
9.3.3.1 
Progression-free Survival (Key Secondary Endpoint) 
The key secondary efficacy endpoint of this study is PFS, defined as the time from the date of 
randomization to the date of objectively determined PD per the investigators using RECIST 
version 1.1 or death from any cause, whichever occurs first. If a given patient is alive at the end 
of the follow-up period or is lost to follow-up without evidence of PD, PFS will be censored at 
the date of their last objective progression-free assessment. If no baseline or post-baseline 
radiologic assessment is available, the patient will be censored at the date of randomization. For 
patients who receive subsequent anticancer therapy prior to PD or death, PFS will be censored at 
the date of the last objective progression-free assessment prior to the date of subsequent therapy. 
Additional details regarding the definition of PFS will be provided in the SAP. 
Comparison of PFS between the treatment groups will be by a stratified log-rank test. A 
treatment hazard ratio (HR) and associated two-sided 90% confidence interval will be estimated 
from a stratified Cox proportional hazards model. The distributions of PFS for each treatment 
group will be estimated by Kaplan-Meier methods. The percentage of patients in each treatment 
group without a PFS event at selected landmarks after randomization (e.g., 24 weeks) based on 
Kaplan-Meier estimates will also be summarized. 
9.3.3.2 
Overall Survival 
OS is defined as the time from the date of randomization to the date of death from any cause. If a 
given patient is alive at the end of the follow-up period or is lost to follow-up, OS data will be 
censored on the last date the patient is known to be alive. Comparison of OS between treatment 
groups will follow the methods used for PFS. 

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9.3.3.3 
Duration of Response 
DoR is defined as the date of objectively determined PR or CR (whichever status is recorded 
first) to the date of objectively determined PD per the investigators using RECIST version 1.1 or 
death from any cause, whichever occurs first. Comparison of DoR between treatment groups will 
follow the methods used for PFS. 
9.3.3.4 
Disease Control Rate 
DCR is defined as the proportion of patients achieving a best response of CR, PR, or SD; SD 
must be documented at least 6 weeks after randomization. Comparison of DCR between 
treatment groups will follow the methods used for ORR. 
9.3.4 
Safety and Population Analyses 
All safety data will be summarized by treatment group. No inferential statistics will be 
performed for safety variables. Safety analyses in addition to those described in the following 
subsections may be determined at any time without prejudice, to clearly enumerate the rates of 
toxicities and to further define the safety profile of the Study Drug in combination with FOLFIRI 
+ bevacizumab. 
9.3.4.1 
Adverse Events 
AEs will be considered treatment-emergent (TEAE) if they start on or after the time of the first 
dose of Study Drug and up to 30 days after the last dose of Study Drug. AEs will be coded using 
MedDRA Version 26.0 (or higher) and summarized by System Organ Class (SOC) and preferred 
term (PT). The severity of AEs will be summarized by National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0 (or higher) grade. 
Non-treatment-emergent AEs will be included in the patient listings and flagged as such but will 
not be included in the summary tables. Adverse events with missing start and/or end dates and/or 
times will be handled as described in the SAP. Where an AE date is partial or missing, and it is 
unclear whether the AE is treatment-emergent, the AE will be assumed to be treatment-
emergent. 
The number and percentage of patients who experience TEAEs will be summarized overall by 
SOC and PT and will also be summarized based on severity and causality.  
Descriptive analysis of AEs will include incidence of TEAEs grouped by: 
• SOC and PT 
• SOC, PT, and severity 

