Clinical trial NCT05824559
Conditions: Colorectal Cancer
Sponsor: MEI Pharma, Inc.
Start date: 2023-08-07; Completion date: 2024-07-23
Enrollment: 23 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a Phase 1b open-label, multiple dose/schedule sequential study to determine the safety and efficacy of the oxidative phosphorylation (OxPhos) pathway inhibitor ME-344 in combination with bevacizumab in subjects with recurrent mCRC.

Detailed description:
This is a Phase 1b open-label, multiple dose/schedule sequential study to determine the safety and efficacy of the oxidative phosphorylation (OxPhos) pathway inhibitor ME-344 in combination with bevacizumab in subjects with recurrent mCRC.

This study will enroll subjects with metastatic CRC, including but not limited to subjects with RAS wild-type or mutant tumors, MSI-H/pMMR, and BRAF V600E, who have progressed or demonstrated intolerability to standard approved therapies which include fluoropyrimidine, oxaliplatin, irinotecan-based chemotherapies, cetuximab/panitumumab, PD-1 inhibitors, or BRAF inhibitors (if clinically indicated), and/or other checkpoint inhibitors. Approximately 40 subjects will be enrolled in the study, in 2 cohorts of 20 subjects each.

Subjects will continue treatment with ME-344 and bevacizumab until radiological progressive disease, unacceptable AEs, withdrawal of consent, start of new anticancer therapy, or death.

Arms: arm 1: ME-344 (IV) Cohort 1: Days 1, 8, and 15 of each 28-day cycle. Cohort 2: Days 1 and 15 of each 28-day cycle.

Bevacizumab (IV) Cohorts 1 and 2: Days 1 and 15 of each 28-day cycle.
Interventions: intervention 1: ME-344 intervention 2: Bevacizumab
Intervention descriptions: intervention 1: ME-344 will be administered intravenously (IV) intervention 2: Bevacizumab will be administered intravenously (IV)

Protocol documents:
Prot_000.pdf: 
CONFIDENTIAL 
This document is confidential and is the property of MEI Pharma, Inc. No part of this document may be transmitted, 
reproduced, published, or used by other persons without written authorization from MEI Pharma, Inc. 
 
TITLE PAGE 
CLINICAL STUDY PROTOCOL 
A Phase 1b Study of the OxPhos Inhibitor ME-344 Combined with 
Bevacizumab in Previously Treated Metastatic Colorectal Cancer 
Protocol Number: 
ME-344-003 
 
Sponsor: 
MEI Pharma, Inc. 
11455 El Camino Real, Suite 250 
San Diego, CA 92130, USA 
Sponsor Contact: 
Alejandro Ricart, MD 
Senior Vice President, Clinical Development 
Phone: +1 (858) 358-3889 
Email: aricart@meipharma.com   
Study Chair: 
Patrick M. Boland, MD 
Medical Oncology 
Rutgers Cancer Institute of New Jersey 
195 Little Albany St. 
New Brunswick, NJ 08903 
Phone: +1 (732) 235-6628  
Email: pb564@cinj.rutgers.edu   
 
CRO: 
Criterium, Inc. 
358 Broadway, Suite 201 
Saratoga Springs, NY 12866 
 
Investigational Drug: 
ME-344  
IND Number: 
 
Original Protocol: 
 
Amendment 3: 
157,739  
 
10 August 2021 (not implemented) 
Amendments 1 and 2 were not implemented 
06 January 2023 
 


MEI Pharma, Inc. 
 
Protocol: ME-344-003
 
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Version Date: 06 January 2023 
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SPONSOR’S PROTOCOL SIGNATURE PAGE 
By signing below, the Sponsor declares that this study will be conducted in accordance with 
current United States (US) Food and Drug Administration Code of Federal Regulations, Good 
Clinical Practice (GCP) standards, the Declaration of Helsinki (Brazil 2013), and local ethical 
and legal requirements. 
 
 
 
 
Alejandro Ricart, MD 
Senior Vice President, Clinical Development 
 
Date 
09-Jan-2023 | 12:51 PST


MEI Pharma, Inc. 
 
Protocol: ME-344-003
 
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INVESTIGATOR’S SIGNATURE PAGE 
By signing below, the Investigator agrees to adhere to the protocol as written and agrees that any 
changes to the protocol must be approved by MEI Pharma, Inc. before seeking approval from the 
Institutional Review Board (IRB)/Ethics Committee (IEC). 
The study will be conducted in accordance with the current International Council for 
Harmonisation (ICH) Guidelines, the Guidelines for GCP, and local ethical and regulatory 
requirements. 
The information contained in this protocol is proprietary and provided to me in confidence, 
and may not be disclosed to any other party, in any form, without prior authorization from 
MEI Pharma, Inc., except to the extent necessary for the conduct of the study at this study site. 
 
 
Principal Investigator: 
 
 
 
Signature 
 
 
 
 
 
Date 
Printed Name 
 
 
 


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PROTOCOL SYNOPSIS 
Protocol Number: ME-344-003 
Title of Study:  
A Phase 1b Study of the OxPhos Inhibitor ME-344 Combined with Bevacizumab in Previously Treated 
Metastatic Colorectal Cancer 
Name of Investigational Product: ME-344 
Other Co-administered drug: Bevacizumab 
Study Center(s): Approximately 8 sites in the United States 
Principal Investigator: Patrick M. Boland, MD 
Study Population: Adults with previously treated metastatic colorectal cancer (mCRC) who have progressed on, 
or are intolerant to, standard chemotherapy drugs including fluoropyrimidine, oxaliplatin, irinotecan, and 
cetuximab/panitumumab (if clinically indicated) 
Studied Period (years): 2 years 
Estimated date first subject enrolled: March 2023 
Estimated date last subject completed: February 2025 
Phase of development:  
Phase 1b 
Study Duration: Approximately 24 months 
 
Objectives 
Endpoints 
Primary 
 
 To estimate progression-free survival (PFS) at 
16 weeks of treatment in subjects with mCRC 
administered ME-344 in combination with 
bevacizumab  
 PFS rate at 16 weeks 
Secondary 
 
 To evaluate the preliminary efficacy of ME-344 
administered in combination with bevacizumab 
in subjects with mCRC 
 PFS 
 Overall or Objective response rate (ORR) using 
Response Evaluation Criteria in Solid Tumors 
(RECIST) v1.1 
 Duration of Response (DOR) 
 Overall survival (OS) 
 To determine the safety and tolerability of 
ME-344 administered in combination with 
bevacizumab 
 Incidence and severity of treatment-emergent 
adverse events (TEAEs) and their relationship to 
study drug; change from baseline in physical 
examinations, vital signs, 12-lead 
electrocardiograms (ECGs), and clinical laboratory 
evaluations 
 To evaluate the pharmacokinetics (PK)of 
ME-344 administered in combination with 
bevacizumab 
 Maximum observed concentration (Cmax), last 
observed quantifiable concentration (Clast), area 
under the concentration-time curve from time zero 
to time of last measurable concentration (AUClast)  
Exploratory 
 
 To evaluate correlatives of mitochondrial 
metabolism 
 Determine changes in isoleucine/leucine, 
tricarboxylic acid (TCA) cycle intermediates, short 
chain acyl carnitine, and nucleotide and TCA cycle 
intermediates 
 
 


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Study Design: 
This is a Phase 1b open-label, multiple dose/schedule sequential study to determine the safety and efficacy of the 
oxidative phosphorylation (OxPhos) inhibitor ME-344 in combination with bevacizumab in subjects with 
recurrent mCRC. 
This study will enroll subjects who have progressed or demonstrated intolerability to standard approved therapies 
which include fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapies, and 
cetuximab/panitumumab, programmed cell death protein 1(PD-1) inhibitors, or BRAF (v-raf murine sarcoma 
viral oncogene homolog B1) inhibitors (if clinically indicated) in the metastatic setting. Approximately 
40 subjects will be enrolled in the study, in 2 cohorts of 20 subjects each. 
This study consists of 3 periods: (i) screening, (ii) treatment, and (iii) follow-up. During screening, each potential 
subject will provide informed consent prior to starting any study-specific procedures. Screening assessments will 
be completed within 28 days prior to administration of ME-344 combined with bevacizumab. 
During the treatment period, subjects enrolled in Cohort 1 will receive ME-344 at a dose of 10 mg/kg 
intravenously (IV) on Days 1, 8, and 15 in combination with bevacizumab at a dose of 5 mg/kg IV administered 
on Days 1 and 15 of each 28-day cycle. 
Cohort 2 will initiate enrollment after at least 4 subjects in Cohort 1 have completed 4 cycles of therapy without 
evidence of disease progression (i.e., have achieved stable disease (SD) or a response), thus establishing a lack of 
progression in at least 4 [20%] subjects over the first 16 weeks of therapy. Subjects in Cohort 2 will receive 
ME-344 at a dose of 10 mg/kg IV on Days 1 and 15 combined with bevacizumab at a dose of 5 mg/kg IV 
administered on Days 1 and 15 of each 28-day cycle. If Cohort 1 does not meet the criteria for initiation of 
Cohort 2, the Safety Review Committee will determine whether or not to keep active subjects on study treatment 
or to close the study due to lack of efficacy. 
Follow-up includes the End of Treatment (EOT) visit and survival follow-up. After patients have discontinued 
treatment for any reason, they will be followed every 3 months, or more frequently as needed, until withdrawal of 
consent, the patient is lost to follow-up, death, or defined end of study. If patients withdraw consent, they will be 
asked if they are willing to be contacted via telephone for survival status. If the patient refuses to be contacted, 
attempts to determine survival status should be made via access to public records, where permitted by local laws. 
All radiographic tumor assessments, preferably computed tomography (CT), or alternatively magnetic resonance 
imaging (MRI), will be carried out in accordance with RECIST v1.1, and are to be performed every 8 weeks 
(±7 days) relative to first dose of study drug for the first 6 months, then every 3 months until 1 year, and every 
4 months thereafter. Tumor assessments will be repeated until progressive disease (PD), or as per standard 
practice post-progression. 
There is no maximum duration of treatment for this study; subjects will discontinue study drug once there is 
disease progression, unacceptable AEs (adverse events), withdrawal of consent, start of new anticancer therapy, 
or death. 
Safety will be assessed via TEAEs, physical examinations, vital signs, 12-lead ECGs, and clinical laboratory 
evaluations (hematology, serum chemistry, coagulation [at screening for all subjects and Day 1 of every cycle for 
subjects on anticoagulation therapy], urinalysis). Severity grading of TEAEs will use the National Cancer 
Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0. 
Blood samples for PK analysis will be collected during Cycle 1 on Days 1 and 15 pre-dose, 5 minutes after the 
end of infusion, and 1, 2, 3, 6, and 24 hours after the completion of the infusion.  
The metabolomic correlative study will be performed on samples obtained from subjects enrolled at Rutgers 
Cancer Institute of New Jersey who consent to the metabolomic sample collection and analysis portion of this 
study. Plasma samples will be collected at timepoints specified in the Schedule of Assessments (Appendix 1). 
Samples will be stored at -70°C until analyzed. Specific markers of the mitochondrial oxidative phosphorylation 
pathway will be analyzed based on the outcomes from the planned nonclinical studies at the site. 
See the Schedule of Assessments (Appendix 1) for a detailed list of study procedures and timing. 
 


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Number of Subjects (planned):  
Approximately 40 subjects will be enrolled in 2 cohorts of 20 subjects each. 
Diagnosis and Main Criteria for Inclusion:  
Inclusion Criteria 
Subjects must meet ALL the following inclusion criteria to qualify for the study: 
1. Provide written informed consent to participate. 
2. Male or female subjects ≥18 years of age. 
3. Histological or cytological documentation of adenocarcinoma of the colon or rectum that is metastatic 
(all other histological types are excluded). 
4. Measurable disease following RECIST v1.1. 
5. Subjects who progressed or demonstrated intolerability to prior standard approved therapies which 
include fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapies, and 
cetuximab/panitumumab (if clinically indicated e.g., RAS wild-type tumors) in the advanced or 
metastatic setting. 
6. Subjects with microsatellite instability-high/deficient mismatch repair (MSI-H/dMMR) CRC should 
have failed or demonstrated intolerance to prior programmed death receptor-1 (PD 1)-blocking antibody. 
7. Subjects with BRAF V600E mutation should have failed or demonstrated intolerance to BRAF-targeted 
therapy. 
8. Previous treatment with any investigational drug or anticancer treatment must be completed >28 days or 
5 half-lives, whichever is longer, before the first dose of study treatment. 
9. Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1 (within 14 days prior 
to the initiation of study treatment). 
10. Adequate bone marrow, liver, and renal function as assessed by the following laboratory requirements 
(within 7 days before Day 1): 
a. 
Total bilirubin ≤1.5 × the upper limit of normal (ULN). 
b. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 × ULN (5 × ULN for 
subjects with liver metastases). 
c. 
Creatinine clearance (CrCL) ≥60 mL/min as calculated using the Cockcroft-Gault equation 
(Appendix 2) 
d. Hemoglobin ≥8.0 g/dL. 
e. 
Platelet count >100,000/mm3, absolute neutrophil count (ANC) >1500/mm.3 
f. 
International normalized ratio (INR)/prothrombin time (PT) 1.5 × ULN (subjects who are 
therapeutically treated with an agent such as warfarin or heparin will be allowed to participate 
provided that no prior evidence of underlying abnormality in coagulation parameters exists. 
g. Urine protein <2+. Subjects discovered to have ≥2+ proteinuria on dipstick urinalysis at baseline 
will undergo a 24-hour urine collection and must demonstrate <2.0 g of protein in 24 hours.  
11. QT-interval corrected according to Fridericia’s formula (QTcF) ≤470 milliseconds (msec). 
12. Women of childbearing potential and men must agree to use adequate contraception before entering the 
program until at least 8 weeks after the last study drug (ME-344) administration and for at least 
6 months after the last dose of bevacizumab. The Investigator or designee is to advise the subject on how 
to achieve adequate contraception. Adequate contraception is defined in the study as any medically 
recommended method (or combination of methods) as per standard of care. Women of childbearing 
potential must have a blood or urine pregnancy test performed a maximum of 7 days before start of 
study treatment, and a negative result must be documented before start of study treatment. Women are 
considered not of childbearing potential if they have been without menses for 1 year and have 
follicle-stimulating hormone (FSH) levels considered to be post-menopausal. 


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Exclusion Criteria 
Subjects must NOT meet any of the following exclusion criteria to qualify for the study: 
1. Untreated brain metastases, spinal cord compression, or primary brain tumor. 
2. Symptomatic brain metastases, leptomeningeal disease, spinal cord compression, or primary brain 
tumor. Notes: Patients previously treated or untreated for this condition who are asymptomatic in the 
absence of corticosteroid and anti-epileptic therapy are allowed. Brain metastases must be stable for 
≥4 weeks, with imaging (e.g., MRI or CT) demonstrating no current evidence of progressive brain 
metastases at screening. 
3. History of central nervous system (CNS) disease (excluding asymptomatic lacunar infarction) except 
cerebrovascular accident (CVA) >6 months with preserved performance status. 
4. History of pulmonary hemorrhage/hemoptysis Grade ≥2 (defined as bright red blood of at least 2.5 mL) 
within 1 month prior to enrollment. 
5. Evidence of uncontrolled or unstable cardiovascular disease, myocardial infarction (within 6 months), 
unstable angina pectoris, New York Heart Association (NYHA) classification ≥ Grade II congestive 
heart failure, serious arrhythmias requiring drug therapy, history of congenital long QT syndrome, 
congenital short QT syndrome, Torsades de Pointes, or Wolff-Parkinson-White syndrome. 
6. Bevacizumab or aflibercept therapy ≤3 weeks prior to starting study treatment. 
7. Peripheral neuropathy Grade ≥2. 
8. Any of the following comorbidities: 
a. 
Uncontrolled hypertension (systolic blood pressure >150 mmHg or diastolic blood pressure 
>90 mmHg) despite best medical management. 
b. Uncontrolled diabetes mellitus (with HbA1c >8.5% at Screening). 
c. 
Active peptic ulcer. 
d. Unhealed wound (except for suturing associated with implanted port placement) 
e. 
Other clinically significant diseases (such as interstitial pneumonia or renal impairment) 
f. 
Systemic infection requiring treatment. 
9. Other severe, acute, or chronic medical or psychiatric condition or laboratory abnormality that may 
increase the risk associated with study participation or study drug administration or that may interfere 
with the interpretation of study results and, in the judgment of the Investigator, would make the patient 
an inappropriate candidate for the study. 
10. Major surgical procedure within 28 days prior to study treatment initiation (such as open chest, 
thoracoscopic surgery, laparoscopic surgery), unless only colostomy is performed; open biopsy or 
suturing for major trauma within 14 days of study treatment initiation; or planned major surgical 
procedure (open chest, laparoscopy) during the study (“major surgical procedures” does not include 
central venous port insertion). 
11. Pregnant, breastfeeding, positive pregnancy test, or women who are unwilling to use contraception; men 
who are unwilling to use contraception during the study. 
12. Known seropositive for, or active infection with hepatitis B virus: 
 
Hepatitis B surface antigen (HBsAg) positive. 
 
HBsAg negative, anti-HBs positive and/or anti-HBc positive and detectable viral DNA by PCR  
Note: Subjects who are HBsAg positive and viral DNA PCR negative are eligible. These subjects should 
receive prophylactic therapy for hepatitis as per institutional standards. 
13. Known seropositive for, or active infection with hepatitis C virus: 
 
Subjects with positive hepatitis C virus (HCV) antibodies are eligible with negative PCR test for 
HCV. 
14. Active and uncontrolled infection with human immunodeficiency virus (HIV), or with acquired 
immunodeficiency syndrome (AIDS), or currently taking medications for HIV that are contraindicated 
for concomitant use in this study. 


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15. Symptomatic or uncontrolled infection with human T-cell leukemia virus type 1. 
16. History of other primary malignancy in the past 5 years or concurrent active malignancies (synchronous 
malignancies, requiring treatment; excluding malignancies that are expected to be completely cured, 
such as intramucosal carcinoma and carcinoma in situ, curatively treated cervical cancer in situ, 
non-melanoma skin cancer, superficial bladder tumors [Ta (non-invasive tumor), Tis (carcinoma in situ), 
and T1 (tumor invades lamina propria)], and asymptomatic localized prostate cancer with no 
requirement for systemic therapy or requiring only hormonal therapy and with normal prostate-specific 
antigen values within ≥12 months prior to enrollment). Breast cancer survivors on hormone therapy may 
be eligible if blood count is adequate and history of remission is >5 years ago. 
17. Venous thromboembolism (unless appropriately treated and stable on anticoagulant for at least 2 weeks). 
18. Arterial thrombosis or arterial thromboembolism such as myocardial infarction, transient ischemic 
attack, or cerebrovascular attack in the last 6 months prior to enrollment. 
19. Subjects who discontinued prior treatment with bevacizumab, ziv-aflibercept, and/or ramucirumab 
because of severe events of hemorrhages, hypertension, fistula, perforation, arterial/venous 
thromboembolism, posterior reversible encephalopathy syndrome (PRES), renal injury, or proteinuria. 
20. Concomitant use of strong inhibitors and strong inducers of cytochrome P450 (CYP) enzymes and 
transporters. 
Investigational Product, Dosage, and Mode of Administration: 
ME-344 will be suspended in 250 mL sterile saline and will be infused IV over 30 minutes. 
Cohort 1: 10 mg/kg on Days 1, 8, and 15 of each 28-day cycle. 
Cohort 2: 10 mg/kg on Days 1 and 15 of each 28-day cycle. 
Co-administered Therapy, Dosage, and Mode of Administration:  
Bevacizumab (Avastin®) or any U.S. approved biosimilar of bevacizumab ) will be administered IV at a dose of 
5 mg/kg on Days 1 and 15 of each 28-day cycle in Cohorts 1 and 2. Infusion will be based on the product’s 
US Prescribing Information (Avastin [US Prescribing Information] September 2022 or biosimilar). 
Duration of Treatment:  
Subjects will continue treatment with ME-344 and bevacizumab until radiological progressive disease, based on 
RECIST v1.1 criteria or symptomatic deterioration per the Investigator. If the disease progresses in a subject, 
both drugs will be stopped. Other reasons for a subject to discontinue therapy include unacceptable toxicity, 
withdrawal of consent, start of new anticancer therapy, or death. Safety follow-up will conclude at the EOT visit 
of the study. After subjects have discontinued treatment for any reason, they will be followed every 3 months, or 
more frequently as needed, until withdrawal of consent, the patient is lost to follow-up, death, or defined end of 
study. If patients withdraw consent, they will be asked if they are willing to be contacted via telephone for 
survival status. If the subject refuses to be contacted, attempts to determine survival status should be made via 
access to public records, where permitted by local laws. 
Statistical Methods: 
Sample Size Justification 
With a sample size of 20 subjects in each cohort, assuming the true PFS rate at 16 weeks is 30%, there is 89% 
chance to observe PFS rate ≥20% (i.e., ≥4 of 20 subjects progression-free). 
Analysis Populations 
The Intent-to-Treat (ITT) Population is defined as all enrolled subjects who receive at least one dose of ME-344. 
The Efficacy Evaluable (EE) Population includes all subjects who receive at least one dose of ME-344 and have 
adequate Week 16 efficacy assessments or develop progression of disease (or died) prior to Week 16. The 
EE Population will be used as the primary analysis population for assessing response to the study drugs. 
The PK Population includes all subjects who receive at least one dose of ME-344 and have at least one evaluable 
post-baseline ME-344 PK concentration. PK analysis will be conducted using the PK Population. 
The Safety Population includes all subjects who receive at least one dose of ME-344. Safety analyses will be 
performed on the Safety Population. 