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• SOC, PT, and causality 
• SOC and PT leading to discontinuation from the study  
• SOC and PT for events with CTCAE Grade ≥ 3 
• SOC and PT leading to death 
Individual listings of all AEs will also be provided. 
9.3.4.2 
Laboratory Parameters 
Laboratory results (hematology, serum chemistry, coagulation parameters and urinalysis) will be 
classified according to NCI-CTCAE, Version 5.0. Laboratory results not corresponding to an 
NCI-CTCAE term will not be graded. Laboratory data will be listed, and abnormal results will 
be flagged. Planned analyses of laboratory data will be described in the SAP. 
9.3.4.3 
Vital Signs 
Planned analyses of clinically significant changes in vital sign parameters (as defined in the 
SAP), including systolic and diastolic blood pressure, heart rate, and body weight will be 
described in the SAP. Any clinically significant abnormal values will be captured as AEs. Vital 
signs data will be listed. 
9.3.4.4 
ECOG Performance Status 
ECOG performance status will be summarized by cycle and worst status overall; ECOG 
performance status will be presented in data listing format. 
9.3.4.5 
Physical Examination 
The analysis of physical examination will focus on patients who develop abnormalities post-
baseline or whose evaluations worsen after Baseline. The results of abnormal physical 
examinations will be listed as adverse events. 
9.3.4.6 
Electrocardiograms 
The proportions of patients with treatment-emergent clinically significant ECG abnormalities (as 
defined in the SAP) will be tabulated, and changes in ECG findings will be presented in data 
listing format. Categorical analyses of QTc interval data will be performed per the SAP.  
9.3.5 
Steady State Pharmacokinetics Analysis 
The steady state pharmacokinetics of ompenaclid will be analyzed from the samples collected on 
Day 15 in Cycles 1 and 2. Concentration data will be summarized descriptively for each 
scheduled sampling time point. 

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9.3.6 
Population Data 
Disposition, including primary reason for withdrawal from the study, will be summarized by 
treatment group for the ITT population. Demographic information and patient characteristics 
including, but not limited to, sex, age, baseline ECOG performance score, prior therapies, and 
medical and cancer histories will also be summarized by treatment group for the ITT population.  
Medications will be coded using the World Health Organization Drug Dictionary and listed by 
subject. A summary of concomitant medications by treatment group and medication class will 
also be tabulated. 
Major Protocol deviations will be listed and summarized by treatment group and category. 
9.3.7 
Other Analyses 
Subgroup analyses of the primary and secondary endpoints may be made to assess consistency of 
the investigational intervention effect (ORR, PFS, OS, DoR, and DCR) across subgroups, for 
example:  
• Prior bevacizumab or EMA-approved biosimilar treatment (yes vs. no) 
• Sex 
• Time from initiation of first-line treatment to PD (< 6 months, 6 to 12 months, 
>12 months) 
Additional subgroups may be specified in the SAP. 
9.4 Interim Analysis 
The DMC will conduct unblinded interim safety analyses approximately every 6 months 
following randomization of the first patient. The DMC will also conduct unblinded interim 
efficacy analyses, the timing and scope of which will be outlined in the DMC charter.   
The DMC charter will describe the planned interim analyses in greater detail. 
9.5 Sample Size Determination 
The sample size calculation is based on a one-sided Z-test (unpooled variance) of the difference 
in two proportions for comparing ORR between the treatment groups, with the following 
assumptions: 
• ORR = 35% and 10% for the ompenaclid and placebo groups, respectively. 
• One-sided type 1 error = 5% 

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• Power ≥ 80% 
Under these assumptions, 70 patients will be randomized 1:1 into the treatment groups.  
Additional patients may be randomized into the study in order to ensure at least 40 disease 
progression events are observed for evaluation of the key secondary objective of the study. This 
number of events will provide ≥70% power to detect a HR of 0.50 with one-sided type 1 
error = 5%. 

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10 Supporting Documentation and Operational Considerations 
10.1 Appendix 1: Regulatory, Ethical, and Study Oversight Considerations 
10.1.1 Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with: 
• Consensus ethical principles derived from international guidelines including the Declaration 
of Helsinki and Council for International Organizations of Medical Sciences (CIOMS) 
international ethical guidelines. 
• Applicable International Council for Harmonisation (ICH) Good Clinical Practice (GCP) 
guidelines. 
• Applicable laws and regulations. 
The protocol, protocol amendments, ICF, Investigator’s Brochure, and other relevant documents 
(e.g., advertisements) must be submitted to an IRB/IEC by the Investigator and reviewed and 
approved by the IRB/IEC before the study is initiated. 
Any amendments to the protocol will require IEC/IRB approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. 
Protocols and any substantial amendments to the protocol will require health authority approval 
prior to initiation except for changes necessary to eliminate an immediate hazard to study 
participants. 
The Investigator will be responsible for the following, as applicable: 
• Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by the 
IRB/EC. 
• Notifying the IRB/IEC of SAE or other significant safety findings as required by IRB/IEC 
procedures. 
• Overall conduct of the study at the site and adherence to requirements of 21 CFR, ICH GCP 
guidelines, the IRB/IEC, European regulation 536/2014 for clinical studies, European 
Medical Device Regulation 2017/745 for clinical device research, and all other applicable 
local regulations. 

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10.1.2 Financial Disclosure 
The Investigators and subinvestigators are required to provide financial disclosure information to 
allow the Sponsor to submit the complete and accurate certification or disclosure statements 
required under 21 CFR 54. In addition, the Investigator and subinvestigators must provide to the 
Sponsor a commitment to update promptly this information if any relevant changes occur during 
the course of the investigation and for 1 year after the completion of the study. 
Neither the Sponsor nor the CRO is financially responsible for further testing/treatment of any 
medical condition, which may be detected during the screening process. In addition, in the 
absence of specific arrangements, neither the Sponsor nor the CRO is financially responsible for 
further treatment of the patient’s disease. 
10.1.3 Informed Consent Process 
The Investigator or the Investigator’s representative at each center will explain the nature of the 
study, including the risks and benefits, to the potential participant and answer all questions 
regarding the study. 
Potential participants must be informed that their participation is voluntary. The potential 
participant will be required to sign a statement of informed consent that meets the requirements 
of 21 CFR 50, local regulations, ICH guidelines, privacy, and data protection requirements, 
where applicable, and the IRB/IEC or study center. 
The medical record must include a statement that written informed consent was obtained before 
the patient was enrolled in the study and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF. 
Patients must be re-consented to the most current version of the ICF(s) during their participation 
in the study. 
A copy of the ICF(s) must be provided to the patient. 
If a protocol amendment is required, the ICF may need to be revised to reflect the changes to the 
protocol. If the ICF is revised, it must be reviewed and approved by the appropriate IEC/IRB and 
signed by all participants subsequently enrolled in the study as well as those currently enrolled in 
the study. 

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10.1.4 Data Protection 
Patients will be assigned a unique identifier by the Sponsor. Any patient records or datasets that 
are transferred to the Sponsor will contain the identifier only; patient names or any information 
which would make the patient identifiable will not be transferred. 
The patient must be informed that their personal study-related data will be used by the Sponsor 
in accordance with local data protection law. The level of disclosure must also be explained to 
the patient who will be required to give consent for their data to be used as described in the 
informed consent. 
The patient must be informed that their medical records may be examined by Clinical Quality 
Assurance auditors or other authorized personnel appointed by the Sponsor, by appropriate 
IRB/IEC members, and by inspectors from regulatory authorities. All patient personal data will 
be processed in accordance with the General Data Protection Regulatory (No 2016/679 from 
25May2018). 
The Sponsor will implement technical and organizational measures to ensure the security and 
privacy of any personal data that the Sponsor will collect, receive, process, disclose or store 
throughout the duration of the study, including the execution of Standard Contractual Clauses to 
ensure the valid transfer of personal data outside the EU.  Two other key components of the 
technical and organizational measures include a Privacy Breach Response Plan that will guide 
the identification, risk assessment, containment, notification and remediation of a breach. The 
second component to comply with Data Protection requirements includes the development of a 
Data Protection Impact Assessment that identifies the privacy risks, including security breaches, 
and the mitigations that will be implemented to manage these risks. 
10.1.4.1 Data Monitoring Committee 
Interim analyses of safety and efficacy will be monitored by the DMC, which will be governed 
by the DMC charter.  
10.1.5 Dissemination of Clinical Study Data 
A summary of the results of the clinical study together with a summary that is understandable to 
a layperson will be provided after the global end (or early termination) of the study in all 
countries concerned to ensure full availability of all clinical data under this protocol, within 
12 months. 
Within the EU, the Sponsor will submit independent Annual Safety Reports for all study 
interventions in this clinical study. 