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Statistical Analysis 
The primary efficacy endpoint (PFS rate at Week 16) will be evaluated using the Kaplan-Meier (KM) method 
when the last subject in Cohort 1 completes the efficacy assessment at Week 16 (or discontinues, develops 
disease progression, or dies, whichever occurs earlier). The KM estimates for median, first and third quartiles 
(Q1 and Q3, respectively), and the PFS rate at Week 16 will be presented. 
The OS will be analyzed using the KM method. 
The secondary efficacy endpoints ORR will be summarized by the number and percentage of subjects achieving 
ORR. The 2-sided exact 95% confidence interval (CI) based on the Clopper-Pearson method will be provided.  
Safety will be assessed through the analysis of the reported incidence, severity, and relationship of TEAEs, 
including serious adverse events (SAEs), adverse events of special interest, AEs leading to withdrawal of study 
drug, and AEs related to study treatment. Change from baseline in physical examinations, vital signs, 12-lead 
ECGs, and clinical laboratory evaluations will be summarized. 
Information regarding study drug administration, study drug compliance, and other safety variables will also be 
summarized or listed. Extent of exposure to study drug will be generated from the study drug administration data. 
Exposure data will be summarized by cohort. 
All analyses will be conducted by cohort. Pooled summaries (Cohort 1 + Cohort 2) may be conducted if deemed 
meaningful. Subgroup analysis by baseline demographic or disease characteristics may be conducted. 


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TABLE OF CONTENTS 
SPONSOR’S PROTOCOL SIGNATURE PAGE ...........................................................................2 
INVESTIGATOR’S SIGNATURE PAGE ......................................................................................3 
PROTOCOL SYNOPSIS.................................................................................................................4 
LIST OF ABBREVIATIONS ........................................................................................................14 
1. 
INTRODUCTION ......................................................................................................17 
1.1. 
Disease Background ...................................................................................................17 
1.2. 
Current Therapeutic Options ......................................................................................17 
1.3. 
ME-344 .......................................................................................................................18 
1.3.1. 
Nonclinical Studies .....................................................................................................19 
1.3.2. 
Clinical Studies ...........................................................................................................20 
1.4. 
Study Rationale ...........................................................................................................21 
2. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................22 
3. 
INVESTIGATIONAL PLAN .....................................................................................22 
3.1. 
Overall Study Design ..................................................................................................22 
3.2. 
Number of Subjects ....................................................................................................24 
3.3. 
Treatment Assignment ................................................................................................24 
3.4. 
Dose Adjustment Criteria ...........................................................................................24 
3.4.1. 
Criteria for Withholding, Adjustment, or Discontinuing ME-344 Doses ..................26 
3.4.2. 
Criteria for Withholding or Discontinuing Bevacizumab Doses ................................27 
3.5. 
Criteria for Study Termination ...................................................................................27 
4. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................27 
4.1. 
Subject Inclusion Criteria ...........................................................................................27 
4.2. 
Subject Exclusion Criteria ..........................................................................................28 
4.3. 
Discontinuation of Treatment and Subject Withdrawal Criteria ................................30 
5. 
STUDY DRUG MATERIALS AND MANAGEMENT AND 
TREATMENT OF SUBJECTS ..................................................................................31 
5.1. 
ME-344 .......................................................................................................................31 
5.1.1. 
Description of the Active Pharmaceutical Ingredient .................................................31 
5.1.2. 
Description of the Study Drug Product ......................................................................31 
5.1.3. 
Study Drug Packaging and Labeling ..........................................................................31 
5.1.4. 
Study Drug Storage .....................................................................................................31 
5.1.5. 
Study Drug Preparation ..............................................................................................31 


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5.1.6. 
Study Drug Administration .........................................................................................32 
5.1.7. 
Study Drug Accountability .........................................................................................32 
5.1.8. 
Study Drug Disposition ..............................................................................................32 
5.2. 
Bevacizumab ...............................................................................................................32 
5.3. 
Concomitant Medications ...........................................................................................33 
5.3.1. 
Permitted Concomitant Medications ..........................................................................33 
5.3.2. 
Prohibited Concomitant Medications .........................................................................34 
5.4. 
Treatment Compliance ................................................................................................34 
5.5. 
Randomization and Blinding ......................................................................................34 
6. 
ASSESSMENT OF EFFICACY ................................................................................34 
6.1. 
Tumor Response .........................................................................................................34 
6.2. 
Pharmacokinetics ........................................................................................................35 
6.3. 
Correlatives of Mitochondrial Metabolism ................................................................35 
7. 
ASSESSMENT OF SAFETY .....................................................................................36 
7.1. 
Safety Parameters .......................................................................................................36 
7.1.1. 
Demographic/Medical History ...................................................................................36 
7.1.2. 
Vital Signs ..................................................................................................................36 
7.1.3. 
Weight and Height ......................................................................................................36 
7.1.4. 
Physical Examination .................................................................................................36 
7.1.5. 
ECOG Performance Status .........................................................................................36 
7.1.6. 
Electrocardiogram (ECG) ...........................................................................................36 
7.1.7. 
Laboratory Evaluations ...............................................................................................36 
8. 
ADVERSE EVENTS ..................................................................................................38 
8.1. 
Assessment of Severity ...............................................................................................39 
8.2. 
Assessment of Causality .............................................................................................39 
8.3. 
Documenting Adverse Events ....................................................................................39 
8.4. 
Clinical Laboratory Changes ......................................................................................39 
8.5. 
Adverse Event Follow-up ...........................................................................................39 
8.6. 
Documenting Action Taken with Study Drug in Response to the AE .......................40 
8.7. 
Outcome of Adverse Event .........................................................................................40 
8.8. 
Serious Adverse Events ..............................................................................................40 
8.8.1. 
Definition ....................................................................................................................40 


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8.8.2. 
Definition of Terms ....................................................................................................41 
8.8.3. 
Reporting Serious Adverse Events .............................................................................41 
8.8.4. 
Sponsor Reporting to Regulatory Authorities ............................................................42 
8.8.5. 
Pregnancies .................................................................................................................42 
9. 
STATISTICS ..............................................................................................................43 
9.1. 
Sample Size Justification ............................................................................................43 
9.2. 
Analysis Populations ..................................................................................................43 
9.3. 
Statistical Analysis ......................................................................................................44 
9.3.1. 
General Methodology .................................................................................................44 
9.3.2. 
Demographics, Baseline Characteristics, and Subject Disposition ............................44 
9.3.3. 
Efficacy Analysis ........................................................................................................44 
9.3.4. 
Safety Analysis ...........................................................................................................45 
9.3.5. 
Pharmacokinetic Analysis ..........................................................................................45 
9.3.6. 
Analysis of Correlatives of Mitochondrial Metabolism .............................................45 
10. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .........................................45 
10.1. 
Study Monitoring ........................................................................................................45 
10.2. 
Audits and Inspections ................................................................................................46 
10.3. 
Institutional Review Board (IRB) ...............................................................................46 
10.4. 
Safety Review Committee ..........................................................................................46 
11. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................47 
12. 
ETHICS ......................................................................................................................47 
12.1. 
Ethics Review .............................................................................................................47 
12.2. 
Ethical Conduct of the Study ......................................................................................47 
12.3. 
Written Informed Consent ..........................................................................................47 
13. 
DATA HANDLING AND RECORDKEEPING .......................................................48 
13.1. 
Inspection of Records .................................................................................................48 
13.2. 
Data Protection and Privacy .......................................................................................48 
13.3. 
Retention of Records ..................................................................................................48 
14. 
PUBLICATION POLICY ..........................................................................................48 
15. 
REFERENCES ...........................................................................................................49 
APPENDIX 1.  SCHEDULE OF ASSESSMENTS .....................................................................51 
APPENDIX 2.  CREATININE CLEARANCE ............................................................................53 


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APPENDIX 3.  DRUGS THAT PROLONG THE QTC INTERVAL AND/OR 
INDUCE TORSADES DE POINTES ................................................................54 
APPENDIX 4.  SENSITIVE IN VIVO CYP SUBSTRATES AND CYP 
SUBSTRATES WITH NARROW THERAPEUTIC RANGE ..........................60 
APPENDIX 5.  CYTOCHROME P450 DRUG-INTERACTIONS FOR INHIBITORS, 
INDUCERS, AND TRANSPORTERS ..............................................................61 
APPENDIX 6.  EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) 
PERFORMANCE STATUS SCALE .................................................................63 
 
LIST OF TABLES 
Table 1: 
Toxicity Management .................................................................................................24 
Table 2: 
Clinical Laboratory Tests ...........................................................................................37 
Table 3: 
NCI CTCAE v5.0 Adverse Event Grading System ....................................................39 
Table 4: 
Observed Progression-free Survival Rate with Exact 95% and 80% 
Confidence Intervals ...................................................................................................43 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
adverse event 
AIDS 
acquired immunodeficiency syndrome 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
AUClast 
area under the concentration-time curve from time zero to time of last measurable 
concentration 
BRAF 
B-Raf murine sarcoma viral oncogene homolog B 
BUN 
blood urea nitrogen 
CI 
confidence interval 
CL 
Clearance 
Clast 
last observed quantifiable concentration 
Cmax  
maximum observed concentration 
CNS 
central nervous system  
CR 
complete response 
CrCL 
creatinine clearance 
CRF 
case report form 
CRO 
contract research organization 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA-4 
cytotoxic T lymphocyte-associated antigen-4 
CVA 
cerebrovascular accident 
CYP 
cytochrome P450 
dMMR 
deficient mismatch repair 
DNA 
deoxyribonucleic acid 
DOR 
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EE 
Efficacy Evaluable 
EGFR 
epidermal growth factor receptor 


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Abbreviation 
Definition 
EOT 
End of Treatment 
FOLFIRI 
fluorouracil with leucovorin and irinotecan 
FOLFOX 
fluorouracil with leucovorin and oxaliplatin 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
HBcAb 
hepatitis B core antibody 
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus  
hERG 
human ether-à-go-go-related gene 
HIV 
human immunodeficiency virus 
ICF 
Informed Consent Form 
ICH 
International Council on Harmonisation 
IEC 
Independent Ethics Committee 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IV 
intravenous(ly) 
KM 
Kaplan-Meier 
LDH 
lactate dehydrogenase 
MCH 
mean corpuscular hemoglobin 
mCRC 
metastatic colorectal cancer 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
MSI-H 
microsatellite instability-high  
MSS 
microsatellite stable 
MTD 
maximum tolerated dose 
mAbs 
monoclonal antibodies 
mTOR 
mammalian target of rapamycin 
NCI 
National Cancer Institute 
NOAEL 
no-observed-adverse-effect level 
NYHA 
New York Heart Association 
ORR 
Overall or Objective Response rate 
OS 
overall survival 
OxPhos 
oxidative phosphorylation 


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Abbreviation 
Definition 
PCR 
polymerase chain reaction  
PD 
progressive disease 
PD-1 
programmed cell death protein 1 
PFS 
progression-free survival 
PK 
pharmacokinetic(s) 
P-gp 
P-glycoprotein 
pMMR 
mismatch repair proficient 
PO 
oral(ly) 
PR 
partial response 
PRES 
posterior reversible encephalopathy syndrome 
PT 
prothrombin time 
RBC 
red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumors 
ROS 
reactive oxygen species  
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SCLC 
small cell lung cancer  
SD 
stable disease 
SRC 
Safety Review Committee 
STD10 
severely toxic dose 
SUSAR 
suspected unexpected serious adverse reaction 
t½  
apparent terminal elimination half-life 
T1 
tumor invades lamina propria 
Ta 
non-invasive tumor  
Tis 
carcinoma in situ 
TCA 
tricarboxylic acid 
TEAE 
treatment-emergent adverse event 
TG-1 
transglutaminase-1 
Tmax 
time to maximum observed concentration 
ULN 
upper limit of normal 
US 
United States 
Vdss 
volume of distribution at steady state 
VEGF 
vascular endothelial growth factor 
WBC 
white blood cell 
WHO 
World Health Organization 


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1. 
INTRODUCTION 
1.1. 
Disease Background 
Colorectal cancer is one of the most common tumors, and approximately 20–25% of patients are 
diagnosed in advanced Stage IV disease (Aran 2016). Colorectal cancer patients with 
unresectable metastases have a limited median survival of around 5 months if only treated with 
best supportive care (Wang 2016). Significant improvements have been made in the treatment of 
metastatic colorectal cancer (mCRC), particularly in the first- and second-line setting; however, 
it is inevitable that these patients eventually progress. Although these patients may still have 
good performance status after second-line therapy, third-line treatment options are limited. In the 
third- and later-line setting, regorafenib and trifluridine/tipiracil are available for patients with 
mCRC (Grothey 2013, Benson 2021). However, the PFS in the third-line setting remains at 
<3 months with a median OS around 8–9 months. There is, therefore, an unmet clinical need for 
treatment options in the third line setting for mCRC. 
The rationale of continuing to target the vascular endothelial growth factor (VEGF) pathway in 
mCRC was confirmed when third-line monotherapy with the VEGF receptor inhibitor 
regorafenib improved survival in the CORRECT (Grothey 2013) and CONCUR (Li 2015) study 
populations. However, the efficacy of regorafenib is limited and its adverse effects, particularly 
fatigue and palmar-plantar erythrodysesthesia can pose management difficulties and worsen 
quality of life (Grothey 2013). 
Tumors treated with antiangiogenic therapy can correct hypoxia and downregulate aerobic 
glycolysis. Tumors eventually adapt and show metabolic plasticity, switching to mitochondrial 
metabolism, which is mediated by adenosine monophosphate-activated protein kinase (AMPK), 
protein kinase A (PKA), and peroxisome proliferator-activated receptor alpha (PPARα). Because 
of this adaptation, mitochondrial metabolism becomes essential for tumor survival. Thus, 
antimitochondrial agents induce metabolic synthetic lethality in this situation (Navarro 2016). 
1.2. 
Current Therapeutic Options 
Chemotherapy: In early-stage CRC, the standard treatment includes tumor resection and adjuvant 
chemotherapy. In metastatic disease, the standard treatment includes various lines of 
chemotherapy combined with targeted therapies or immunotherapies according to tumor subtype 
and gene mutations identified (Benson 2021). 
Three main classes of chemotherapeutic agents, fluoropyrimidine, irinotecan, and oxaliplatin, are 
used to treat mCRC. Fluorouracil with leucovorin and oxaliplatin (FOLFOX) and fluorouracil 
with leucovorin and irinotecan (FOLFIRI) are most used as the first-line treatment for patients 
with unresectable mCRC (Aparicio 2020). However, these treatments appear to be largely 
ineffective for late-stage colon cancer. 
Targeted therapy: Options for patients with mCRC include agents targeting either VEGF or the 
epidermal growth factor receptor (EGFR) (Benson 2021, Ciardiello 2019). Specifically, 
bevacizumab, a humanized monoclonal antibody that inhibits VEGF, combined with 
fluoropyrimidine-based chemotherapy, is approved as first- and second-line treatment for 
patients with mCRC (Benson 2021, Ciardiello 2019). Several therapy options are available for 
treating patients with RAS wild type mCRC. The best sequence for first-to-second-line therapy is 


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cetuximab-based therapy, followed by a bevacizumab-based regimen (Wu 2021). Cetuximab 
(chimeric monoclonal antibody targeting EGFR) is used as a single agent in mCRC patients 
expressing EGFR who failed both irinotecan- and oxaliplatin-containing regimens or in patients 
who are intolerant to irinotecan-based regimens; a combination of cetuximab with irinotecan is 
used in patients who are refractory to irinotecan-based chemotherapy (Benson 2021, 
Ciardiello 2019). Panitumumab (humanized monoclonal antibody against EGFR) is approved as 
monotherapy for treating mCRC with disease progression after prior treatment with various 
chemotherapeutic agents (Benson 2021, Ciardiello 2019). However, anti-EGFR agents such as 
cetuximab or panitumumab are ineffective in mCRC patients with RAS and RAF (specifically 
BRAF V600E) gene mutations, as EGF receptor inhibition is unattainable because of constitutive 
oncogenic signaling (Benvenuti 2007, Benson 2021, Ciardiello 2019). Thus, systemic treatment 
options in patients with RAS mutations currently include chemotherapy with or without 
angiogenic agents such as bevacizumab in first-line, bevacizumab or aflibercept or ramucirumab 
in the second-line, followed by later-line treatment such as trifluridine/tipiracil and regorafenib 
(Patelli 2021, Van Cutsem 2019). 
BRAF Mutation: Several therapeutic options are available for patients with BRAF-mutated 
mCRC, including treatment with BRAF inhibitor such as encorafenib in combination with 
cetuximab (Tabernero 2016, van Geel 2017, Quintela-Fandino 2020, Mauri 2021, Wu 2021). 
Immunotherapy: The development of immune checkpoint inhibitors, such as anti-cytotoxic 
T lymphocyte-associated antigen-4 (CTLA-4) monoclonal antibodies (mAbs) (ipilimumab, 
tremelimumab), anti-PD-1 mAbs (nivolumab, pembrolizumab), has dramatically changed the 
therapeutic scenario for mCRC with high microsatellite instability (MSI-H). For most patients 
with MSI-H/dMMR, the first-line treatment options include combination chemotherapy plus 
targeted therapy, as well as immunotherapy, whether it be PD-1 monotherapy or a combination 
with ipilimumab (Benson 2021). For patients with MSI-H/dMMR tumors who progress or recur 
after chemotherapy, pembrolizumab or nivolumab with or without low-dose ipilimumab 
represents a preferred second-line treatment option (Keytruda® USPI 2017, Golshani 2020). 
Whereas in dMMR or MSI-H mCRC, there is clear clinical evidence for a therapeutic role of 
immune checkpoint inhibitors, the majority of mCRC patients with mismatch repair proficient 
(pMMR) or microsatellite stable (MSS) tumors do not benefit from immunotherapy. 
1.3. 
ME-344 
ME-344 is a synthetic small molecule mitochondrial inhibitor based on the isoflavone ring 
structure. Specifically, it directly targets the OxPhos complex 1, a pathway involved in the 
production of adenosine triphosphate in the mitochondria. Preliminary screening studies have 
identified ME-344 as a candidate for development as an anticancer product, given its broad 
antiproliferative activity against a panel of human cancer cells representative of most major 
organ systems. 
ME-344 was derived from a parental compound, genistein, and has been shown to disrupt signal 
transduction upstream and downstream of the mammalian target of rapamycin (mTOR) 1 
and mTOR2. 