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10.1.6 Data Quality Assurance 
All participant data relating to the study will be recorded on eCRFs unless transmitted to the 
Sponsor via a paper record, e.g., hard-copy SAE report. The Investigator is responsible for 
verifying that data entries are accurate and correct by electronically signing the CRF. 
Guidance on completion of CRFs will be provided in the electronic data capture system. 
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and Regulatory 
Agency inspections and provide direct access to source documents. 
Monitoring details describing strategies, including definition of study critical data items and 
processes (e.g., risk-based initiatives in operations and quality such as risk management and 
mitigation strategies and analytical risk-based monitoring), methods, responsibilities and 
requirements, including handling of noncompliance issues and monitoring techniques (central, 
remote, or on-site monitoring) are provided in the monitoring plan. 
The Sponsor or designee is responsible for the data management of this study including quality 
checking of the data. 
The Sponsor assumes accountability for actions delegated to other individuals (e.g., contract 
research organizations). 
The Investigator will retain the records of the study for 2 years following the last date that a 
marketing application for ompenaclid is approved in any ICH region, or if marketing approval is 
not obtained, for 2 years after the European Medicines Evaluation Agency (EMEA) application 
for ompenaclid has been closed in EMEA region or until there are no pending contemplated 
marketing applications in an ICH region. These documents should be retained for a longer 
period; however, if required by the application regulatory requirements or by an agreemnet with 
the Sponsor. The Sponsor will notify Investigators when study records retention is no longer 
required. No records may be destroyed during the retention period without the written approval 
of the Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor. 
All data generated by the site personnel will be captured electronically at each study center using 
eCRFs. Once the eCRF clinical data have been submitted to the central server at the independent 
data center, corrections to the data fields will be captured in an audit trail. The reason for change, 
the name of the person who performed the change, together with the time and date will be logged 
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If additional corrections are needed, the responsible monitor or data manager will raise a query in 
the electronic data capture (EDC) application. The appropriate staff at the study site will answer 
queries sent to the Investigator. The name of the staff member responding to the query, and time 
and date stamp will be captured to provide an audit trail. Once all source data verification is 
complete and all queries are closed, the monitor will freeze the eCRF page. 
The specific procedures to be used for data entry and query resolution using the EDC 
system/eCRF will be provided to study sites in a training manual. In addition, site personnel will 
receive training on the EDC system/eCRF. 
10.1.7 Source Documents 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site. 
Data reported in the eCRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained. The Investigator may need to 
request previous medical records or transfer records, depending on the study. Also, current 
medical records must be available. 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
The Sponsor or designee will perform monitoring to confirm that data entered into the eCRF by 
authorized site personnel are accurate, complete, and verifiable from source documents; that the 
safety and rights of participants are being protected; and that the study is being conducted in 
accordance with the currently approved protocol and any other study agreements, ICH GCP, and 
all applicable regulatory requirements. 
10.1.8 Study and Site Start and Closure 
First Act of Recruitment 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The first act of recruitment is the first participant signing first informed consent in line with first 
subject first visit and will be the study start date. 
 

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Study/Site Termination 
The Sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study site closure visit has been performed. 
The Investigator may initiate study site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include but are 
not limited to: 
For study termination: 
• Discontinuation of further Study Drug development. 
For site termination: 
• Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, the Sponsor's procedures, or GCP guidelines. 
• Inadequate or no recruitment (evaluated after a reasonable amount of time) of participants by 
the Investigator. 
• Total number of participants included earlier than expected. 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by the 
applicable regulatory requirements. The Investigator shall promptly inform the participant and 
should assure appropriate participant therapy and/or follow-up. 
10.1.9 Publication Policy 
The results of this multicenter study may be published or presented at scientific meetings by the 
Sponsor. Other publication policies will be described in each site’s Clinical Trial Agreement.   
The Sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating Investigator will be designated by the Sponsor. 

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10.1.10 Protocol Approval and Amendment 
Before the start of the study, the study protocol and/or other relevant documents will be approved 
by the IEC/IRB/Competent Authorities, in accordance with local legal requirements. The 
Sponsor must ensure that all ethical and legal requirements have been met before the first patient 
is enrolled in the study. 
This protocol is to be followed exactly. To alter the protocol, amendments must be written, 
receive approval from the appropriate personnel, and receive IRB/IEC/Competent Authority 
approval prior to implementation (if appropriate). In the US: Following approval, the protocol 
amendment(s) will be submitted to the IND under which the study is being conducted. 
Administrative changes (not affecting the patient benefit/risk ratio) may be made without the 
need for a formal amendment. All amendments will be distributed to all protocol recipients, with 
appropriate instructions. 
10.1.11 Liability and Insurance 
The Sponsor will take out reasonable third-party liability insurance cover in accordance with all 
legal requirements. The civil liability of the Investigator, the persons instructed by him or her 
and the hospital, practice, or institute in which they are employed and the liability of the Sponsor 
with respect to financial loss due to personal injury and other damage that may arise as a result of 
the carrying out of this study are governed by the applicable law. 
The Sponsor will arrange for patients participating in this study to be insured for personal injury 
caused by the Study Drug or by properly performed medical steps taken in the course of the 
study in accordance with the protocol. 
10.1.12 Access to Source Data 
During the study, a monitor will make site visits to review protocol compliance, compare eCRF 
entries and individual participant’s medical records, assess drug accountability, and ensure that 
the study is being conducted according to pertinent regulatory requirements. eCRF entries will be 
verified with source documentation. The review of medical records will be performed in a 
manner to ensure that participant confidentiality is maintained. 
Checking of the eCRF entries for completeness and clarity, and cross-checking with source 
documents, will be required to monitor the progress of the study. Moreover, regulatory 
authorities of certain countries, IRBs, IECs, and/or the Sponsor’s Clinical Quality Assurance 
Group may wish to carry out such source data checks and/or on-site audit inspections. Direct 
access to source data will be required for these inspections and audits; they will be carried out 