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1.3.1. 
Nonclinical Studies 
In vitro studies in a range of cancer cell lines showed that ME-344 disrupts the mitochondrial 
oxidative phosphorylation via the electron transport chain thereby causing energy starvation. 
Two forms of ME-344 induced cell death have been identified as a result of energy starvation; 
caspase-independent autophagy and apoptotic cell death induced by a BAX-mediated loss of 
mitochondrial membrane potential. 
Further investigation into the mechanism of antitumor activity of ME-344 was performed in 
sensitive and resistant lung cancer cell lines. In sensitive cell lines the drug-induced cell death 
was associated with increased levels of reactive oxygen species (ROS) that resulted in 
downstream interference with tumor cell redox homeostasis and mitochondrial function leading 
to tumor cell death. 
In human xenograft models including sensitive NCI-H460 large cell lung cancer cells, ME-344 
exhibited notable activity against tumor growth. 
Further inhibition of tumor growth and cancer cell proliferation was demonstrated in an in vivo 
polyoma middle T-antigen driven murine model. ME-344, when used in combination with 
antiangiogenic protein tyrosine kinase inhibitors (TKI), nintedanib or regorafenib, demonstrated 
significant increase in tumor growth inhibition (TGI) index while single agent activity was 
limited. The anti-tumor efficacy of ME-344 and regorafenib, a multi-kinase inhibitor, was tested 
in a CT26 murine colon carcinoma xenograft model. Both drugs resulted in tumor growth delay 
as single agents; however, there was enhanced anti-tumor efficacy with the combination. All 
treatments were well tolerated with no deaths or mean body weight losses on study. The PK of 
IV administered ME-344 were assessed in conjunction with rat and dog repeat-dose toxicology 
studies. ME-344 plasma concentration profiles displayed rapid maximum concentrations 
followed by rapid elimination with no marked differences between sexes. The time to maximum 
observed concentration (Tmax) was 0.167 hours, the first sampling point post-dose. The apparent 
terminal elimination half-life (t½) in rats ranged from 0.32 to 2.25 hours depending on dose 
(higher dose levels generally corresponded with increasing t½). In the dog, t½ was less than 
1 hour. Systemic exposure, as assessed by Cmax and area under the concentration-time curve from 
time zero to time of AUClast, was approximately dose proportional (doses ranging from 35 to 
140 mg/kg). 
Safety pharmacology in vitro testing with ME-344 on cloned human ether-à-go-go-related gene 
(hERG) potassium channels expressed in human embryonic kidney cells resulted in a 
half-maximal inhibitory concentration (IC50) of 18.0 µM for the inhibitory effect of ME-344 on 
hERG potassium current. There were no changes in ECGs observed in dogs administered up to 
140 mg/kg ME-344 weekly for three weeks, which resulted in group plasma Cmax >870 µM. 
Furthermore, there were no microscopic findings of myocardial inflammation in male or female 
dogs. 
The no observed adverse effect level (NOAEL) for ME-344 when administered once weekly for 
three weeks in female rats and dogs was 35 mg/kg and 140 mg/kg, respectively. The NOAEL in 
male rats and dogs was <35 mg/kg and 140 mg/kg, respectively. Treatment-related effects in 
both species included transient decreases in food consumption and body weight gain seen 
amongst animals that received 140 mg/kg. The only other potentially treatment-related effect in 
dogs was reduced testes organ weights in males at 140 mg/kg. 


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The rat was deemed the more sensitive species to ME-344 toxicities. In addition to the 
observations in dogs, studies in rats show decreased erythroid parameters and slightly increased 
leukograms, primarily at 140 mg/kg. Microscopic findings were present in the epididymides/
testes (degeneration of spermatozoa), spleen (hematopoiesis), and heart. The cardiovascular 
findings were mild, patchy, dose-dependent myocardial inflammatory cell infiltrates, which were 
not associated with any biochemical or clinical sequelae. Similar cardiovascular events were not 
observed in either male or female dogs. Finally, the death of one male rat, three days after 
receiving the first 140 mg/kg dose could potentially be attributable to ME-344 administration. 
As such, the 140 mg/kg dose in rats was considered the severely toxic dose in 10% of the 
animals (STD10). 
1.3.2. 
Clinical Studies 
A Phase 1 clinical study (ME-344-001) enrolled 30 subjects with refractory solid tumors and no 
standard therapeutic alternatives in dose cohorts of ME-344 between 1.25 and 20 mg/kg IV 
weekly. 
Results indicated that weekly infusions of ME-344 were generally well tolerated up to 10 mg/kg. 
The primary dose limiting toxicity (DLT) was peripheral neuropathy, which was observed at the 
15 mg/kg and 20 mg/kg weekly dosing schedules and was generally reversible following 
discontinuation of study drug and appeared to be more frequent with rapid ME-344 infusion rate 
and in patients with pre-existing neuropathy. Other TEAEs reported for >10% of subjects 
(serious and non-serious) were nausea, dizziness, fatigue, vomiting, diarrhea, and asthenia. 
No significant effects on QTc interval, cardiac function (as assessed by echocardiography), 
or cardiac injury (as assessed by CK-MB and troponin) were observed. A maximum tolerated 
dose (MTD) of 10 mg/kg was established. 
The PK analyses showed that ME-344 plasma concentrations declined in a multi-exponential 
fashion with a mean t½ of approximately 6 hours. There was a linear relationship between dose 
and both Day 1 Cmax levels and exposure (AUC), with good correlation between Day 1 and 
Day 15 results. ME‐344 values for volume of distribution at steady state (Vdss), t½, and clearance 
(CL) appeared to be dose‐independent. Additionally, there were no statistical differences for CL 
and Vdss between Day 1 and Day 15. 
The efficacy analyses revealed some evidence of clinical activity. Of the 30 subjects, one with 
small cell lung cancer (SCLC) treated at the 5 mg/kg dose level achieved a durable partial 
remission. In addition, 10 (33.3%) patients experienced SD, 4 of which were prolonged (41 to 
89 weeks). 
A Phase 1b study (ME-344-002) was conducted to evaluate the safety and tolerability of 
10 mg/kg ME-344 (Days 1, 8, 15, and 22) given in combination with 4 mg/m2 topotecan 
(Days 1, 8, and 15) in subjects with solid tumors. The study enrolled 46 cancer patients: 
28 ovarian, 13 lung, and 5 cervical. AEs reported for >20% of subjects were predominantly 
gastrointestinal disorders: nausea [48%], diarrhea [46%], vomiting [39%], and constipation, 
[33%]); other frequently reported AEs were fatigue (65%), neutropenia (46%), hypertension 
(41%), decreased appetite (41%), thrombocytopenia (39%), and anemia (35%). Of the 
17 subjects experiencing SAEs, only 1 had an event (diarrhea) that was considered related to 
ME-344 administration. Of the 6 deaths on study (i.e., during the study and within 30 days of last 
treatment administration) that were reported, 5 (11%) were attributed to the underlying disease, 


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and 1 (2%) was due to an AE (neutropenic sepsis). Peripheral neuropathy, including sensory 
neuropathy, has been reported in prior clinical studies of ME-344 as a single agent or in 
combination with topotecan. 
The overall response rate (complete remission + partial remission) was 2.4% for the Efficacy 
Population (consisting of patients with evaluable or measurable disease at baseline who 
completed at least 1 cycle of treatment and either underwent at least one follow-up tumor 
evaluation or discontinued treatment prior to the first tumor evaluation due to clinical 
progression). Due to this response rate, the DOR was not applicable. In the Safety Population 
(all patients who received at least one dose of ME-344), median PFS was 3.0 months, and 
median time for OS was 3.3 months. 
A placebo-controlled window of opportunity study (CNIO-BR-009) (Quintela-Fandino 2020) 
evaluated the pharmacodynamics of 10 mg/kg ME-344 for one cycle on Days 8, 15, and 21 of a 
28-day cycle in combination with the antiangiogenic antibody bevacizumab in 41 patients with 
HER2-negative breast cancer. The study demonstrated a biologic activity of ME-344 as 
documented by a decrease in Ki67, a marker of cell proliferation, and no new safety signals were 
identified. The combination treatment was tolerable, with most of the AEs being Grade 1 in 
severity. The Grade 1 AEs were diarrhea and asthenia (25% each), and headache and nausea 
(15% each). Grade 2 AEs included headache (15%). There were 2 cases of Grade 3 
hypertension; however, 1 of the subjects had prior Grade 3 hypertension at enrollment, which 
continued despite use of two antihypertensive drugs. 
Additional information regarding nonclinical and clinical experience with ME-344 may be found 
in the Investigator’s Brochure. 
1.4. 
Study Rationale 
It is hypothesized that in cases where antiangiogenics such as bevacizumab led to vascular 
normalization and resultant tumor tissue hypoxia, chronic high-rate glycolysis is offset, with the 
potential for tumors to switch to an alternative metabolic source, primarily mitochondrial energy. 
If this source is essential for tumor survival, it would open a therapeutic opportunity for 
mitochondrial inhibitors such as ME-344 to induce metabolic synthetic lethality, resulting in 
tumor suppression and thereby prolonging PFS. This study will assess tumor response in subjects 
treated concurrently with bevacizumab and ME-344. 
Two schedules will be explored in this study, 10 mg/kg weekly for 3 weeks followed by a week 
of rest (Cohort 1) and 10 mg/kg every 2 weeks (Cohort 2), both schedules administered in 
28-day cycles. In a prior Phase 1 study, the MTD was defined as 10 mg/kg weekly, which will be 
used in Cohort 1. The second dose regimen, 10 mg/kg every 2 weeks, will be used for Cohort 2, 
allowing for a more convenient bi-weekly dosing compatible with the majority of current 
treatment regimens for metastatic colorectal cancer. 


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2. 
STUDY OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary 
 
 To estimate PFS at 16 weeks of treatment in 
subjects with mCRC administered ME-344 in 
combination with bevacizumab 
 PFS rate at 16 weeks 
Secondary 
 
 To evaluate the preliminary efficacy of ME-344 
administered in combination with bevacizumab 
in subjects with mCRC 
 PFS 
 ORR using RECIST v1.1 
 DOR 
 OS 
 To determine the safety and tolerability of 
ME-344 administered in combination with 
bevacizumab 
 Incidence and severity of TEAEs and their 
relationship to study drug; change from baseline in 
physical examinations, vital signs, 12-lead ECGs, 
and clinical laboratory evaluations 
 To evaluate the PK of ME-344 administered in 
combination with bevacizumab 
 Maximum observed concentration (Cmax), last 
observed quantifiable concentration (Clast), area 
under the concentration-time curve from time zero 
to time of AUClast  
Exploratory 
 
 To evaluate correlatives of mitochondrial 
metabolism 
 Determine changes in isoleucine/leucine, TCA 
cycle intermediates, short chain acyl carnitine, and 
nucleotide and TCA cycle intermediates 
3. 
INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design 
This is a Phase 1b open-label, multiple dose/schedule sequential study to determine the safety 
and efficacy of the OxPhos inhibitor ME-344 in combination with bevacizumab in subjects with 
recurrent mCRC. 
This study will enroll subjects with metastatic CRC, including but not limited to subjects with 
RAS wild-type or mutant tumors, MSI-H/pMMR, and BRAF V600E, who have progressed or 
demonstrated intolerability to standard approved therapies which include fluoropyrimidine-, 
oxaliplatin-, and irinotecan-based chemotherapies, cetuximab/panitumumab, PD-1 inhibitors, or 
BRAF inhibitors (if clinically indicated), and/or checkpoint inhibitors. Approximately 
40 subjects will be enrolled in the study, in 2 cohorts of 20 subjects each. 
This study consists of three periods: (i) screening, (ii) treatment, and (iii) follow-up. During 
screening, each potential subject will provide informed consent prior to starting any 
study-specific procedures. Screening assessments will be completed within 28 days prior to 
administration of ME-344 combined with bevacizumab. 


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During the treatment period, subjects enrolled in Cohort 1 will receive ME-344 at a dose of 
10 mg/kg IV on Days 1, 8, and 15 in combination with bevacizumab at a dose of 5 mg/kg IV 
administered on Days 1 and 15 of each 28-day cycle.  
Cohort 2 will initiate enrollment after at least 4 subjects in Cohort 1 have completed 4 cycles of 
therapy without evidence of disease progression (i.e., have achieved SD or a response), thus 
establishing a lack of progression in at least 4 [20%] subjects over the first 16 weeks of therapy. 
Subjects in Cohort 2 will receive ME-344 at a dose of 10 mg/kg IV on Days 1 and 15 combined 
with bevacizumab at a dose of 5 mg/kg IV administered on Days 1 and 15 of each 28-day cycle. 
If Cohort 1 does not meet the criteria for initiation of Cohort 2, the Safety Review Committee 
(SRC) will determine whether or not to keep active subjects on study treatment or to close the 
study due to lack of efficacy.  
There is no maximum duration of treatment for this study; subjects will discontinue study drug 
once there is disease progression, unacceptable adverse event(s) (AEs), withdrawal of consent, 
start of new anticancer therapy, or death. 
Follow-up includes the EOT visit and survival follow-up. After patients have discontinued 
treatment for any reason, they will be followed every 3 months, or more frequently as needed, 
until withdrawal of consent, the patient is lost to follow-up, death, or defined end of study. If 
patients withdraw consent, they will be asked if they are willing to be contacted via telephone for 
survival status. If the patient refuses to be contacted, attempts to determine survival status should 
be made via access to public records, where permitted by the local laws. 
All radiographic tumor assessments, preferably CT, or alternatively MRI, will be carried out in 
accordance with RECIST v1.1, and are to be performed every 8 weeks (±7 days) relative to first 
dose of study drug for the first 6 months, then every 3 months until 1 year, and every 4 months 
thereafter. Tumor assessments will be repeated until objective disease relapse, progression, or as 
per standard practice post-progression. 
Safety will be assessed via TEAEs, physical examinations, vital signs, 12-lead ECGs, and 
clinical laboratory evaluations (hematology, serum chemistry, coagulation [at screening for all 
subjects and Day 1 of every cycle for subjects on anticoagulation therapy], urinalysis). Severity 
grading of TEAEs will use the NCI CTCAE v5.0. 
Blood samples for PK analysis will be collected during Cycle 1 on Days 1 and 15 pre-dose, 
5 minutes after the end of infusion, and 1, 2, 3, 6, and 24 hours after the completion of the 
infusion.  
The metabolomic correlative study will be performed on samples obtained from subjects enrolled 
at Rutgers Cancer Institute of New Jersey who consent to the metabolomic sample collection and 
analysis portion of this study. Plasma samples will be collected at timepoints specified in the 
Schedule of Assessments (Appendix 1). Samples will be stored at -70°C until analyzed. Specific 
markers of the mitochondrial oxidative phosphorylation pathway will be analyzed based on the 
outcomes from the planned nonclinical studies at the site. 
See the Schedule of Assessments (Appendix 1) for a detailed list of study procedures and timing. 
Amendments 1 and 2 were not implemented.  


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3.2. 
Number of Subjects 
Approximately 40 subjects will be enrolled in 2 cohorts of 20 subjects each. 
3.3. 
Treatment Assignment 
Enrollment will occur continuously into Cohort 1 until 20 subjects complete radiological 
assessments at 16 weeks or discontinue, progress, start new anticancer therapy, or die, whichever 
happens earlier. 
Subjects enrolled in Cohort 1 will receive ME-344 at a dose of 10 mg/kg IV on Days 1, 8 and 15 
in combination with bevacizumab at a dose of 5 mg/kg IV administered on Days 1 and 15 of 
each 28-day cycle. 
If Cohort 1 demonstrates adequate safety, tolerability, and efficacy, Cohort 2 will open to 
continuous enrollment of 20 subjects. 
Subjects enrolled in Cohort 2 will receive ME-344 at a dose of 10 mg/kg IV on Days 1 and 15 
combined with bevacizumab at a dose of 5 mg/kg IV administered on Days 1 and 15 of each 
28-day cycle. 
Subjects who discontinue bevacizumab due to tolerability may continue treatment with the single 
agent ME-344 at the investigator's discretion, if in the investigator’s opinion they benefit from 
single-agent treatment. Subjects with persistent proteinuria ≥2 g/24 hours must discontinue 
bevacizumab and ME-344. The results of the Phase I study demonstrated that ME-344 alone 
treatment displayed single agent activity leading to PR or SD responses in subjects with solid 
tumors. 
3.4. 
Dose Adjustment Criteria 
If toxicity occurs, the toxicity will be assessed utilizing the NCI CTCAE v5.0, and appropriate 
supportive care treatment will be administered to decrease the signs and symptoms thereof, in 
accordance with the toxicity management guidelines in Table 1. 
No intra-patient dose escalation will be permitted. 
Table 1: 
Toxicity Management 
Adverse 
Reaction 
Severity a 
Drug Modification 
Bevacizumab 
ME-344 
Hypertension  
 Grade 3 or 4 
 (Systolic BP ≥160  
OR Diastolic BP ≥100) 
 Hold bevacizumab until 
BP improves to 
<160/100 mmHg for 
one week with 
treatment; then resume 
at the same dose 
 Hold ME-344 until BP 
improves to 
<160/100 mmHg; then 
resume at the same dose 
 For recurrence despite 
adequate use of 
antihypertensive 
medications, hold ME-344 
and resume at 75% dose 
 Hypertensive crisis 
 
 Discontinue 
bevacizumab  
 Discontinue ME-344 


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Table 1: Toxicity Management (Continued) 
Adverse 
Reaction 
Severity a 
Drug Modification 
Bevacizumab 
ME-344 
 
 Hypertensive 
encephalopathy 
 
 Discontinue ME-344 
PRES 
 Any 
 Discontinue 
bevacizumab 
 Discontinue ME-344 
Congestive 
Heart Failure 
 Any 
 Discontinue 
bevacizumab 
 Discontinue ME-344 
Infusion-related 
reaction 
(see additional 
guidance 
provided in 
Section 5.1.6) 
 Severe 
 If due to bevacizumab, 
discontinue bevacizumab 
 If due to ME-344, 
discontinue ME-344 
 Clinically significant 
 Interrupt infusion, 
resume at a decreased 
rate of infusion after 
symptoms resolve 
 Interrupt infusion, resume 
at a decreased rate of 
infusion after symptoms 
resolve 
 Mild, clinically 
insignificant 
 Decrease infusion rate  
 Decrease infusion rate 
Hemorrhage 
 Grade 3 or 4 
 Discontinue 
bevacizumab 
 Discontinue ME-344  
Renal Injury and 
Proteinuria 
 Nephrotic syndrome; 
proteinuria ≥3.5 g/24 h 
 Discontinue 
bevacizumab 
 Discontinue ME-344 
 Proteinuria ≥2–3.5g/ 
24 h 
 Withhold bevacizumab 
until proteinuria <2 g/24h 
 Withhold ME-344 until 
proteinuria <2 g/24h 
Gastrointestinal 
Perforations and 
Fistulae 
 Gastrointestinal 
perforation, any grade 
 Tracheoesophageal 
fistula, any grade 
 Fistula, Grade 4 
 Fistula formation 
involving any internal 
organ 
 Discontinue 
bevacizumab 
 Discontinue ME-344 
Wound Healing 
Complications 
 Any 
 Withhold bevacizumab 
until adequate wound 
healing 
 Hold ME-344 and resume 
at the same dose once 
adequately healed 
 Necrotizing fasciitis 
 Discontinue 
bevacizumab 
 Discontinue ME-344 


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Table 1: Toxicity Management (Continued) 
Adverse 
Reaction 
Severity a 
Drug Modification 
Bevacizumab 
ME-344 
Neuropathy 
 Grade 2  
 Continue bevacizumab 
 Hold ME-344 and resume 
at 50% dose once the AE 
has resolved to Grade 1  
 Grade 3-4  
 Continue bevacizumab 
 Discontinue ME-344 
Hematologic 
Toxicity 
 Grade 4 
 Hold bevacizumab until 
resolution to Grade 1 or 
baseline; resume at the 
same dose 
 Hold ME-344 until 
resolution to Grade 1 or 
baseline; resume at the 
same dose 
 For recurrence, hold 
ME-344 and resume at 
50% dose 
Other clinically 
significant 
nonhematologic 
toxicity  
 Grade 3  
 If related to 
bevacizumab; hold 
bevacizumab until 
resolution to Grade 1 or 
baseline; resume at the 
same dose  
 Hold ME-344 until 
resolution to Grade 1 or 
baseline; resume at the 
same dose 
 For recurrence, hold 
ME-344 and resume at 
50% dose 
 
 Grade 4 
 If related to 
bevacizumab; hold 
bevacizumab until 
resolution to Grade 1 or 
baseline; resume at the 
same dose if considered 
safe by Investigator 
 For recurrence, 
discontinue bevacizumab 
 Hold ME-344 until 
resolution to Grade 1 or 
baseline; resume at 50% 
dose 
For dose modifications for other adverse reactions reported in subjects treated with bevacizumab refer to the 
Avastin USPI.  
Abbreviations: AE = adverse event; BP = blood pressure; CTCAE = Common Terminology Criteria for Adverse Events; 
NCI = National Cancer Institute; PRES = posterior reversible encephalopathy syndrome. 
a Severity grading per NCI CTCAE v5.0. 
3.4.1. 
Criteria for Withholding, Adjustment, or Discontinuing ME-344 Doses 
Infusion reactions may develop with the first or any subsequent infusion of ME-344. 
Investigators and support staff should be alert to the signs and symptoms that are typically 
associated with infusions reactions. Standard medical intervention should be initiated based on 
the severity of symptoms and good clinical practice. Interventions may include H1 specific 
antihistamines, glucocorticoids, epinephrine, bronchodilators, and general cardio-pulmonary 
support. Refer to Table 1 for guidance regarding infusion reaction management, and for 
additional guidance regarding holding or discontinuing the ME-344 dose. 


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3.4.2. 
Criteria for Withholding or Discontinuing Bevacizumab Doses 
Refer to Table 1 and the bevacizumab US Prescribing Information (Avastin® [US Prescribing 
Information] September 2022 or biosimilar) for additional guidance on holding or discontinuing 
the bevacizumab dose. Except for persistent proteinuria >2+, if bevacizumab is discontinued due 
to intolerability the subject may continue treatment with ME-344 single agent per the 
investigator's discretion. 
3.5. 
Criteria for Study Termination 
Study termination is defined as the time when all study-specific assessments and data collection 
are completed. Upon termination of the study, the Sponsor or designee will conduct site closure 
activities with the Investigator or site staff (as appropriate), in accordance with applicable 
regulations. 
The Sponsor reserves the right to temporarily suspend or terminate the study at any time for 
reasons including, but not limited to, safety issues or ethical reasons. The Sponsor or designee 
will also promptly inform the relevant regulatory authorities of the suspension/termination along 
with the reasons for such action, when applicable. Where required by applicable regulations, 
the Investigator or head of the medical institution must inform the IRB/Independent Ethics 
Committee (IEC). 
4. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
4.1. 
Subject Inclusion Criteria 
Subjects must meet ALL the following inclusion criteria to qualify for the study: 
1. Provide written informed consent to participate. 
2. Male or female subjects ≥18 years of age. 
3. Histological or cytological documentation of adenocarcinoma of the colon or rectum that 
is metastatic (all other histological types are excluded). 
4. Measurable disease following RECIST v1.1. 
5. Subjects who progressed or demonstrated intolerability to prior standard approved 
therapies which include fluoropyrimidine-, oxaliplatin-, and irinotecan-based 
chemotherapies, and cetuximab/panitumumab (if clinically indicated e.g., RAS wild-type 
tumors) in the advanced or metastatic setting. 
6. Subjects with MSI-H/dMMR CRC should have failed or demonstrated intolerance to 
prior programmed death receptor-1 (PD 1)-blocking antibody. 
7. Subjects with BRAF V600E mutation should have failed or demonstrated intolerance to 
BRAF-targeted therapy. 
8. Previous treatment with any investigational drug or anticancer treatment must be 
completed >28 days or 5 half-lives, whichever is longer, before the first dose of study 
treatment. 


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9.  ECOG Performance Status score of 0 or 1 (within 14 days prior to the initiation of study 
treatment). 
10. Adequate bone marrow, liver, and renal function as assessed by the following laboratory 
requirements (within 7 days before Day 1): 
a. Total bilirubin ≤1.5 × the ULN. 
b. ALT and AST ≤2.5 × ULN (5 × ULN for subjects with liver metastases). 
c. CrCL ≥60 mL/min as calculated using the Cockcroft-Gault equation (Appendix 2). 
d. Hemoglobin ≥8.0 g/dL. 
e. Platelet count >100,000/mm3, ANC >1500/mm3. 
f. INR/PT 1.5 × ULN (subjects who are therapeutically treated with an agent such as 
warfarin or heparin will be allowed to participate provided that no prior evidence of 
underlying abnormality in coagulation parameters exists. 
g. Urine protein <2+. Subjects discovered to have ≥2+ proteinuria on dipstick urinalysis 
at baseline will undergo a 24-hour urine collection and must demonstrate <2.0 g of 
protein in 24 hours.  
11. QT-interval corrected according to Fridericia’s formula (QTcF) ≤470 milliseconds 
(msec). 
12. Women of childbearing potential and men must agree to use adequate contraception 
before entering the program until at least 8 weeks after the last study drug (ME-344) 
administration and for at least 6 months after the last dose of bevacizumab. The 
Investigator or designee is to advise the subject on how to achieve adequate 
contraception. Adequate contraception is defined in the study as any medically 
recommended method (or combination of methods) as per standard of care. Women of 
childbearing potential must have a blood or urine pregnancy test performed a maximum 
of 7 days before start of study treatment, and a negative result must be documented 
before start of study treatment. Women are considered not of childbearing potential if 
they have been without menses for 1 year and have follicle stimulating hormone (FSH) 
levels considered to be post-menopausal. 
4.2. 
Subject Exclusion Criteria 
Subjects must NOT meet any of the following exclusion criteria to qualify for the study: 
1. Untreated brain metastases, spinal cord compression, or primary brain tumor. 
2. Symptomatic brain metastases, leptomeningeal disease, spinal cord compression, or 
primary brain tumor. Notes: Patients previously treated or untreated for this condition 
who are asymptomatic in the absence of corticosteroid and anti-epileptic therapy are 
allowed. Brain metastases must be stable for ≥ 4 weeks, with imaging (e.g., MRI or CT) 
demonstrating no current evidence of progressive brain metastases at screening. 
3. History of CNS disease (excluding asymptomatic lacunar infarction) except CVA 
>6 months with preserved performance status. 


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4. History of pulmonary hemorrhage/hemoptysis Grade ≥2 (defined as bright red blood of at 
least 2.5 mL) within 1 month prior to enrollment. 
5. Evidence of uncontrolled or unstable cardiovascular disease, myocardial infarction 
(within 6 months), unstable angina pectoris, NYHA classification ≥ Grade II congestive 
heart failure, serious arrhythmias requiring drug therapy, history of congenital long QT 
syndrome, congenital short QT syndrome, Torsades de Pointes, or Wolff-Parkinson-
White syndrome. 
6. Bevacizumab or aflibercept therapy ≤ 3 weeks prior to starting study treatment 
7. Peripheral neuropathy Grade ≥ 2 
8. Any of the following comorbidities: 
a. Uncontrolled hypertension (systolic blood pressure >150 mmHg or diastolic blood 
pressure >90 mmHg) despite best medical management. 
b. Uncontrolled diabetes mellitus (with HbA1c >8.5% at Screening). 
c. Active peptic ulcer. 
d. Unhealed wound (except for suturing associated with implanted port placement). 
e. Other clinically significant disease (such as interstitial pneumonia or renal 
impairment). 
f. Systemic infection requiring treatment. 
9. Other severe, acute, or chronic medical or psychiatric condition or laboratory abnormality 
that may increase the risk associated with study participation or study drug administration 
or that may interfere with the interpretation of study results and, in the judgment of the 
Investigator, would make the patient an inappropriate candidate for the study. 
10. Major surgical procedure within 28 days prior to study treatment initiation (such as open 
chest, thoracoscopic surgery, laparoscopic surgery), unless only colostomy is performed; 
open biopsy or suturing for major trauma within 14 days of study treatment initiation; or 
planned major surgical procedure (open chest, laparoscopy) during the study (“major 
surgical procedures” does not include central venous port insertion). 
11. Pregnant, breastfeeding, positive pregnancy test, or women who are unwilling to use 
contraception; men who are unwilling to use contraception during the study. 
12. Known seropositive for, or active infection with hepatitis B virus: 
 HBsAg positive. 
 HBsAg negative, anti-HBs positive and/or anti-HBc positive and detectable viral 
DNA by PCR. 
Note: Subjects who are HBsAg positive and viral DNA PCR negative are eligible. These 
subjects should receive prophylactic therapy for hepatitis as per institutional standards.  
13. Known seropositive for, or active infection with hepatitis C virus: 
 Subjects with positive hepatitis C virus (HCV) antibodies are eligible with negative 
PCR test for HCV. 


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14. Active and uncontrolled infection with HIV, or with AIDS, or currently taking 
medications for HIV that are contraindicated for concomitant use in this study. 
15. Symptomatic or uncontrolled infection with human T-cell leukemia virus type 1. 
16. History of other primary malignancy in the past 5 years or concurrent active malignancies 
(synchronous malignancies, requiring treatment; excluding malignancies that are 
expected to be completely cured, such as intramucosal carcinoma and carcinoma in situ, 
curatively treated cervical cancer in situ, non-melanoma skin cancer, superficial bladder 
tumors [Ta (non-invasive tumor), Tis (carcinoma in situ), and T1 (tumor invades lamina 
propria)], and asymptomatic localized prostate cancer with no requirement for systemic 
therapy or requiring only hormonal therapy and with normal prostate-specific antigen 
values within ≥12 months prior to enrollment). Breast cancer survivors on hormone 
therapy may be eligible if blood count is adequate and history of remission is >5 years 
ago. 
17.  Venous thromboembolism (unless appropriately treated and stable on anticoagulant for 
at least 2 weeks). 
18. Arterial thrombosis or arterial thromboembolism such as myocardial infarction, transient 
ischemic attack, or cerebrovascular accident in the last 6 months prior to enrollment. 
19. Subjects who discontinued prior treatment with bevacizumab, ziv-aflibercept, and/or 
ramucirumab because of severe events of hemorrhages, hypertension, fistula, perforation, 
arterial/venous thromboembolism, PRES, renal injury, or proteinuria. 
20. Concomitant use of strong inhibitors and strong inducers of CYP enzymes and 
transporters. 
4.3. 
Discontinuation of Treatment and Subject Withdrawal Criteria 
Subjects will be discontinued from study treatment for any of the following reasons: 
 Disease progression (see Section 6). 
 Intolerable toxicity, including unacceptable and clinically significant laboratory values 
thought to be related to drug toxicity. 
 Pregnancy. 
 Subject request to discontinue treatment. 
 Subject request to withdraw from the study. 
 Conditions requiring therapeutic intervention not permitted by the protocol. 
 Intercurrent illness (at the Investigator’s discretion). 
 Non-compliance/lost to follow-up. 
 Investigator or Sponsor determines it is in the best interest of the subject. 
After discontinuation from study treatment, subjects must be followed for AEs for 30 calendar 
days after their last dose of study medication and return for the End of Treatment (EOT) visit. 
All new AEs occurring during this period must be reported and followed until resolution, unless, 


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in the opinion of the Investigator, these AEs are not likely to improve because of the underlying 
disease. In such case, the Investigator must record the reason for this decision in the subject’s 
medical record. 
All subjects who have Grade ≥3 laboratory abnormalities (NCI CTCAE v5.0) at the time of 
discontinuation must be followed until the laboratory values have returned to Grade ≤2 or 
baseline, unless in the opinion of the Investigator it is not likely that these values will improve. 
In such case, the Investigator must record the reason for this decision in the subject’s medical 
record. 
5. 
STUDY DRUG MATERIALS AND MANAGEMENT AND 
TREATMENT OF SUBJECTS 
5.1. 
ME-344 
5.1.1. 
Description of the Active Pharmaceutical Ingredient 
The ME-344 drug substance is a small molecule manufactured by chemical synthesis and 
contains no animal or plant-derived components. ME-344 is a chiral compound and is 
manufactured predominantly as a single stereoisomer that is dextrorotatory. 
5.1.2. 
Description of the Study Drug Product 
The drug product is an aqueous solution for IV infusion. The drug substance is formulated as a 
35 mg/mL solution in 30% weight per volume (w/v) Captisol® (b-cyclodextrin sulfobutyl ethers, 
sodium salts) in water for injection. The drug product comprises the same formulation used in 
the Good Laboratory Practice (GLP) preclinical toxicology studies, and similar Captisol 
formulations are currently used for several marketed drugs. 
5.1.3. 
Study Drug Packaging and Labeling 
ME-344 is supplied in glass vials, packaged into boxes. 
5.1.4. 
Study Drug Storage 
The drug product is stored refrigerated (2–8°C, 36–46°F).  
Any variance from these storage conditions should be reported to the Sponsor on detection, and 
ME-344 should be quarantined until the Sponsor authorizes usage or otherwise. 
5.1.5. 
Study Drug Preparation 
Calculate the amount of ME-344 required based on body weight at 10 mg per kg body weight, up 
to a maximal dose of 1000 mg (100 kg x 10 mg/kg) for subject with body weight exceeding 
100 kg. Use aseptic technique for preparation. ME-344 drug for infusion should only be prepared 
the morning of the planned dosing date –do not prepare and store overnight. Calculate the 
amount of ME-344 and add to normal saline (0.9% Sodium Chloride) to bring the total volume 
to 250 mL. The infusion line may be primed with normal saline. Overfill of normal saline in the 
bag should follow institutional procedures and not be >5%. On visual inspection, the solution for 


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infusion should be colorless to slightly yellowish and free of particles. Ensure proper labeling of 
the ME-344 study drug infusion bag. 
The infusion bag should be prepared the morning of infusion, protected from sunlight with 
infusion completed within 24 hours of reconstitution, as dictated by standard operating 
procedures (SOPs) at the site. 
5.1.6. 
Study Drug Administration 
ME-344 will be infused IV over up to 60 minutes. 
 Cohort 1: 10 mg/kg on Days 1, 8, and 15 of each 28-day cycle. 
 Cohort 2: 10 mg/kg on Days 1 and 15 of each 28-day cycle. 
ME-344 will be infused 30 minutes prior to bevacizumab administration. 
The following guidance may be instituted prior to administration of ME-344 if there is a concern 
for increased blood pressure or potential infusion reactions. 
Approximately 30 minutes prior to the start of the ME-344 infusion, pre-medicate with: 
 650 mg acetaminophen orally (PO). 
 25–50 mg diphenhydramine PO or IV. 
 20 mg famotidine PO or IV or equivalent available H2 blocker. 
If infusion reaction is experienced, refer to Table 1 for guidance regarding infusion reaction 
management. 
5.1.7. 
Study Drug Accountability 
The Investigator or designee is responsible for accountability of all used and unused ME-344 
supplies at the site. 
The Sponsor or its representatives must be granted access on reasonable request to check drug 
storage, dispensing procedures, and accountability records. All ME-344 inventories must be 
made available for inspection by the monitor, Sponsor or its designee, and regulatory agency 
inspectors upon request. 
5.1.8. 
Study Drug Disposition 
At the end of the study, ME-344 will be returned to the Sponsor or designee or destroyed. 
ME-344 must not be destroyed unless prior approval has been granted by the Sponsor or 
designee. 
5.2. 
Bevacizumab 
Bevacizumab (Avastin brand or any US-approved biosimilar) will be administered IV at a dose 
of 5 mg/kg on Days 1 and 15 of each 28-day cycle in Cohorts 1 and 2. To the extent possible 
each subject should use a single bevacizumab product throughout the trial.  
Bevacizumab will be prepared for infusion per package insert instructions and/or institutional 
procedures. 


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US-licensed brand name or biosimilar bevacizumab will be sourced commercially. Refer to the 
US Prescribing Information (Avastin [US Prescribing Information] September 2022 or 
biosimilar) for further details regarding storage, handling, preparation, and administration. 
5.3. 
Concomitant Medications 
Prior and concomitant medications will be recorded from 28 days prior to Cycle 1 Day 1 until 
the EOT visit or start of new anticancer treatment (whichever occurs first). 
5.3.1. 
Permitted Concomitant Medications 
Premedication with antiemetics is allowed according to standard practice guidelines. 
Medications considered necessary for the subject’s safety and well-being may be given at the 
discretion of the Investigator except for those listed in Section 5.3.2. 
Vaccinations, including the COVID-19 vaccine, are permitted, except for live attenuated 
vaccines. It is recommended that vaccinations be administered at least 2 weeks prior to Day 1 of 
the study. 
The following medications should be used with caution: 
 Medications Which Alter Serum Electrolytes 
Subjects requiring medications that have the potential to alter serum electrolytes 
(e.g., diuretics) should be monitored closely for electrolyte abnormalities, as these can 
contribute to the risk of QT prolongation and ventricular arrhythmias. 
 Medications Known to Prolong the QT Interval 
Although no significant effect on QTc interval was observed in Study ME-344-001, 
drugs known to prolong the QT interval should be used with caution. If, after a subject 
has been enrolled, he/she requires the concomitant use of any of the medications that may 
cause QT interval prolongation (Appendix 3), study drugs will be held in the event the 
QTc is prolonged beyond 500 msec. If the QTc returns to ≤470 msec, the subject may 
resume study treatment with the approval of the Medical Monitor if no more than 2 
ME-344 doses were missed. 
Ondansetron or palonosetron should be used with caution due to the possible risk of 
QT prolongation (Appendix 3); IV doses of 0.15 mg/kg every 4 hours for 3 doses may be 
used (no single IV dose should exceed 16 mg), or a single oral dose of 24 mg may be 
used. Prochlorperazine and Aprepitant may be used safely. 
 Sensitive In Vivo CYP Substrates or CYP Substrates with a Narrow Therapeutic 
Range  
In in vitro studies with human liver microsomes, ME-344 inhibited all CYP enzymes 
tested. In subjects receiving ME-344 as an IV infusion, plasma concentrations declined 
rapidly and were approximately 1% of Cmax around 6 hours after the end of infusion. 
Since ME-344 is administered either weekly (on Days 1, 8, and 15), or every two weeks 
(on Days 1 and 15) dosing regimen, the potential for clinically relevant inhibition of CYP 
enzymes is low. Nevertheless, concomitant use of medications that are sensitive in vivo 


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CYP substrates or CYP substrates with a narrow therapeutic range (Appendix 4) should 
be used with caution during the study. 
5.3.2. 
Prohibited Concomitant Medications 
The following treatments are prohibited while in this study: 
 No other investigational therapy should be given to subjects. 
 No other anticancer agents should be given to subjects. If such agents are required, the 
subject must first be withdrawn from the study. 
 Herbal products and dietary supplements are not allowed throughout the study. Subjects 
are required stop use of these products prior to the first dose of study drug. 
 Medications Metabolized via Cytochrome P450: 
No clinical information is available on drug-drug interactions for ME-344. Given the lack 
of information regarding the cytochrome P450 (CYP) enzymes responsible for the 
metabolism of ME-344, concomitant medications that are strong inhibitors or inducers of 
major CYP metabolizing enzymes are prohibited. A list of all agents (with strong 
modulators appearing in bold font) is presented in Appendix 5. Closely monitor for 
safety or efficacy for concomitant use of moderate inhibitors and inducers of CYP 
enzymes and transporters. 
5.4. 
Treatment Compliance 
Subjects will be administered study drugs under the supervision of the Investigator or designated 
study site personnel. Study drug dose, date of administration, and infusion start and stop times 
will be documented. 
5.5. 
Randomization and Blinding 
Not applicable; this is an open-label study. 
6. 
ASSESSMENT OF EFFICACY 
6.1. 
Tumor Response 
Baseline tumor measurements by CT or MRI should be performed as close as possible to the 
start of treatment, but no longer than 6 weeks prior to Cycle 1 Day 1. Subjects should be 
re-evaluated at the Investigator’s discretion, but at a minimum of every 8 weeks (±7 days) from 
Cycle 1 Day 1 for the first 6 months, then every 3 months until 1 year, and every 4 months 
thereafter. Radiologic images should be performed consistently for the areas of disease 
involvement taken for the study evaluation. 
Assessments of disease response and progression should be made according to RECIST v1.1 
(Eisenhauer 2009). 