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giving due consideration to data protection and medical confidentiality. The Investigator assures 
the Sponsor, and Parexel if involved in monitoring/data management, of the necessary support at 
all times. 
 

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10.3 Appendix 3: AEs and SAEs: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting 
10.3.1 Definition of AE 
AE Definition 
An AE is any untoward medical occurrence in a patient or clinical study participant, temporally 
associated with the use of a study intervention, whether or not considered related to the study 
intervention. 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use 
of a study intervention. 
Events Meeting the AE Definition 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other 
safety assessments (e.g., ECG, radiological scans, vital signs measurements), including those that 
worsen from baseline, considered clinically significant in the medical and scientific judgment of 
the Investigator (e.g., not related to progression of underlying disease, or more severe than 
expected for the participant’s condition). 
Exacerbation of a chronic or intermittent pre-existing condition including either an increase in 
frequency and/or intensity of the condition. 
New condition detected or diagnosed after study intervention administration even though it may 
have been present before the start of the study. 
Signs, symptoms, or the clinical sequelae of a suspected intervention-intervention interaction. 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention or 
a concomitant medication. Overdose per se will not be reported as an AE/SAE unless it is an 
intentional overdose taken with possible suicidal/self-harming intent. Such overdoses should be 
reported regardless of sequelae. 
Lack of efficacy or failure of expected pharmacological action per se will not be reported as an 
AE or SAE. Such instances will be captured in the efficacy assessments. However, the signs, 
symptoms, and/or clinical sequelae resulting from lack of efficacy will be reported as AE or SAE 
if they fulfill the definition of an AE or SAE. 

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Events NOT Meeting the AE/SAE Definition 
Clinical Disease progression. Similarly, hospice admission or hospitalization for respite care 
related to disease progression are not to be reported as SAEs. 
Any abnormal laboratory findings or other abnormal safety assessments that are associated with 
the underlying disease. 
The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied. 
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that leads to the 
procedure is the AE. 
Situations in which an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital). 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected 
at the start of the study that do not worsen. 
10.3.2 Definition of SAE 
An SAE is an AE that: 
a. Results in death 
b. Is life-threatening 
The term life-threatening in the definition of serious refers to an event in which the participant 
was at risk of death at the time of the event. It does not refer to an event, which hypothetically 
might have caused death, if it were more severe. 
c. Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been admitted (usually involving at 
least an overnight stay) at the hospital or emergency ward for observation and/or intervention 
that would not have been appropriate in the physician’s office or outpatient setting. 
Complications that occur during hospitalization are AE. If a complication prolongs 
hospitalization or fulfills any other serious criteria, the event is serious. When in doubt as to 
whether hospitalization occurred or was necessary, the AE should be considered serious. 
Hospitalization for elective intervention of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 

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d. Results in persistent or significant disability/incapacity 
The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions. 
This definition is not intended to include experiences of relatively minor medical significance 
such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma 
(e.g., sprained ankle) that may interfere with or prevent everyday life functions but do not 
constitute a substantial disruption. 
e. Is a congenital anomaly/birth defect 
f. Other situations 
Medical or scientific judgment should be exercised by the Investigator in deciding whether SAE 
reporting is appropriate in other situations such as significant medical events that may jeopardize 
the participant or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These events should usually be considered serious. 
• Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse. 
10.3.3 Recording and Follow-up of AE and SAE 
AE and SAE Recording 
When an AE/SAE occurs, it is the responsibility of the Investigator to review all documentation 
(e.g., hospital progress notes, laboratory, and diagnostics reports) related to the event. 
The Investigator will then record all relevant AE/SAE information. 
It is not acceptable for the Investigator to send photocopies of the participant’s medical records 
to the safety team in lieu of completion of the required EDC or paper back-up SAE form. 
There may be instances when copies of medical records for certain cases are requested by the 
safety team. In this case, all participant identifiers, with the exception of the participant number, 
will be blinded on the copies of the medical records before submission to the Sponsor safety 
team. 
The Investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. In such cases, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE/SAE. 