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6.2. 
Pharmacokinetics 
Blood samples for PK analysis will be collected during Cycle 1 on Days 1 and 15 pre-dose 
ME-344, 5 minutes after the end of infusion, and 1, 2, 3, 6, and 24 hours after the completion of 
the infusion.  
PK parameters include: 
 maximum observed concentration (Cmax). 
 last observed quantifiable concentration (Clast). 
 area under the concentration-time curve from time zero to time of AUClast. 
Data from this study may be pooled with other studies and may be analyzed by other methods. 
6.3. 
Correlatives of Mitochondrial Metabolism 
Metabolomics analysis will be performed at a single center on patient plasma samples as 
a correlative study. Similar to ME-344, metformin is a mitochondrial Complex I inhibitor. 
Metabolomics analysis of tumor biopsies from ovarian cancer patients after metformin treatment 
revealed suppressed TCA cycle intermediates and short chain acyl carnitine, increased 
isoleucine/leucine, and changes in nucleotide intermediates and glutathione-related metabolites. 
Consistent with the metformin-induced metabolic changes, metabolomics analysis of a human 
acute myeloid leukemia cell line treated in vitro with ME-344 revealed changes in several 
pathways, including pyrimidine and purine metabolism, valine/isoleucine/leucine biosynthesis, 
ascorbate and aldarate metabolism, pantothenate and Co-A biosynthesis, and TCA cycle 
intermediates. A metabolomics analysis of plasma from type 2 diabetes mellitus (T2DM) 
patients treated with metformin revealed similar changes to those detected in the ovarian cancer 
tumor samples, supporting the analysis of plasma samples to analyze the metabolic changes 
induced by mitochondrial Complex I inhibitors.  
Blood samples will be collected from patients at the following time points: 
 Cycle 1 Day 1 (pre-dose and 6 hours post-dose). 
 Cycle 1 Day 15, Cycle 2 Day 1, and Cycle 3 Day 1. 
Blood will be collected in a fasting state with minimum fasting time of 4 hours. Plasma samples 
will be flash frozen, processed, and analyzed for metabolomics markers. It is anticipated that 
changes will be detected in isoleucine/leucine, TCA cycle intermediates, short chain acyl 
carnitine, and nucleotide and TCA cycle intermediates. 
The metabolomic correlative study will be performed on samples obtained from subjects enrolled 
at Rutgers Cancer Institute of New Jersey who consent to the metabolomic sample collection 
and analysis portion of this study. Plasma samples will be collected at timepoints specified in the 
Schedule of Assessments (Appendix 1). Samples will be stored at -70°C until analyzed. Specific 
markers of the mitochondrial oxidative phosphorylation pathway will be analyzed based on the 
outcomes from the planned nonclinical studies at the site. 


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7. 
ASSESSMENT OF SAFETY 
The Schedule of Assessments (Appendix 1) summarizes the frequency and timing of all 
applicable study assessments, including allowable windows for study visits and 
assessments/procedures. Written informed consent must be provided before any study related 
procedures are performed. 
See Section 4.1 and Section 4.2 for eligibility criteria. Eligibility must be confirmed by the 
Medical Monitor prior to the first dose of study drug. 
7.1. 
Safety Parameters 
7.1.1. 
Demographic/Medical History 
Demographic information includes age, gender, race, and ethnicity. Relevant medical history 
(past and concurrent) includes cancer diagnosis (and tumor locations) and history, 
histopathology, date and method of diagnosis, and prior antitumor therapy. 
7.1.2. 
Vital Signs 
Vital signs include blood pressure (systolic and diastolic), heart rate, and temperature. 
7.1.3. 
Weight and Height 
Weight is measured on Day 1 of each cycle, as both study drugs are dosed based on weight. 
Height is measured only at screening. 
7.1.4. 
Physical Examination 
Complete physical examination, including assessment of peripheral neuropathy, is required at the 
Screening and EOT visits. Symptom-directed physical examinations, including assessment of 
peripheral neuropathy will be performed at all other visits. 
7.1.5. 
ECOG Performance Status 
The scale in Appendix 6 is to be used to assess ECOG Performance Status (Oken 1982). 
7.1.6. 
Electrocardiogram (ECG) 
Subjects should be resting and semi-recumbent for triplicate ECGs. Data collection includes 
abnormal findings; if abnormal finding(s) are assessed as clinically significant, the finding(s) 
should be reported as AE(s). The Investigator is responsible for interpreting and measuring ECG 
data. 
7.1.7. 
Laboratory Evaluations 
Blood and urine for laboratory evaluations will be collected and analyzed at a local/site 
laboratory in accordance with quality laboratory standards. Hematology, serum chemistry, 
urinalysis, and other parameters to be tested are listed in Table 2. 


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Table 2: 
Clinical Laboratory Tests 
Laboratory 
Test Category 
Specific Laboratory Tests 
Hematology: 
Hemoglobin 
Neutrophils (absolute) 
Hematocrit 
Monocytes 
Erythrocyte (red blood cell [RBC]) count 
Eosinophils 
Quantitative platelet count 
Lymphocytes 
Total leukocyte (white blood cell [WBC]) count 
Basophils 
Mean corpuscular hemoglobin (MCH) 
Platelets 
Serum 
Chemistry: 
Aspartate aminotransferase (AST) 
Calcium 
Alanine aminotransferase (ALT) 
CO2 or bicarbonate 
Alkaline phosphatase (ALP) 
Blood urea nitrogen (BUN) or urea 
Albumin 
Creatinine 
Total bilirubin (if total bilirubin is ≥2 × ULN 
with no evidence of Gilbert’s syndrome, then 
fractionate into direct and indirect bilirubin) 
Glucose 
Sodium 
Chloride 
Potassium 
Lipase 
Total protein 
Lactate dehydrogenase (LDH) 
Phosphorus 
Amylase, magnesium 
Coagulation: 
Activated partial thromboplastin time (aPTT) 
International normalized ratio for 
prothrombin time (INR/PT) 
Urinalysis: 
pH 
Blood 
Protein 
Specific gravity 
Glucose 
Ketones 
Serology: 
Hepatitis B core antibody (HBcAb) 
Hepatitis C antibody 
Hepatitis B surface antibody (HBsAb) 
Hepatitis C PCR (only if hepatitis C 
antibody is positive) 
Hepatitis B surface antigen (HBsAg) 
 
Hepatitis B PCR (only if HBcAb and HBsAg 
are positive) 
 
Pregnancy 
Serum beta human chorionic gonadotropin 
(βhCG) pregnancy test for females of 
childbearing potential (screening only), urine 
or serum test at all other visits 
 


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8. 
ADVERSE EVENTS 
An AE is any untoward medical event that occurs in a subject following the start of study drug 
administration, whether or not the event is considered drug related. An AE can therefore be any 
of the following: 
 A pre-existing medical condition can be recorded as an AE if the condition worsens by at 
least one grade following the start of study drug administration and if the frequency, 
severity, or character of the condition worsens during the study. When recording on the 
electronic case report form (eCRF) it is important to capture applicable descriptors 
(e.g., more frequent arthritic pain). 
 Disease-related out-of-range laboratory values will not be considered AEs/SAEs if there 
is no change from the screening laboratory values. Any deterioration in a laboratory value 
or other clinical test that is associated with symptoms or leads to a change in study 
treatment or concomitant treatment or discontinuation from study drug or deemed 
clinically significant by the Investigator will be considered an AE. 
AEs will be recorded using the terminology defined in the Medical Dictionary for Regulatory 
Activities (MedDRA). 
A TEAE is defined as an AE starting or worsening in CTCAE grade after the first dose until 
30 days after the last dose of study drug, or start of new anticancer therapy, whichever is earlier. 
Death related to disease progression is not considered an AE. Signs and symptoms related to 
disease progression are not considered AEs. Anticipated fluctuations of pre-existing conditions, 
including the disease under study that do not represent a clinically significant exacerbation or 
worsening, need not be considered AEs. 
Only one AE term should be recorded in the event field on the AE eCRF if a specific AE is 
attributable to a primary diagnosis. AEs that are secondary to other events should be identified 
by their primary cause with the exception of severe or serious secondary events. For example: 
 If a subject initially had diarrhea and is subsequently diagnosed with colitis, this event 
should be consolidated to one data entry, which is colitis. 
 If a subject had diarrhea that resulted in mild dehydration, only diarrhea should be 
reported in the eCRF. 
 If a subject who had diarrhea developed acute renal failure, both acute renal failure and 
diarrhea will be entered separately. 
For AEs, a diagnosis should be recorded on the AE eCRF rather than individual signs and 
symptoms (e.g., record only colitis rather than diarrhea, abdominal pain, decreased appetite). 
However, if a constellation of signs and symptoms cannot be medically characterized as a single 
diagnosis or syndrome, each individual event should be reported on the AE eCRF. If a diagnosis 
is subsequently established, all previously reported AEs based on signs and symptoms should be 
nullified and replaced on the AE eCRF based on a single diagnosis, with a starting date that 
corresponds to the starting date of the first symptom of the eventual diagnosis. 


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8.1. 
Assessment of Severity 
The term “severity” is used to describe the intensity of an AE. Severity will be graded according 
to NCI CTCAE v5.0.  For AEs not covered by CTCAE, each AE will be assigned a category by 
the Investigator as described in Table 3. 
Table 3: 
NCI CTCAE v5.0 Adverse Event Grading System 
Grade 
Comments 
1 
Asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not 
indicated 
2 
Minimal, local, or noninvasive intervention indicated, limiting age appropriate instrumental ADLa 
3 
Hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADLb 
4 
Urgent intervention indicated 
5 
Death related to AE 
Abbreviations: ADL = activities of daily living; AE = adverse event. 
a Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc. 
b Self-care ADL refers to bathing, dressing, and undressing, feeding self, using the toilet, taking medications, and not 
bedridden. 
8.2. 
Assessment of Causality 
The Investigator is obligated to assess the relationship between study drug and the occurrence 
of each AE. The Investigator is to use his/her best medical judgement in determining the likely 
relationship of the AE to ME-344 and to bevacizumab. The relationship of an AE or SAE to 
study drug is to be classified as either ‘Related’ or ‘Not Related’. 
8.3. 
Documenting Adverse Events 
AEs should be documented in the source documents and entered in the subject’s case report form 
(CRF; or eCRF) with action taken with respect to the study drug and outcome. 
8.4. 
Clinical Laboratory Changes 
Clinical laboratory measurements are reported in the subject’s CRF (or eCRF). Laboratory 
abnormalities are to be reported as AEs only when deemed clinically significant (i.e., led to 
treatment interruption or discontinuation, associated with initiation of concomitant therapy, or 
with hospitalization). 
8.5. 
Adverse Event Follow-up 
AEs occurring on study will be followed until resolution or return to baseline. AEs leading to 
discontinuation of study drug will be followed for minimum of 30 days after the last dose of 
study drug or until resolution, whichever comes first. 


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8.6. 
Documenting Action Taken with Study Drug in Response to the AE  
The Investigator will record the action taken regarding the study treatment in response to an AE: 
 Dose not changed 
 Dose-reduced 
 Study drug interrupted 
 Study drug withdrawn 
 Not applicable 
8.7. 
Outcome of Adverse Event 
The Investigator will record the outcome of the AE as follows: 
 Recovered/resolved 
 Recovered/resolved with sequelae  
 Not recovered/not resolved 
 Death 
 Unknown 
8.8. 
Serious Adverse Events 
8.8.1. 
Definition  
An SAE is an event that meets any of the following criteria: 
 Adverse event resulting in death (Grade 5 toxicity) 
 Life-threatening 
 Inpatient hospitalization or prolongation of existing hospitalization 
 Persistent or significant disability/incapacity 
 Congenital anomaly/birth defect in the offspring of a subject who received any study 
drug 
 Other: Important medical events that may not result in death, be life-threatening, or 
require hospitalization, may be considered an SAE when, based upon appropriate medical 
judgment, they may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. 
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 inpatient hospitalization 
 Development of drug dependency or drug abuse 


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8.8.2. 
Definition of Terms 
Life threatening: An AE is life threatening if the subject was at immediate risk of death from 
the event as it occurred (i.e., it does not include a reaction that if it had occurred in a more 
serious form might have caused death). For example, drug induced hepatitis that resolved 
without evidence of hepatic failure would not be considered life threatening even though 
drug -induced hepatitis can be fatal. 
Hospitalization: Adverse events requiring hospitalization should be considered SAEs. 
Hospitalization for elective surgery or routine clinical procedures that are not the result of an AE 
(e.g., elective surgery for a pre-existing condition that has not worsened) need not be considered 
AEs or SAEs. If anything, untoward is reported during the procedure, that occurrence must be 
reported as an AE, either 'serious' or 'non-serious' according to the usual criteria. 
If there is a question as to whether 'hospitalization' occurred or was necessary, the AE should be 
considered serious. 
Disability/incapacitation: An AE is incapacitating or disabling if the experience results in 
a substantial and/or permanent disruption of the subject's ability to carry out normal life 
functions. 
8.8.3. 
Reporting Serious Adverse Events 
All SAEs must be reported to the Sponsor or Sponsor’s designee (the Pharmacovigilance 
contract research organization [CRO]) within 24 hours of the Investigator becoming aware of the 
SAE. 
To report an SAE, please refer to the applicable study manual or eCRF for SAE reporting 
instructions. 
The 4 minimum criteria for a valid SAE report include: 
 Study identifier 
 Subject identifier 
 Event term 
 Study drug 
All SAEs will be reported for up to 30 days after the last dose of study drug. After 30 days 
post-last dose, only SAEs deemed related to study drug will be reported to the Sponsor. 
The Investigator must report new significant follow-up information for these events to the CRO 
immediately (i.e., no more than 24 hours after becoming aware of the information). 
New significant information includes the following: 
 New signs or symptoms or a change in the diagnosis 
 Significant (requiring therapy or hospitalization) new diagnostic test results  
 Change in causality based on new information 
 Change in the event’s outcome, including recovery 
 Additional narrative information on the clinical course of the event 


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All deaths should be recorded and reported to the Sponsor. Disease progression, hospitalization 
to assess disease progression, and death due to disease progression as determined by the 
Investigator are not considered SAEs. All other causes of death must be reported as SAEs. The 
Investigator should make every effort to obtain and send death certificates and autopsy reports 
for all deaths to the Sponsor. 
All SAEs also must be reported by each site to the appropriate IRB/IEC in accordance with local 
requirements for reporting SAEs to their IRB/IEC. 
In the event of a medical emergency (requiring immediate attention regarding operation of the 
clinical study and/or the use of study drug), study site staff will apply appropriate medical 
intervention according to current standards of care and will contact the Medical Monitor or 
designee (e.g., CRO representative) for further consultation and guidance. 
8.8.4. 
Sponsor Reporting to Regulatory Authorities 
The Sponsor is responsible for reporting suspected unexpected serious adverse reactions 
(SUSARs) in an expedited manner to regulatory authorities, as required per local regulations. 
The Sponsor or designee will report to the original manufacturer any SAE deemed to be related 
to bevacizumab and considered unexpected according to the US Prescribing Information. 
8.8.5. 
Pregnancies 
To ensure subject safety, any pregnancy in a subject on study treatment must be reported within 
24 hours of learning of its occurrence. Pregnancy occurring up to 3 months after receiving the 
last dose of study drug must be reported. 
Study drug must be discontinued in a subject who becomes pregnant. The pregnancy must be 
followed to determine outcome, including spontaneous or voluntary termination, details of the 
birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications. Subjects must be followed at least 8 weeks after giving birth to 
a child. 
Pregnancy in and of itself is not an AE; however, certain situations and/or outcomes of 
pregnancy can be (see below). Any pregnancies should be recorded on a Pregnancy Form and 
reported by the Investigator to the Sponsor or designee. Pregnancy follow-up should be recorded 
and should include an assessment of the possible relationship to the study drug of any pregnancy 
outcome  
Examples of pregnancy outcomes that are SAEs include reports of: 
 Congenital anomalies or developmental delay in the fetus or the child 
 Fetal death or spontaneous abortion 
 Suspected adverse reactions in the neonate that are classified as serious 
Pregnancy case information should be collected for the female partners of any males who took 
study treatment in this study. Consent to report information regarding these pregnancy outcomes 
must first be obtained from the mother. 


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9. 
STATISTICS 
A Statistical Analysis Plan (SAP) will be prepared and finalized before study database lock and 
analysis of data. Any deviations from the final SAP will be described and justified in the clinical 
study report. All statistical analyses will be performed using the statistical software application 
SAS®. 
9.1. 
Sample Size Justification 
The PFS rate >20% is considered as a positive efficacy signal to proceed to a later stage trial. 
With a sample size of 20 subjects in each cohort, assuming the true PFS rate at 16 weeks is 30%, 
there is 89% chance to observe PFS rate ≥20% (i.e., ≥4 of 20 subjects progression-free) based on 
binomial distribution. If 7 out of 20 subjects achieve PFS at 16 weeks (observed PFS rate of 
35%), we are 90% confident that the true PFS rate >20% as the lower bound of 80% CI is 20.7%. 
If 12 out of 40 subjects achieve PFS at 16 weeks (observed PFS rate of 30%), we are 90% 
confident that the true PFS rate >20% as the lower bound of 80% CI is 20.5%. 
Table 4 summarizes the 95% and 80% exact CIs when observed PFS rate are 20% to 50%, 
respectively.  
Table 4: 
Observed Progression-free Survival Rate with Exact 95% and 80% 
Confidence Intervals 
 
N=20 
N=40 
Observed 
PFS Rate 
Number of 
PFS Subjects 
95% CI (%) 
80% CI 
(%) 
Number of 
PFS Subjects 
95% CI 
(%) 
80% CI 
(%) 
20% 
4 
5.7, 43.7 
9.0, 36.1 
8 
9.1, 35.6 
12.0, 30.4 
25% 
5 
8.7, 49.1 
12.7, 41.5 
10 
12.7, 41.2 
16.2, 35.9 
30% 
6 
11.9, 54.3 
16.6, 46.7 
12 
16.6, 46.5 
20.5, 41.2 
35% 
7 
15.4, 59.2 
20.7, 51.8 
14 
20.7, 51.7 
24.9, 46.3 
40% 
8 
19.1, 63.9 
24.9, 56.7 
16 
24.9, 56.7 
29.4, 51.4 
45% 
9 
23.1, 68.5 
29.3, 61.5 
18 
29.3, 61.5 
34.1, 56.3 
50% 
10 
27.2, 72.8 
33.8, 66.2 
20 
33.8, 66.2 
38.8, 61.2 
If 10 (50%) of 20 subjects experience Grade ≥3 treatment-emergent neuropathy, the 95% CI for 
incidence rate of Grade ≥3 neuropathy will be (27.2%, 72.8%) based on exact method. 
9.2. 
Analysis Populations 
 The ITT Population is defined as all enrolled subjects who receive at least one dose of 
ME-344. 
 The EE Population includes all subjects who receive at least one dose of ME-344 and 
have adequate Week 16 efficacy assessments or develop progression of disease (or died) 
prior to Week 16. The EE Population will be used as the primary analysis population for 
assessing response to the study drugs. 


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 The PK Population includes all subjects who receive at least one dose of ME-344 and 
have at least one evaluable post-baseline ME-344 PK concentration. PK analysis will be 
conducted using the PK Population. 
 The Safety Population includes all subjects who receive at least one dose of ME-344. 
Safety analyses will be performed on the Safety Population. 
9.3. 
Statistical Analysis 
9.3.1. 
General Methodology 
In general, data will be summarized using number and percentage for discrete parameters, and by 
descriptive statistics (number of observations, mean, standard deviation, median, minimum, and 
maximum) for continuous parameters. 
No imputation of values for missing data will be performed. 
All analyses will be conducted by cohort. Pooled summaries (Cohort 1 and Cohort 2) may be 
conducted if deemed meaningful. Subgroup analysis by baseline demographic or disease 
characteristics may be conducted. 
9.3.2. 
Demographics, Baseline Characteristics, and Subject Disposition 
Demographic and baseline disease characteristics will be summarized by cohort for the 
ITT Population. Data to be tabulated will include demographic features such as gender, age, race, 
and ethnicity, as well as disease specific status. The number and percentage of subjects who 
complete the study or who withdraw for any reason will be presented by cohort. Disposition of 
study treatment will be summarized as well for the ITT Population. 
Prior and concomitant medications will be coded using the World Health Organization (WHO) 
Drug Dictionary and summarized for the Safety Population. 
9.3.3. 
Efficacy Analysis 
The primary efficacy endpoint (PFS rate at Week 16) will be evaluated using the KM method for 
the ITT Population when the last subject in Cohort 1 completes the efficacy assessment at 
Week 16 (or discontinues, develops disease progression, starts new anticancer therapy, or dies, 
whichever occurs earlier). The KM estimates for median, first and third quartiles (Q1 and Q3, 
respectively), and the PFS rate at Week 16 will be presented. The PFS KM plot will be 
generated. Time-to-event (progression or death due to any cause) will be calculated from the day 
of first study drug dose to the first observation of progressive disease (PD) as assessed by the 
Investigator per RECIST v.1.1 or death from any cause. Subjects without a PD or death event 
will be censored at last adequate assessment date or first dose date if no adequate postbaseline 
assessment is available. 
The OS time is defined as the time from first study drug dose to death from any cause. Subjects 
without a death event will be censored at the last date when the patient was known to be alive. 
The OS will be analyzed using the KM method. 