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Assessment of Intensity 
The Investigator will make an assessment of intensity (Grade) for each AE and SAE reported 
during the study according to NCI CTCAE Criteria v5.0.   
For events with no corresponding CTCAE Criteria intensity should be assigned it to one of the 
following categories: 
Grade 1 (Mild): An event that is easily tolerated by the participant, causing minimal discomfort, 
and not interfering with everyday activities. 
Grade 2 (Moderate): An event that causes sufficient discomfort to interfere with normal 
everyday activities. 
Grade 3 (Severe): An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category used for rating the intensity of 
an event; and both AE and SAE can be assessed as severe. 
An event is defined as ‘serious’ when it meets at least one of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe. 
Grade 4 (Life-threatening):  An event in which the participant was at risk of death at the time of 
the event. It does not refer to an event, which hypothetically might have caused death, if it were 
more severe. 
Grade 5 (Death) 
Assessment of Causality 
The Investigator is obligated to assess the relationship between study intervention and each 
occurrence of each AE/SAE. The Investigator will use clinical judgment to determine the 
relationship. 
A reasonable possibility of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than that a relationship simply cannot be ruled 
out. 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, as 
well as the temporal relationship of the event to study intervention administration will be 
considered and investigated. 

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The Investigator will also consult the Investigator’s Brochure and/or Product Information, for 
marketed products, in their assessment. 
For each AE/SAE, the Investigator must document in the medical notes that he/she has reviewed 
the AE/SAE and has provided an assessment of causality. 
There may be situations in which an SAE has occurred, and the Investigator has minimal 
information to include in the initial report in the electronic data collection tool. However, it is 
very important that the Investigator always make an assessment of causality for every 
event before the initial transmission of the SAE data to the electronic data collection tool. 
The Investigator may change their opinion of causality in light of follow-up information and 
send an SAE follow-up report with the updated causality assessment. 
The following “binary” decision choice will be used by the Investigator to describe the initial 
causality assessment: 
• Related: Reasonable possibility of a relatedness 
• Not related: No reasonable possibility of relatedness. 
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
Follow-up of AE and SAE 
The Investigator may be requested by the Sponsor to perform or arrange for the conduct of 
supplemental measurements and/or evaluations as medically indicated to elucidate the nature 
and/or causality of the AE or SAE as fully as possible. This may include additional laboratory 
tests or investigations, histopathological examinations, or consultation with other health care 
professionals. 
New or updated information will be recorded in the originally completed form. 
The Investigator will submit any updated SAE data to the Sponsor within 24 hours of receipt of 
the information. 
10.3.4 Reporting of SAE 
SAE Reporting via Electronic Data Collection Tool 
The primary mechanism for reporting an SAE will be the electronic data collection tool. 

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If the electronic system is unavailable, then the site will use the paper SAE data collection tool 
(see next table) to report the event within 24 hours of awareness. 
The site will enter the SAE data into the electronic system as soon as it becomes available. 
The Investigator and the Sponsor (or Sponsor’s designated agent) will review each SAE report 
and the Sponsor/Parexel will evaluate the seriousness and the causal relationship of the event to 
study intervention. In addition, the Sponsor (or Sponsor’s designated agent) will evaluate the 
expectedness according to the Reference Safety Information (Investigator Brochure or Summary 
of Product Characteristics). Based on the Investigator and Sponsor’s assessment of the event, a 
decision will be made concerning the need for further action. 
After the study is completed at a given site, the electronic data collection tool will be taken 
offline to prevent the entry of new data or changes to existing data. 
If a site receives a report of a new SAE from a study participant or receives updated data on a 
previously reported SAE after the electronic data collection tool has been taken offline, then the 
site can report this information on a paper SAE form (see next table). 
Contacts for SAE reporting can be found below. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) 
SUSAR reporting will be in adherence to requirements of EU pharmacovigilance legislation, 
Clinical Trial Regulation (CTR) legislation and guidance. EU CTR 536/2014; CT-3 and all other 
applicable local regulations. 
Serious Adverse Events Contact Details 
To report an SAE when the EDC is down, please refer to the applicable study manual or eCRF 
guidance for SAE reporting instructions.  
If the EDC is down, SAEs should be reported to the following phone number: 
France (Paris): +33 1 44 90 32 90 
For back-up paper reporting, SAEs shall be reported to RGX202002@ Parexel.com. 
 

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10.4 Appendix 4: Contraceptive and Barrier Guidance 
10.4.1 Woman of Childbearing Potential  
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below). 
Women in the following categories are not considered WOCBP: 
1. 
Premenarchal 
2. 
Premenopausal female with either: 
• Documented hysterectomy 
• Documented bilateral salpingectomy 
• Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other than the above 
(e.g., Mullerian agenesis, androgen insensitivity), Investigator discretion should be applied to 
determining study entry. 
Note: Documentation for any of the above categories can come from the site personnel’s review 
of the subject’s medical records, medical examination, or medical history interview. The method 
of documentation should be recorded in the subject’s medical record for the study. 
10.4.2 Acceptable Methods of Contraception 
For WOCBP who participate in the study, the following methods of contraception, if used 
properly and used for the duration of the study, are generally considered reliable: oral 
contraceptives, patch contraceptives, injection contraceptives, implantable hormonal 
contraceptives, male condom with intravaginal spermicide, diaphragm or cervical cap with 
spermicide, vaginal contraceptive ring, intrauterine device or system, surgical sterilization 
(hysterectomy, bilateral oophorectomy, and/or bilateral salpingectomy), tubal ligation/occlusion, 
vasectomized partner, or sexual abstinence, if this is the subject’s current practice. Periodic 
abstinence, i.e., calendar, symptothermal, or post-ovulation methods, are not an acceptable form 
of contraception for this study. 
These methods of contraception also apply to female partners of male subjects. 

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The Investigator and each subject will determine the appropriate method of contraception for the 
subject during the participation in the study. This will be documented in the subject’s source 
documentation/medical record. 
 
 
 
 

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11 References 
 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: 
Revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228-247. 
International Council for Harmonisation. E8: General Considerations of for Clinical Trials, July 
1997. 
International Council for Harmonisation. S9: Nonclinical Evaluation for Anticancer 
Pharmaceuticals, March 2010. 
Karas S, Innocenti F. All You Need to Know About UGT1A1 Genetic Testing for Patients Treated 
With Irinotecan: A Practitioner-Friendly Guide. JCO Oncol Pract. 2022 Apr;18(4):270-277.  
Loo JM, Scherl A, Nguyen A, Man FY, et al. Extracellular metabolic energetics can promote 
cancer progression. Cell. 2015; 60 (3):393-406. 
Metzner L, Dorn M, Markwardt F, Brandsch M. The orally active antihyperglycemic drug 
b-guanidinopropionic acid is transported by the human proton-coupled amino acid transporter 
hPAT1. Mol Pharmeceut. 2009;6(3):1006-1011. 
 

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Investigator Agreement Page 
 
 
Declaration of the Investigator 
Title: A randomized Phase 2 Study of ompenaclid versus placebo in combination with FOLFIRI 
plus bevacizumab in patients with previously treated RAS mutant advanced or metastatic 
colorectal cancer 
All documentation for this study that is supplied to me and that has not been previously 
published will be kept in the strictest confidence. This documentation includes this study 
protocol, Investigator's Brochure, electronic CRF, and other scientific data. 
The study will not be commenced without the prior written approval of a properly constituted 
IRB or IEC. No changes will be made to the study protocol without the prior written approval of 
the Sponsor and the IRB or IEC, except where necessary to eliminate an immediate hazard to the 
participants. 
I have read and understood and agree to abide by all the conditions and instructions contained in 
this protocol. 
Responsible Investigator of the Local Study Center 
 
_____________________________________ 
_____________________ 
Signature  
 
 
 
 
 
Date 
_____________________________________ 
Name (block letters) 
_____________________________________ 
Title (block letters) 
_____________________________________ 
Institution (block letters) 
_____________________________________ 
Phone number