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The secondary efficacy endpoints overall response rate (ORR; defined as the proportion of 
patients achieving complete response [CR] or partial response [PR] per RECIST v.1.1). 
The 2-sided exact 95% CI based on the Clopper--Pearson method will be provided. 
All efficacy analysis will be conducted by cohort. Pooled analysis (Cohort 1 + Cohort 2) may be 
conducted if deemed meaningful. Subgroup analysis by baseline demographic or disease 
characteristics may be conducted. 
9.3.4. 
Safety Analysis 
A TEAE is defined as an AE starting or worsening per CTCAE grade after the first dose until 
30 days after the last dose of study drug, or start of new anticancer therapy, whichever is earlier. 
Safety will be assessed through the analysis of the reported incidence, severity, and relationship 
of TEAEs, including SAEs, adverse events of special interest, AEs leading to withdrawal of 
study drug, and AEs related to study treatment. 
The AEs will be summarized by MedDRA coding terms, System Organ Class, and Preferred 
Term (PT) by cohort using the Safety Population.  
Change from baseline in physical examinations, vital signs, 12-lead ECGs, and clinical 
laboratory evaluations will be summarized.  
Information regarding study drug administration, study drug compliance, and other safety 
variables will also be summarized or listed. Extent of exposure to study drug will be generated 
from the study drug administration data. Exposure data will be summarized by cohort. 
9.3.5. 
Pharmacokinetic Analysis 
Plasma levels of ME-344 will be listed and summarized by cohort. Estimation of PK parameters 
will be performed by non-compartmental methods using the PK Population, with descriptive 
results presented by cohort. Data from this study may be pooled with data from other studies 
and may be analyzed by other methods. 
9.3.6. 
Analysis of Correlatives of Mitochondrial Metabolism 
The metabolomics data will be summarized if the sample assay data are available. 
10. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
10.1. 
Study Monitoring 
Before an investigational site can enter a patient into the study, a representative of MEI Pharma 
(the Sponsor) or its designee will evaluate the investigational study site to: 
 Determine the adequacy of the facilities. 
 Discuss with the Investigator(s) and other personnel their responsibilities with regard to 
protocol adherence, and the responsibilities of the Sponsor or its representatives. This 
will be documented in a Clinical Study Agreement between the Sponsor and the 
Investigator. 


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During the study, a monitor from the Sponsor or its designee will have regular contacts with the 
investigational site, for the following: 
 Provide information and support to the Investigator(s). 
 Confirm that facilities remain acceptable. 
 Confirm that the investigational team is adhering to the protocol, that data are being 
accurately recorded in the eCRFs, and that investigational product accountability checks 
are being performed. 
 Perform source data verification. This includes a comparison of the data in the CRFs with 
the subject’s medical records at the hospital or practice, and other records relevant to the 
study. This will require direct access to all original records for each subject (e.g., clinic 
charts). 
 Record and report any protocol deviations. 
 Confirm AEs and SAEs have been properly recorded on CRFs, confirm any SAEs have 
been forwarded to the Sponsor or its designee, and confirm those SAEs that met criteria 
for reporting have been forwarded to the IRB. 
The monitor will be available between visits if the Investigator(s) or other staff need information 
or advice. 
10.2. 
Audits and Inspections 
Authorized representatives of the Sponsor or its designee, regulatory authorities, or the IRB/IEC 
may visit the site to perform audits or inspections, including source data verification. The 
purpose of an audit or inspection is to systematically and independently examine all 
study-related activities and documents to determine whether these activities were conducted, and 
data were recorded, analyzed, and accurately reported according to the protocol, GCP guidelines 
of the ICH, and any applicable regulatory requirements. The Investigator should contact the 
Sponsor or its designee immediately if contacted by a regulatory agency about an inspection. 
10.3. 
Institutional Review Board (IRB) 
The Investigator must obtain IRB approval for the investigation. Initial IRB approval, and all 
materials approved by the IRB for this study including the subject consent form and recruitment 
materials must be maintained by the Investigator and made available for inspection. 
10.4. 
Safety Review Committee 
A SRC consisting of the study chair, MEI Pharma medical lead, the study Medical Monitor, the 
study biostatistician, and the Principal Investigators involved in the study will provide safety 
oversight for its conduct. The SRC will meet on a regular basis, with the first meeting occurring 
after the first 5 subjects complete 1 cycle of therapy, and then every 2–3 months thereafter. The 
SRC will review the totality of safety data, including AEs, SAEs, and laboratory results, with the 
primary purpose of protecting the safety of study participants, the credibility of the study, and the 
validity of study results. The SRC will provide their recommendation whether the combination is 
deemed safe, and Cohort 2 can be opened for enrollment. 


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11. 
QUALITY CONTROL AND QUALITY ASSURANCE 
To ensure compliance with GCP and all applicable regulatory requirements, the Sponsor or its 
designee may conduct a quality assurance audit. See Section 10.2 for more details regarding the 
audit process. 
12. 
ETHICS 
12.1. 
Ethics Review 
The final study protocol, including the final version of the Informed Consent Form (ICF), must 
be approved, or given a favorable opinion in writing by an IRB/IEC as appropriate. The 
Investigator must submit written approval to the Sponsor or its designee before enrollment of 
subjects. 
The Investigator is responsible for informing the IRB/IEC of any amendment to the protocol in 
accordance with local requirements. In addition, the IRB/IEC must approve all advertising used 
to recruit subjects for the study. The protocol must be re-approved by the IRB/IEC upon receipt 
of amendments and annually, as local regulations require. 
The Investigator is also responsible for providing the IRB/IEC with any reportable serious 
adverse drug reactions from any other study conducted with the investigational product. 
The Sponsor or its designee will provide this information to the Investigator. 
Progress reports and notifications of serious adverse drug reactions will be provided to the 
IRB/IEC according to local regulations and guidelines. 
12.2. 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/GCP and applicable regulatory 
requirements. 
12.3. 
Written Informed Consent 
The Investigator(s) at each study center will ensure that the subject is given full and adequate 
oral and written information about the nature, purpose, possible risk, and benefit of the study. 
Subjects must also be notified that they are free to discontinue from the study at any time. 
The subject should be given the opportunity to ask questions and allowed time to consider the 
information provided. 
The subject’s signed and dated informed consent must be obtained before conducting any study 
procedures. 
The Investigator must maintain the original, signed ICF. A copy of the signed ICF must be given 
to the subject. 


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13. 
DATA HANDLING AND RECORDKEEPING 
13.1. 
Inspection of Records 
The Sponsor or its designee will be allowed to conduct site visits of the investigational facilities 
for the purpose of monitoring any aspect of the study. The Investigator agrees to allow the 
monitor to inspect the drug storage area, study drug stocks, drug accountability records, subject 
charts, study source documents, and other records related to study conduct. 
13.2. 
Data Protection and Privacy 
In order to verify subject eligibility criteria and ensure ongoing subject safety during the study 
and preserve the integrity of study data, notwithstanding source data verification at the study site, 
the Sponsor/CRO may request to review subject source medical data. Should the Sponsor request 
copies of subject medical data, the rationale for such request will be ethically and scientifically 
justified. Such records will promptly be destroyed by the Sponsor/CRO when the purpose of the 
review has been met. 
13.3. 
Retention of Records 
The Investigator must maintain all documentation relating to the study for a period of 2 years 
after the last marketing application approval, or if not approved, for 2 years following the 
discontinuation of the investigational use. If it becomes necessary for the Sponsor or the 
regulatory authority to review any documentation relating to the study, the Investigator must 
permit access to such records. 
14. 
PUBLICATION POLICY 
The Sponsor intends to publish the results of this study as soon as possible following completion 
of data analysis. Data derived from the study are the exclusive property of the Sponsor. 
Authorship (both inclusion and sequence) will be determined by mutual agreement. In the event 
of a disagreement on authorship, the Sponsor will serve as adjudicator. 


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15. 
REFERENCES 
Aparicio J, Esposito F, Serrano S, Falco E, Escudero P, Ruiz-Casado A, et al. Metastatic 
Colorectal Cancer. First Line Therapy for Unresectable Disease. J Clin Med. 2020; 9(12): 3889. 
doi: 10.3390/jcm9123889.  
Aran V, Victorino AP, Thuler LC, Ferreira CG. Colorectal cancer: epidemiology, disease 
mechanisms and interventions to reduce onset and mortality. Clin Colorectal Canc. 2016; 15(3): 
195–203. doi: 10.1016/j.clcc.2016.02.008. 
Avastin [US Prescribing Information]. Genentech, Inc. US; Rev September 2022. 
Benson AB, Venook AP, Al-Hawary MM, Arain MA, Chen YJ, Ciombor KK, et al. Colon 
Cancer, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc 
Netw. 2021; 19(3): 329–359. doi: 10.6004/jnccn.2021.0012.  
Benvenuti S, Sartore-Bianchi A, Di Nicolantonio F, Zanon C, Moroni M, Veronese S, et al. 
Oncogenic activation of the RAS/RAF signaling pathway impairs the response of metastatic 
colorectal cancers to anti-epidermal growth factor receptor antibody therapies. Cancer Res. 
2007; 67(6): 2643–2648. doi: 10.1158/0008-5472. 
Ciardiello D, Vitiello PP, Cardone C, Martini G, Troiani T, Martinelli E, et al. Immunotherapy of 
colorectal cancer: Challenges for therapeutic efficacy. Cancer Treat Rev. 2019; 76: 22–32. 
doi: 10.1016/j.ctrv.2019.04.003. 
Eisenhauer E, Therasse P, Bogaerts J, Schwartz L, Sargent D, Ford R., et al. New Response 
Evaluation Criteria in Solid Tumours: Revised RECIST Guideline (version 1.1) Eur J. Cancer. 
2009; 45: 228–247. doi: 10.1016/j.ejca.2008.10.026. 
Golshani G, Zhang Y. Advances in immunotherapy for colorectal cancer: a review. Therap Adv 
Gastroenterol. 2020; 13: 1756284820917527. doi: 10.1177/1756284820917527.  
Grothey A, Van Cutsem E, Sobrero A, Siena S, Falcone A, Ychou M, et al. Regorafenib 
monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, 
multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013; 381(9863): 303–312. 
doi:10.1016/S0140-6736 (12)61900-X. 
Li J, Qin S, Xu R, Yau TCC, Ma B, Pan H, et al. Regorafenib plus best supportive care versus 
placebo plus best supportive care in Asian patients with previously treated metastatic colorectal 
cancer (CONCUR): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 
2015; 16(6): 619–629. doi:10.1016/S1470-2045(15) 70156-7. 
Mauri G, Bonazzina E, Amatu A, Tosi F, Bencardino K, Gori V, et al. The Evolutionary 
Landscape of Treatment for BRAFV600E Mutant Metastatic Colorectal Cancer. Cancers (Basel). 
2021; 13(1): 137. doi: 10.3390/cancers13010137. 
Navarro P, Bueno MJ, Zagorac I, Mondejar T, Sanchez J, Mourón S, et al. Targeting tumor 
mitochondrial metabolism overcomes resistance to antiangiogenics. Cell Reports. 2016; 
15: 2705–2718. doi: 10.1016/j.celrep.2016.05.052. 
Oken MM, Creech, RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and 
response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982; 5: 
649-655. 


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Patelli G, Tosi F, Amatu A, Mauri G, Curaba A, Patanè DA, et al. Strategies to tackle 
RAS-mutated metastatic colorectal cancer. ESMO Open. 2021; 6(3): 100156. 
doi: 10.1016/j.esmoop.2021.100156. 
Quintela-Fandino M, Morales S, Cortés-Salgado A, Manso L, Apala JV, Muñoz M, et al. 
Randomized Phase 0/I trial of mitochondrial inhibitor ME-344 or placebo added to bevacizumab 
in early HER2-negative breast cancer. Clin Cancer Res. 2020; 26(1): 35–45. 
Tabernero J, Geel RV, Guren TK, Yaeger RD, Spreafico A, Faris JE, et al. Phase 2 results: 
Encorafenib (ENCO) and cetuximab (CETUX) with or without alpelisib (ALP) in patients with 
advance BRAF-mutant colorectal cancer (BRAFm CRC). Journal of Clinical Oncology 2016; 
34(no. 15_suppl): 3544–3544.DOI: 10.1200/JCO.2016.34.15_suppl.3544.  
Van Cutsem E, Huijberts S, Grothey A, Yaeger R, Cuyle PJ, Elez E, et al. Binimetinib, 
Encorafenib, and Cetuximab Triplet Therapy for Patients With BRAF V600E-Mutant Metastatic 
Colorectal Cancer: Safety Lead-In Results From the Phase III BEACON Colorectal Cancer 
Study. J Clin Oncol. 2019; 37(17): 1460–1469. doi: 10.1200/JCO.18.02459.  
van Geel RMJM, Tabernero J, Elez E, Bendell JC, Spreafico A, Schuler M, et al. A Phase Ib 
Dose-Escalation Study of Encorafenib and Cetuximab with or without Alpelisib in Metastatic 
BRAF-Mutant Colorectal Cancer. Cancer Discov. 2017; (6): 610–619. doi: 10.1158/2159-
8290.CD-16-0795. 
Wang Z, Liang L, Yu Y, Wang Y, Zhuang R, Chen Y, et al. Primary tumour resection could 
improve the survival of unresectable metastatic colorectal cancer patients receiving 
bevacizumab-containing chemotherapy. Cell Physiol Biochem. 2016; 39: 1239–1246. doi: 
10.1159/000447829.  
Wu CC, Hsu CW, Hsieh MC, Wang JH, Chang MC, Yang CS, et al. Optimal Sequence and 
Second-Line Systemic Treatment of Patients with RAS Wild-Type Metastatic Colorectal Cancer: 
A Meta-Analysis. J Clin Med. 2021; 10(21): 5166. doi:10.3390/jcm10215166. 
 


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APPENDIX 1. SCHEDULE OF ASSESSMENTS 
Assessment/Procedure 
Screening 
Cycles 1 and 2 
Cycles ≥3 
EOT 
Survival 
Follow-up 
Day(s) of Cycle 
-28 to -1 
1 
8 a 
15 
1 
8 a 
15 
30 days 
after last 
dose 
Every 12 weeks 
after EOT 
Visit Window (days) 
 
 
±2 
±2 
 
±2 
±2 
±7 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
Physical examination b 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital signs c 
X 
X 
X 
X 
X 
X 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
X 
 
 
X 
 
ECOG performance status d 
X d 
X 
 
 
X 
 
 
X 
 
Pregnancy test e 
X 
X 
 
 
X 
 
 
X 
 
Hepatitis B & C tests f 
X 
 
 
 
 
 
 
 
 
HIV antibody test 
X 
 
 
 
 
 
 
 
 
12-lead electrocardiogram (triplicate)g 
X 
Xg 
 
Xg 
 
 
 
X 
 
Hematology h 
X 
X 
 
X 
X 
 
X 
X 
 
Serum chemistry i 
X 
X 
 
X 
X 
 
X 
X 
 
Coagulation j 
X 
X j 
 
 
X j 
 
 
 
 
Urinalysis (dipstick) k 
X 
X 
 
X 
X 
 
X 
X 
 
ME-344 10 mg/kg infusion (Cohort 1) 
 
X 
X 
X 
X 
X 
X 
 
 
ME-344 10 mg/kg infusion (Cohort 2) 
 
X 
 
X 
X 
 
X 
 
 
Bevacizumab 5 mg/kg infusion 
 
X 
 
X 
X 
 
X 
 
 
PK sample collection l 
 
X l 
 
X l 
 
 
 
 
 
Metabolomics sample collection m 
 
X 
 
X 
X 
 
 
 
 
Adverse event collection n 
 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant medication recording o 
X 
X 
X 
X 
X 
X 
X 
X 
 
Disease/response assessment p 
X 
 
 
 
X 
 
 
 
 
Survival status q 
 
 
 
 
 
 
 
 
X 


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Abbreviations: AE = adverse event; ALP = alkaline phosphatase; ALT = alanine aminotransferase; ANC = absolute neutrophil count; aPTT = activated partial 
thromboplastin time; AST = aspartate aminotransferase; BUN = blood urea nitrogen; CT = computed tomography; ECOG = Eastern Cooperative Oncology 
Group; EOT = End of Treatment; INR = international normalized ratio; IV = intravenous; LDH = lactate dehydrogenase; MCH = mean corpuscular hemoglobin; 
MRI = magnetic resonance imaging; PCR = polymerase chain reaction; PK = pharmacokinetic; INR/PT = International Normalized Ratio of prothrombin time; 
RBC = red blood cell; WBC = white blood cell. 
a Day 8 – ME-344 dosing and study procedures on Day 8 are only applicable to subjects in Cohort 1. No ME-344 dosing or study procedures are performed for 
subjects in Cohort 2. 
b Physical examination – Complete physical examination, including assessment of peripheral neuropathy, is required at the Screening and EOT visits. 
Symptom-directed physical examinations, including assessment of peripheral neuropathy will be performed at all other visits.  
c Vital signs – Blood pressure (systolic and diastolic), heart rate, and temperature. 
d ECOG – Must be within 14 days of Cycle 1 Day 1. 
e Pregnancy test – Serum pregnancy test for females of childbearing potential performed at screening within 7 days prior to Cycle 1 Day 1. Urine or serum test 
performed on Day 1 of subsequent cycles. 
f Hepatitis B and C tests – Hepatitis B core antibody, hepatitis B surface antigen, and hepatitis C antibody are required. Hepatitis B PCR is required if hepatitis 
B core antibody and/or surface antigen is positive. Hepatitis C PCR is required if hepatitis C antibody is positive. 
g ECGs are to be obtained at the end of each infusion of ME-344 on Cycle 1 Day 1 and Day 15, EOT, and as clinically indicated. ECGs to be obtained prior to 
collection of matching PK samples on Cycle 1 Day 1 and Day 15 only.  
h Hematology – Hematology tests include WBC, ANC, RBC, hemoglobin, hematocrit, lymphocytes, eosinophils, monocytes, basophils, platelets, and MCH. 
Screening labs must be repeated if performed >7 days prior to Cycle 1 Day 1. 
i Serum chemistry – Serum chemistry tests include glucose, BUN or urea, CO2 or bicarbonates, creatinine, sodium, potassium, chloride, calcium, ALP, AST, 
ALT, total bilirubin, total protein, albumin, lipase, LDH, and phosphorous. Screening labs must be repeated if performed >7 days prior to Cycle 1 Day 1. 
j Coagulation – Coagulation tests include aPTT, INR/PT. Screening labs must be repeated if performed >7 days prior to Cycle 1 Day 1. For subjects on 
anticoagulation therapy test will be performed on Day 1 of every cycle. Close monitoring of at least weekly evaluations will be performed until INR/PT is 
stable based on a measurement that is prior to initiation of study treatment, as defined by the local standard.  
k Urinalysis – Urinalysis tests include dipstick or urine test (pH, specific gravity, glucose, ketones, blood, and protein). Screening labs must be repeated if 
performed >7 days prior to Cycle 1 Day 1. If baseline urine protein is ≥2+, unless due to ureteral stents of urinary diversion, a 24-hour urine collection must be 
performed to confirm urinary protein excretion is<2.0 g/24 hour. 
l PK sampling – Blood samples for PK analysis will be collected during Cycle 1 on Days 1 and 15 pre-dose, 5 minutes after the end of infusion, and 1, 2, 3, 6, 
and 24 hours after the completion of the infusion.  
m Metabolomics sampling – Blood samples for metabolomics analysis will be collected (at Rutgers Cancer Institute of New Jersey) at Cycle 1 Day 1 (pre-dose 
and 6 hours post-dose), Cycle 1 Day 15, Cycle 2 Day 1, and Cycle 3 Day 1 in a fasting state with minimum fasting time of 4 hours. 
n Adverse events – Adverse events are to be recorded from the time of the first dose of study drug on Cycle 1 Day 1 through 30 days after the last dose of study 
drug or start of new anticancer treatment (whichever occurs first). Any untoward occurrence related to a study procedure during screening should also be 
reported as an AE. 
o Concomitant medications – Concomitant medications are to be recorded from 28 days prior to Cycle 1 Day 1 until the EOT visit or start of new anticancer 
treatment (whichever occurs first). 
p Disease/response assessment – CT of the neck, chest, abdomen, and pelvis are to be obtained at screening (within 4 weeks prior to Cycle 1 Day 1) and every 
8 weeks (±7 days) from Cycle 1 Day 1 for the first 6 months, then every 3 months until 1 year, and every 4 months thereafter. CT scans are to be performed 
using IV or oral contrast. For subjects intolerant to contrast agents, MRI scans may be used. 
q Survival status – Survival information to be collected every 12 weeks following the EOT visit. 


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APPENDIX 2. CREATININE CLEARANCE 
In the event the local laboratory does not calculate CrCL based on the most recent serum 
creatinine value, estimate the subject’s CrCL using the serum creatinine value provided by the 
local laboratory, actual body weight, and the appropriate Cockcroft-Gault formula:  
𝐶𝑟𝐶𝐿ൌ 
ሺ140 െ𝑎𝑔𝑒ሻ ൈ ሺ𝑤𝑒𝑖𝑔ℎ𝑡 𝑖𝑛 𝑘𝑔ሻ
72 ൈሺ𝑠𝑒𝑟𝑢𝑚 𝑐𝑟𝑒𝑎𝑡𝑖𝑛𝑖𝑛𝑒 𝑖𝑛 𝑚𝑔/𝑑𝐿ሻ ൈሺ0.85 𝑖𝑓 𝑓𝑒𝑚𝑎𝑙𝑒ሻ 
If necessary, convert serum creatinine values from µmol/L to mg/dL by dividing by 88.4. For 
example, 100 µmol/L divided by 88.4 equals 1.131 mg/dL. 


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APPENDIX 3. DRUGS THAT PROLONG THE QTC INTERVAL 
AND/OR INDUCE TORSADES DE POINTES 
Medications that have possible risk of prolonging the QT interval and/or Torsades de Pointes 
may have an unacceptable risk of co-administration with ME-344. Medications with a 
conditional risk may be used at the discretion of the Investigator.  
All concomitant medications both prior to enrollment and during study conduct must be carefully 
reviewed and monitored. Subjects should avoid taking grapefruit juice. 
Generic Name 
Brand Names 
Drug Class 
Therapeutic Use 
Alfuzosin 
Uroxatral® 
alpha1-blocker 
benign prostatic 
hyperplasia 
Amantadine 
Symmetrel®, Symadine® 
antiviral 
anti-infective/ 
Parkinson's Disease 
Amiodarone 
Cordarone®, Pacerone®, Nexterone® 
antiarrhythmic 
abnormal heart rhythm 
Amisulpride 
Solian®, Supitac®, Soltus®, 
Amitrex®, Amazeo® 
antipsychotic, atypical 
psychosis 
Amitriptyline 
Elavil® (discontinued), Tryptomer®, 
Tryptizol®, Laroxyl®, Saroten®, 
Sarotex® Lentizol®, Endep® 
antidepressant, 
tricyclic 
depression 
Amoxapine 
Asendin®, Amokisan®, Asendis®, 
Defanyl®, Demolox®, Moxadil® 
antidepressant, 
tetracyclic 
depression 
Anagrelide 
Agrylin®, Xagrid® 
phosphodiesterase 3 
inhibitor 
thrombocythemia 
Apomorphine 
Apokyn®, Ixense®, Spontane®, 
Uprima® 
dopamine agonist 
Parkinson's disease 
Arsenic trioxide 
Trisenox® 
anticancer 
leukemia 
Atazanavir 
Reyataz® 
antiviral 
HIV/AIDS 
Azithromycin 
Zithromax®, Zmax® 
antibiotic 
bacterial infection 
Bedaquiline 
Sirturo® 
antibiotic 
drug-resistant 
tuberculosis 
Bortezomib 
Velcade®, Bortecad® 
proteasome inhibitor 
multiple myeloma, 
lymphoma 
Bosutinib 
Bosulif® 
tyrosine kinase 
inhibitor 
leukemia 
Chloral hydrate 
Aquachloral®, Novo-Chlorhydrate®, 
Somnos®, Noctec®, Somnote® 
sedative 
sedation/insomnia 
Chloroquine 
Aralen® 
antimalarial 
malaria infection 
Chlorpromazine 
Thorazine®, Largactil®, Megaphen® 
antipsychotic/
antiemetic 
schizophrenia/nausea 
Ciprofloxacin 
Cipro®, Cipro-XR®, Neofloxin® 
antibiotic 
bacterial infection 
Citalopram 
Celexa®, Cipramil® 
antidepressant, SSRI 
depression 


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Generic Name 
Brand Names 
Drug Class 
Therapeutic Use 
Clarithromycin 
Biaxin®, Prevpac® 
antibiotic 
bacterial infection 
Clomipramine 
Anafranil® 
antidepressant, 
tricyclic 
depression 
Clozapine 
Clozaril®, Fazaclo®, Versacloz® 
antipsychotic, atypical 
schizophrenia 
Cocaine 
Cocaine 
local anesthetic 
topical anesthetic 
Crizotinib 
Xalkori® 
kinase inhibitor 
anticancer 
Dabrafenib 
Tafinlar® 
anticancer 
melanoma 
Dasatinib 
Sprycel® 
tyrosine kinase 
inhibitor 
leukemia 
Desipramine 
Pertofrane®, Norpramine® 
antidepressant, 
tricyclic 
depression 
Dexmedetomidine 
Precedex®,  Dexdor®,  Dexdomitor® 
sedative 
sedation 
Dihydroartemisinin
+piperaquine 
Eurartesim® 
antimalarial 
malaria 
Diphenhydramine 
Benadryl®, Nytol®, Unisom®, 
Sominex®, Dimedrol®, Daedalon® 
antihistamine 
allergic rhinitis, 
insomnia 
Disopyramide 
Norpace® 
antiarrhythmic 
abnormal heart rhythm 
Dofetilide 
Tikosyn® 
antiarrhythmic 
abnormal heart rhythm 
Dolasetron 
Anzemet® 
antinausea 
nausea, vomiting 
Doxepin 
Sinequan®, Silenor®, Aponal®, 
Adapine®, Doxal®, Deptran®, 
Sinquan® 
antidepressant, 
tricyclic 
depression 
Dronedarone 
Multaq® 
antiarrhythmic 
atrial fibrillation 
Droperidol 
Inapsine®, Droleptan®, Dridol®, 
Xomolix® 
antipsychotic/
antiemetic 
anesthesia adjunct, 
nausea 
Eribulin 
Halaven® 
anticancer 
metastatic breast 
neoplasias 
Erythromycin 
E.E.S.®, Robimycin®, EMycin®, 
Erymax®, Ery-Tab®, Eryc 
Ranbaxy®, Erypar®, Eryped®, 
Erythrocin Stearate Filmtab®, 
Erythrocot®, E-Base®, Erythroped®, 
Ilosone®, MY-E®, Pediamycin®, 
Zineryt®, Abboticin®, Abboticin-
ES®, Erycin®, PCE Dispertab®, 
Stiemycine®, Acnasol®, Tiloryth® 
antibiotic 
bacterial infection; 
increase GI motility 
Escitalopram 
Cipralex®, Lexapro®, Nexito®, 
Anxiset-E® (India), Exodus® 
(Brazil), Esto® (Israel), Seroplex®, 
Elicea®, Lexamil®, Lexam®, Entact® 
(Greece), Losita® (Bangladesh), 
Reposil® (Chile), Animaxen® 
antidepressant, SSRI 
major depression/ 
anxiety disorders 


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Generic Name 
Brand Names 
Drug Class 
Therapeutic Use 
(Colombia), Esitalo® (Australia), 
Lexamil® (South Africa) 
Famotidine 
Pepcid®, Fluxid®, Quamatel® 
H2-receptor antagonist 
peptic ulcer/GERD 
Felbamate 
Felbatol 
anticonvulsant 
seizure 
Fingolimod 
Gilenya® 
sphingosine phosphate 
receptor modulator 
multiple sclerosis 
Flecainide 
Tambocor®, Almarytm®, Apocard®, 
Ecrinal®, Flécaine® 
antiarrhythmic 
abnormal heart rhythm 
Fluconazole 
Diflucan®, Trican® 
antifungal 
fungal infection 
Fluoxetine 
Prozac®, Sarafem®, Fontex® 
antidepressant, SSRI 
depression 
Foscarnet 
Foscavir® 
antiviral 
HIV/AIDS 
Fosphenytoin 
Cerebyx®, Prodilantin® 
anticonvulsant 
seizure 
Furosemide 
(Frusemide) 
Lasix®, Fusid®, Frumex® 
diuretic 
increase urine & salt 
loss 
Galantamine 
Reminyl®, Nivalin®, Razadyne-ER®, 
cholinesterase 
inhibitor 
dementia, Alzheimer's 
Gemifloxacin 
Factive® 
antibiotic 
bacterial infection 
Granisetron 
Kytril®,  Sancuso®, Granisol® 
antinausea 
nausea, vomiting 
Halofantrine 
Halfan® 
antimalarial 
malaria infection 
Haloperidol 
Haldol® (US & UK), Aloperidin®, 
Bioperidolo®, Brotopon®, Dozic®, 
Duraperidol® (Germany), Einalon 
S®, Eukystol®, Halosten®, Keselan®, 
Linton®, Peluces®, Serenace®, 
Serenase®, Sigaperidol® 
antipsychotic 
schizophrenia, agitation 
Hydrochlorothiazide 
Apo-Hydro®, Aquazide H®, BP 
Zide®, Dichlotride®, Hydrodiuril®, 
HydroSaluric®, Hydrochlorot®, 
Microzide®, Esidrex®, Oretic® 
diuretic 
increase urine & salt 
loss 
Ibutilide 
Corvert® 
antiarrhythmic 
abnormal heart rhythm 
Iloperidone 
Fanapt®, Fanapta®, Zomaril® 
antipsychotic, atypical 
schizophrenia 
Imipramine 
(melipramine) 
Tofranil® 
antidepressant, 
tricyclic 
depression 
Indapamide 
Lozol®, Natrilix®, Insig® 
diuretic 
increase urine & salt 
loss 
Isradipine 
Dynacirc® 
antihypertensive 
high blood pressure 
Itraconazole 
Sporanox®, Onmel® 
antifungal 
fungal infection 
Ketoconazole 
Nizoral®, Sebizole®, Ketomed®, 
Keton® 
antifungal 
fungal infection 
Lapatinib 
Tykerb®, Tyverb® 
anticancer 
breast cancer, 
metastatic 


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Generic Name 
Brand Names 
Drug Class 
Therapeutic Use 
Levofloxacin 
Levaquin®, Tavanic® 
antibiotic 
bacterial infection 
Lithium 
Eskalith®, Lithobid® 
antimania 
bipolar disorder 
Methadone 
Dolophine®, Symoron®, Amidone®, 
Methadose®, Physeptone®, 
Heptadon® 
opiate 
pain control, narcotic 
dependence 
Mifepristone 
Korlym®, Mifeprex® 
progesterone 
antagonist 
pregnancy termination 
Mirabegron 
Myrbetriq® 
beta3 adrenergic 
antagonist 
overactive bladder 
Mirtazapine 
Remeron 
antidepressant, 
tetracyclic 
depression 
Moexipril/HCTZ 
Uniretic®, Univasc® 
antihypertensive 
high blood pressure 
Moxifloxacin 
Avelox®, Avalox®, Avelon® 
antibiotic 
bacterial infection 
Nicardipine 
Cardene® 
antihypertensive 
high blood pressure 
Nilotinib 
Tasigna® 
anticancer 
leukemia 
Norfloxacin 
Noroxin®, Ambigram® 
antibiotic 
bacterial infections 
Nortriptyline 
Pamelor®, Sensoval®, Aventyl®, 
Norpress®, Allegron®, Noritren®, 
Nortrilen® 
antidepressant, 
tricyclic 
depression 
Ofloxacin 
Floxin® 
antibiotic 
bacterial infection 
Olanzapine 
Zyprexa®, Zydis®, Relprevv® 
antipsychotic, atypical 
schizophrenia, bipolar 
Ondansetron 
Zofran®, Anset®, Ondemet®, 
Zuplenz®, Emetron®, Ondavell®, 
Emeset®, Ondisolv®, Setronax® 
antiemetic 
nausea, vomiting 
Oxytocin 
Pitocin®, Syntocinon® 
oxytocic 
labor stimulation 
Paliperidone 
Invega®, Xepilon® 
antipsychotic, atypical 
schizophrenia 
Palonosetron 
Aloxi 
antiemetics, selective 
5-HT3 antagonist 
chemotherapy-induced 
nausea and vomiting 
Paroxetine 
Paxil®, Aropax®, Pexeva®, Seroxat®, 
Sereupin® 
antidepressant, SSRI 
depression 
Pasireotide 
Signifor® 
somatostatin analog 
Cushing’s disease 
Pazopanib 
Votrient® 
tyrosine kinase 
inhibitor 
anticancer 
Pentamidine 
NebuPent®, Pentam® 
antibiotic 
pneumocystis 
pneumonia 
Perflutren lipid 
microspheres 
Definity® 
imaging contrast agent 
echocardiography 
Pimozide 
Orap® 
antipsychotic 
Tourette's tics 
Posaconazole 
Noxafil®, Posamol® 
antifungal 
fungal infection 


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Generic Name 
Brand Names 
Drug Class 
Therapeutic Use 
Procainamide (Oral 
off US market) 
Pronestyl®, Procan® 
antiarrhythmic 
abnormal heart rhythm 
Promethazine 
Phenergan® 
antipsychotic/ 
antiemetic 
nausea 
Protriptyline 
Vivactil® 
antidepressant, 
tricyclic 
depression 
Quetiapine 
Seroquel® 
antipsychotic, atypical 
schizophrenia 
Quinidine 
Quinaglute®, Duraquin®, Quinact®, 
Quinidex®, Cin-Quin®, Quinora® 
antiarrhythmic 
abnormal heart rhythm 
Quinine sulfate 
Qualaquin® 
antimalarial 
malaria or leg cramps 
Ranolazine 
Ranexa®, Ranozex® 
antianginal 
chronic angina 
Rilpivirine 
Edurant®, Complera®, Eviplera® 
antiviral 
HIV/AIDS 
Risperidone 
Risperdal® 
antipsychotic, atypical 
schizophrenia 
Ritonavir 
Norvir® 
antiviral 
HIV/AIDS 
Saquinavir 
Invirase®(combo) 
antiviral 
HIV/AIDS 
Sertraline 
Zoloft®, Lustral®, Daxid®, 
Altruline®, Besitran®, Deprax®, 
Elrval®, Emergen®, Gladem®, 
Implicane®, Sedoran®, Sealdin®, 
SerivoLowfin®, Stimuloton®, 
Tresleen®, Sertralin Bluefish® 
antidepressant, SSRI 
depression 
Sevoflurane 
Ulane®, Sojourn® 
anesthetic, general 
anesthesia 
Solifenacin 
VESIcare® 
muscle relaxant 
treatment of overactive 
bladder 
Sorafenib 
Nexavar® 
tyrosine kinase 
inhibitor 
anticancer 
Sotalol 
Betapace®, Sotalex®, Sotacor® 
antiarrhythmic 
abnormal heart rhythm 
Sunitinib 
Sutent® 
anticancer 
renal cell cancer, GIST 
Tacrolimus 
Prograf®, Prograf®, Advagraf®, 
Protopic® 
immunosuppressant 
immune suppression 
Tamoxifen 
Nolvadex®(discontinued), Istubal®, 
Valodex® 
anticancer 
breast cancer 
Telaprevir 
Incivek®, Incivo® 
antiviral 
Hepatitis C 
Telavancin 
Vibativ® 
antibiotic 
bacterial infection 
Telithromycin 
Ketek® 
antibiotic 
bacterial infection 
Tetrabenazine 
(Orphan drug in 
US) 
Nitoman®, Xenazine® 
monoamine 
transporter inhibitor 
chorea (Huntington's 
disease) 
Thioridazine 
Mellaril®, Novoridazine®, Thioril® 
antipsychotic 
schizophrenia 
Tizanidine 
Zanaflex®, Sirdalud® 
muscle relaxant 
spasticity 


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Protocol: ME-344-003
 
Amendment 3
 
Version Date: 06 January 2023 
Confidential 
 
Page 59 of 63
 
Generic Name 
Brand Names 
Drug Class 
Therapeutic Use 
Tolterodine 
Detrol®, Detrusitol® 
muscle relaxant 
bladder spasm 
Toremifene 
Fareston® 
estrogen 
agonist/antagonist 
anticancer 
Trazodone 
Desyrel® (discontinued 6/13), 
Oleptro®, Beneficat®, Deprax®, 
Desirel®, Molipaxin®, Thombran®, 
Trazorel®, Trialodine®, Trittico®, 
Mesyrel® 
antidepressant, SARI 
depression, insomnia 
Trimethoprim-Sulfa 
Septra®, Bactrim®, Sulfatrim®, 
Biseptol®, Co-trimoxazole®, 
Cotrim®, Septrin®, Trisul® 
antibiotic 
bacterial infection 
Trimipramine 
Surmontil®, Rhotrimine®, Stangyl® 
antidepressant, 
tricyclic 
depression 
Vandetanib 
Caprelsa® 
anticancer 
thyroid cancer 
Vardenafil 
Levitra® 
phosphodiesterase 
inhibitor 
vasodilator 
Vemurafenib 
Zelboraf® 
kinase inhibitor 
anticancer 
Venlafaxine 
Effexor®, Efexor® 
antidepressant, SNRI 
depression 
Voriconazole 
VFend® 
antifungal 
antifungal 
Vorinostat 
Zolinza® 
anticancer 
lymphoma 
Ziprasidone 
Geodon®, Zeldox® 
antipsychotic, atypical 
schizophrenia 
 


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APPENDIX 4. SENSITIVE IN VIVO CYP SUBSTRATES AND CYP 
SUBSTRATES WITH NARROW THERAPEUTIC RANGE 
The following agents should be used with caution in patients enrolled in this study: 
CYP Enzymes 
Sensitive substrates a 
Substrates with narrow 
therapeutic range b 
CYP1A2 
alosetron, caffeine, duloxetine, melatonin, 
ramelteon, tacrine, tizanidine 
theophylline, tizanidine 
CYP2B6 c 
bupropion, efavirenz 
  
CYP2C8 
repaglinided 
Paclitaxel 
CYP2C9 
celecoxib 
warfarin, phenytoin 
CYP2C19 
lansoprazole, omeprazole, S-mephenytoin 
S-mephenytoin 
CYP3A e 
alfentanil, aprepitant, budesonide, buspirone, 
conivaptan, darifenacin, darunavir, dasatinib, 
dronedarone, eletriptan, eplerenone, everolimus, 
felodipine, indinavir, fluticasone, lopinavir, 
lovastatin, lurasidone, maraviroc, midazolam, 
nisoldipine, quetiapine, saquinavir, sildenafil, 
simvastatin, sirolimus, tolvaptan, tipranavir, 
triazolam, vardenafil 
alfentanil, astemizole f, cisapride f, 
cyclosporine, dihydroergotamine, 
ergotamine, fentanyl, pimozide, 
quinidine, sirolimus, tacrolimus, 
terfenadine f 
CYP2D6 
atomoxetine, desipramine, dextromethorphan, 
metoprolol, nebivolol, perphenazine, tolterodine, 
venlafaxine 
Thioridazine 
a Sensitive CYP substrates refers to drugs whose plasma AUC values have been shown to increase 5-fold or higher when 
co-administered with a known CYP inhibitor. 
b CYP substrates with narrow therapeutic range refers to drugs whose exposure-response relationship indicates that small 
increases in their exposure levels by the concomitant use of CYP inhibitors may lead to serious safety concerns 
(e.g., Torsades de Pointes). 
c The AUC of these substrates were not increased by 5-fold or more with a CYP2B6 inhibitor, but they represent the most 
sensitive substrates studied with available inhibitors evaluated to date. 
d Repaglinide is also a substrate for OATP1B1, and it is only suitable as a CYP2C8 substrate if the inhibition of OATP1B1 by 
the investigational drug has been ruled out. 
e Because a number of CYP3A substrates (e.g., darunavir, maraviroc) are also substrates of P-glycoprotein (P-gp), 
the observed increase in exposure could be due to inhibition of both CYP3A and P-gp. 
f Withdrawn from the United States (US) market because of safety reasons. 
 


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APPENDIX 5. CYTOCHROME P450 DRUG-INTERACTIONS FOR 
INHIBITORS, INDUCERS, AND TRANSPORTERS 
P450 Drug-Interactions Inhibitors (strong inhibitors are shown in bold font) 
1A2 
2B6 
2C19 
2C9 
2D6 
3A4,5,7 
acyclovir 
amiodarone 
caffeine 
cimetidine 
ciprofloxacin 
enoxacin 
echinacea 
enoxacin 
famotidine 
flutamide 
fluvoxamine 
grapefruit juice 
lidocaine 
lomefloxacin 
mexiletine 
Mexitil 
moclobemide 
norfloxacin 
ofloxacin 
oral 
contraceptives 
perphenazine 
phenacetin 
propafenone 
ropinirole 
tacrine 
ticlopidine 
tocainide 
verapamil 
zileuton 
Zyflo 
clopidogrel 
Plavix 
efavirenz 
fluoxetine 
fluvoxamine 
ketoconazole 
memantine 
nelfinavir 
oral 
contraceptives 
paroxetine 
ritonavir 
thiotepa 
ticlopidine 
Ticlid 
 
artemisinin 
chloramphenicol 
delavirdine 
efavirenz 
esomeprazole 
felbamate 
fluconazole 
fluoxetine 
fluvoxamine 
indomethacin 
inh 
modafinil 
Provigil 
omeprazole 
Prilosec 
oral contraceptives 
oxcarbazepine 
ticlopidine 
topiramate 
voriconazole 
amiodarone 
anastrazole 
cimetidine 
delavirdine 
efavirenz 
fenofibrate 
Tricor 
fluconazole 
{fluoxetine} 
fluvoxamine 
fluvastatin 
isoniazid 
ketoconazole 
leflunomide 
modafiinil 
phenylbutazone 
{sertraline} 
sulfamethoxazole 
sulfaphenazole 
tamoxifen 
teniposide 
valproic acid 
voriconazole 
Vfend 
{zafirlukast}, 
{Accolate} 
5-fluorouracil 
amiodarone 
{amitriptyline} 
bupropion 
celecoxib 
chlorpheniramine 
chlorpromazine 
cimetidine 
cinacalcet 
{citalopram} 
chlorpheniramine 
clomipramine 
{desipramine} 
diphenhydramine 
doxepin 
duloxetine 
{fluvoxamine} 
fluoxetine 
goldenseal 
halofantrine 
haloperidol 
{hydroxyzine} 
imipramine 
methadone 
metoclopramide 
moclobemide 
paroxetine 
pimozide 
propafenone 
quinidine/quinine 
ritonavir 
{sertraline} 
terbinafine 
thioridazine 
ticlopidine 
amiodarone 
amprenavir 
aprepitant -
initially 
atazanavir 
boceprevir 
Reyataz 
{cimetidine} 
ciprofloxacin 
clarithromycin 
delavirdine 
diltiazem 
doxycycline 
echinacea 
enoxacin 
erythromycin 
fluconazole 
fluvoxamine 
grapefruit juice 
imatinib 
indinavir 
itraconazole 
ketoconazole 
miconazole 
nefazodone 
nelfinavir 
ritonavir and 
boosted PIs 
saquinavir 
telithromycin 
verapamil 
voriconazole 
NAT2 
 
Acetaminophen 
 
 
 
 
 


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Protocol: ME-344-003
 
Amendment 3
 
Version Date: 06 January 2023 
Confidential 
 
Page 62 of 63
 
P450 Drug-Interactions Inducers (increase the ability of the enzyme to metabolize the 
substrates) (strong inducers are shown in bold font) 
1A2 
2B6 
NAT2 
2C19 
2C9 
2D6 
3A4,5,7 
carbamazepine 
charbroiled 
meat 
cigarette smoke 
cruciferous 
veggies 
esomeprazole 
griseofulvin 
insulin 
lansoprazole 
marijuana 
smoke 
moricizine 
omeprazole 
rifampin 
ritonavir 
lopinavir/ritonavir 
phenobarbital 
phenytoin 
rifampin 
carbamazepine 
 
 
 
 
retinoic 
acid 
gingko biloba 
rifampin 
St John’s Wort 
aprepitant-long 
term 
barbiturates 
bosentan 
carbamazepine 
rifampin-chronic 
ritonavir and 
boosted protease 
inhibitors 
St John’s Wort-
long-term  
aprepitant-long 
term 
barbiturates 
bosentan 
carbamazepine 
rifampin 
aprepitant -long 
term 
barbiturates 
bosentan 
carbamazepine 
efavirenz 
felbamate 
glucocorticoids 
modafinil 
nafcillin 
nevirapine 
{oxcarbazepine} 
phenytoin 
primidone 
rifampin 
St. John’s Wort 
pioglitazone 
Actos 
topiramate at 
>200 mg/d 
 
Drug-Interactions Transporters 
Carbamazepine 
Cefadroxil 
Cefamandole 
Cefazolin 
Cyclosporine 
Desipramine 
Disopyramide 
Elacridar 
Erythromycin 
Gefitinib 
Isoniazid 
Midazolam 
Norethindrone 
Phenformin 
Phenobarbital 
Phenoxybenzamine 
Prazosin 
Probenecid 
Quinine 
Rifabutin 
Rifampin 
Secobarbital 
Valspodar 
Verapamil 
 


MEI Pharma, Inc. 
 
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Amendment 3
 
Version Date: 06 January 2023 
Confidential 
 
Page 63 of 63
 
APPENDIX 6. EASTERN COOPERATIVE ONCOLOGY GROUP 
(ECOG) PERFORMANCE STATUS SCALE 
The following scale should be used to determine ECOG performance status: 
GRADE  
ECOG  
0 
Fully active, able to carry on all pre-disease performance without restriction.  
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light 
or sedentary nature (e.g., light housework, office work).  
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and 
about more than 50% of waking hours.  
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours.  
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair.  
5 
Dead 
Source: Oken 1982. 
 


Signature Page for VV-CLIN-000341 v6.0
Signature Page for VV-CLIN-000341 v6.0
Approval
Staci Ellis
Regulatory
11-Jan-2023 18:56:26 GMT+0000
Approval
Alex Ricart
Clinical
11-Jan-2023 19:28:32 GMT+0000

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN 
A Phase 1b Study of the OxPhos Inhibitor ME-344 Combined with 
Bevacizumab in Previously Treated Metastatic Colorectal Cancer 
Protocol Number: 
ME-344-003 
Protocol Version Number/Date: 
Amendment 4, 09 February 2024 
Development Phase: 
1 
Sponsor: 
MEI Pharma, Inc. 
11455 El Camino Real, Suite 250 
San Diego, CA 92130, USA 
SAP Version: 
1.0 
SAP Date: 
30 July 2024 
Confidentiality Statement 
The confidential information in this document is the property of MEI Pharma Inc. It is understood that this 
information will not be disclosed to any third party, in any form, without prior written authorization from MEI 
Pharma Inc. 
IND# 157,739


MEI Pharma, Inc. 
Protocol Number: ME-344-003 
Statistical Analysis Plan – Version 1.0 
       30 Jul 2024 
 
Page 2 of 40 
 
SIGNATURE PAGE 
 
A Phase 1b Study of the OxPhos Inhibitor ME-344 Combined with 
Bevacizumab in Previously Treated Metastatic Colorectal Cancer 
 
This Statistical Analysis Plan has been reviewed and approved by the representatives listed 
below: 
 
 
Richard G. Ghalie, MD 
Chief Medical Officer 
 
Date 
 
 
 
 
 
 
 
 
 
Min Tang, PhD 
Biostatistical consutlant 
 
Date 
 
 
 
 
 
 


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Statistical Analysis Plan – Version 1.0 
            30 Jul 20
 
 
 
 
Page 3 of 40 
 
 
 
 
TABLE OF CONTENTS 
A PHASE 1B STUDY OF THE OXPHOS INHIBITOR ME-344 COMBINED WITH 
BEVACIZUMAB IN PREVIOUSLY TREATED METASTATIC COLORECTAL 
CANCER ................................................................................................................................. 1 
1. 
INTRODUCTION ................................................................................................ 6 
2. 
STUDY OBJECTIVES ........................................................................................ 6 
2.1 
Primary Objectives ................................................................................................. 6 
2.2 
Secondary Objectives ............................................................................................. 6 
2.3 
Exploratory Objectives ........................................................................................... 6 
3. 
STUDY DESIGN .................................................................................................. 7 
3.1 
General Study Design and Plan .............................................................................. 7 
3.1.1 
Overall Study Design.............................................................................................. 7 
3.2 
Number of Subjects ................................................................................................ 8 
3.3 
Study Treatment ..................................................................................................... 9 
3.4 
Randomization and Blinding .................................................................................. 9 
3.5 
Study Assessments ................................................................................................. 9 
4. 
SAMPLE SIZE DETERMINATION ................................................................. 9 
5. 
STUDY ENDPOINTS ........................................................................................ 10 
5.1 
Primary Endpoints ................................................................................................ 10 
5.2 
Secondary Endpoints ............................................................................................ 10 
5.3 
Exploratory Endpoint ........................................................................................... 11 
6. 
ANALYSIS  POPULATION ............................................................................. 11 
7. 
GENERAL STATISTICAL CONSIDERATIONS ......................................... 11 
7.1 
Definition of Study Day ....................................................................................... 11 
7.2 
Baseline Definition ............................................................................................... 11 
7.3 
Handling of Missing Data..................................................................................... 11 
8. 
STATISTICAL ANALYSIS .............................................................................. 12 
8.1 
Subject Disposition ............................................................................................... 12 


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8.2 
Demographics and Baseline Characteristics ......................................................... 12 
8.3 
Exposure and Duration of Treatment ................................................................... 12 
8.4 
Duration of Follow-up .......................................................................................... 13 
8.5 
Efficacy Analyses ................................................................................................. 13 
8.5.1 
Progression-Free Survival (PFS) .......................................................................... 13 
8.5.2 
Overall Survival (OS) ........................................................................................... 13 
8.5.3 
Overall Response Rate (ORR) .............................................................................. 14 
8.5.4 
Waterfall Plot ........................................................................................................ 14 
8.6 
Safety Analyses .................................................................................................... 14 
8.6.1 
Adverse Events (AE) ............................................................................................ 14 
8.6.2 
Clinical Laboratory Tests ..................................................................................... 14 
9. 
APPENDIX: TLF SHELL ................................................................................. 15 
Listing 1. Subjects who died in Study ME-344-003 ............................................................... 40 
 
 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
ABBREVIATION 
DEFINITION 
AE 
Adverse event 
CBC 
Complete blood count 
CI 
Confidence interval 
CR 
Complete response 
CTCAE 
Common Terminology Criteria for Adverse Events 
DOR 
Duration of response 
DOT 
Duration of treatment 
ECOG 
Eastern Cooperative Oncology Group 
EOS 
End of Study 
mCRC 
metastatic colorectal cancer 
MedDRA 
Medical Dictionary for Regulatory Activities 
ORR 
Overall response rate 
OS 
Overall Survival 
PD 
Progressive disease 
PFS 
Progression-free survival 
PR 
Partial response 
PT 
Preferred term 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
TEAE 
Treatment-emergent adverse event 
TFLs 
Tables, figures, and listings 


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Statistical Analysis Plan – Version 1.0 
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1. INTRODUCTION 
This Statistical Analysis Plan (SAP) is created based on Protocol ME-344-003 (Original 
version, 10 August 2021, not implemented, Amendments 1 and 2, not implemented, 
Amendment 3, 06 January 2023, Amendment 4, 09 February 2024) and it describes in detail 
the statistical methodology and the statistical analyses to be conducted for the aforementioned 
protocol. The mockup shells of the Tables, Figures, and Listings (TFLs) for the statistical 
analysis described in this SAP are described as the appendix in this document. 
2. STUDY OBJECTIVES 
2.1 
Primary Objectives 
The primary objectives of this study are as follows:   
• To estimate PFS at 16 weeks of treatment in subjects with metastatic colorectal cancer 
(mCRC) administered ME-344 in combination with bevacizumab  
2.2 
Secondary Objectives 
The secondary objectives of the study are as follows:  
• To evaluate the preliminary efficacy of ME-344 administered in combination with 
bevacizumab in subjects with mCRC 
• To determine the safety and tolerability of ME-344 administered in combination with 
bevacizumab 
• To evaluate the pharmacokinetics (PK) of ME-344 administered in combination with 
bevacizumab 
2.3 
Exploratory Objectives 
The exploratory objectives of the study are as follows: 
• To evaluate correlatives of mitochondrial metabolism 


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3. STUDY DESIGN 
3.1 
General Study Design and Plan 
3.1.1 Overall Study Design 
This is a Phase 1b open-label, multiple dose/schedule sequential study to determine the safety 
and efficacy of the OxPhos inhibitor ME-344 in combination with bevacizumab in subjects 
with recurrent mCRC. 
This study will enroll subjects with mCRC, including but not limited to subjects with RAS 
wild-type or mutant tumors, MSI-H/pMMR, and BRAF V600E, who have progressed or 
demonstrated intolerability to standard approved therapies which include fluoropyrimidine-, 
oxaliplatin-, and irinotecan-based chemotherapies, cetuximab/panitumumab, programmed 
cell death protein 1 (PD-1) inhibitors, or BRAF inhibitors (if clinically indicated), and/or 
checkpoint inhibitors. 
This study consists of 3 periods: (i) screening, (ii) treatment, and (iii) follow-up. During 
screening, each potential subject will provide informed consent prior to starting any 
study-specific procedures. Screening assessments will be completed within 28 days prior to 
administration of ME-344 combined with bevacizumab. 
During the treatment period, subjects enrolled in Cohort 1 will receive ME-344 at a dose of 
10 mg/kg IV on Days 1, 8, and 15 in combination with bevacizumab at a dose of 5 mg/kg IV 
administered on Days 1 and 15 of each 28-day cycle.  
The criterion to initiate Cohort 2, at least 4 subjects in Cohort 1 having completed 16 weeks 
of therapy without evidence of disease progression (i.e., have achieved SD or a response), 
was met based on an interim analysis of 23 subjects enrolled in Cohort 1. However, there 
were no objective responses and since there was no increased toxicity, the ME-344 dosing 
schedule has been revised in Amendment 4 for Cohort 2 to add a Day 8 dose to match the 
schedule of Cohort 1 (i.e., on Days 1, 8, and 15 of the cycle). The intent of this amendment 
was to  provide a larger sample size of subjects administered the same dosing schedule to 
increase the precision level of the 16-week PFS point estimate and overall PFS.  However, 
despite meeting the PFS threshold for opening Cohort 2, the Sponsor decided not to open 
enrollment in Cohort 2. 
There is no maximum duration of treatment for this study; subjects will discontinue study 
drug once there is disease progression, unacceptable AEs, withdrawal of consent, start of new 
anticancer therapy, or death. 
Follow-up includes the End of Treatment (EOT) visit and survival follow-up. After subjects 
have discontinued treatment for any reason, they will be followed every 3 months, or more 


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frequently as needed, until withdrawal of consent, the subject is lost to follow-up, death, or 
defined end of study. If subjects withdraw consent, they will be asked if they are willing to 
be contacted via telephone for survival status. If the subject refuses to be contacted, attempts 
to determine survival status should be made via access to public records, where permitted by 
the local laws. 
All radiographic tumor assessments, preferably computed tomography (CT) with contrast, or 
alternatively magnetic resonance imaging (MRI; if CT is considered not indicated), will be 
carried out in accordance with RECIST v1.1, and are to be performed every 8 weeks (±7 
days) relative to first dose of study drug for the first 6 months, then every 3 months in 
Months 7–12, and every 4 months thereafter. Tumor assessments will be repeated until 
progressive disease (PD), or as per standard practice post-progression. 
Safety will be assessed via TEAEs, physical examinations, vital signs, 12-lead ECGs, and 
clinical laboratory evaluations (hematology, serum chemistry, coagulation [at screening for 
all subjects and Day 1 of every cycle for subjects on anticoagulation therapy], urinalysis). 
Severity grading of TEAEs will use the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) v5.0. 
Blood samples for PK analysis will be collected during Cycle 1 on Days 1 and 15 pre-dose, 
5 minutes after the end of infusion, and 1, 2, 3, 6, and 24 hours after the completion of the 
ME-344 infusion. 
The metabolomic correlative study will be performed on samples obtained from Cohort 1 
subjects enrolled at Rutgers Cancer Institute of New Jersey. For Cohort 2, the metabolomic 
correlative study will be performed on samples from all subjects enrolled.  Plasma samples 
will be collected at timepoints specified in the Schedule of Assessments (Error! Reference s
ource not found.). Samples will be stored at -70°C until analyzed. Specific markers of the 
mitochondrial OxPhos pathway will be analyzed, including changes in isoleucine/leucine, 
TCA cycle intermediates, short chain acyl carnitine, and nucleotide and TCA cycle 
intermediates. 
 
3.2 
Number of Subjects 
Approximately 40 subjects will be enrolled in 2 cohorts of approximately 20 efficacy 
evaluable subjects each. 


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3.3 
Study Treatment 
Enrollment into Cohort 1 will continue until 20 subjects complete radiological assessments at 
16 weeks or discontinue, progress, start new anticancer therapy, or die, whichever happens 
earlier. 
Subjects enrolled in Cohort 1 will receive ME-344 at a dose of 10 mg/kg IV on Days 1, 8, 
and 15 in combination with bevacizumab at a dose of 5 mg/kg IV administered on Days 1 
and 15 of each 28-day cycle. 
If Cohort 1 demonstrates adequate safety, tolerability, and efficacy, Cohort 2 will open to 
enrollment of approximately 20 subjects. 
Subjects enrolled in Cohort 2 will receive ME-344 at a dose of 10 mg/kg IV on Days 1, 8, 
and 15 combined with bevacizumab at a dose of 5 mg/kg IV administered on Days 1 and 15 
of each 28-day cycle. 
Subjects who discontinue bevacizumab due to tolerability may continue treatment with the 
single agent ME-344 at the investigator’s discretion, if in the investigator’s opinion they 
benefit from single-agent treatment. Subjects with persistent proteinuria ≥2 g/24 hours must 
discontinue bevacizumab and ME-344. The results of the Phase I study demonstrated that ME-
344 alone treatment displayed single agent activity leading to partial responses [PRs] or SD in 
subjects with solid tumors. 
3.4 
Randomization and Blinding 
Not applicable. 
3.5 
Study Assessments 
For the detailed schedule of expected events and study procedures to be conducted at each 
visit, please refer to the protocol.  
4. SAMPLE SIZE DETERMINATION 
The PFS rate ≥20% is considered as a positive efficacy signal to proceed to a later stage trial. 
With a sample size of approximately 20 efficacy evaluable subjects in each cohort, assuming 
the true PFS rate at 16 weeks is 30%, there is an 89% chance to observe PFS rate ≥20% 
(i.e., ≥4 of 20 subjects are progression-free) based on binomial distribution. With a sample 
size of approximately 40 efficacy evaluable subjects in combined cohorts 1 and 2, assuming 
the true PFS rate at 16 weeks is 30%, there is an 94% chance to observe PFS rate ≥20% (i.e., 
≥8 of 40 subjects are progression-free) based on binomial distribution. If 7 out of 20 subjects 


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achieve PFS at 16 weeks (observed PFS rate of 35%), there is 90% confidence that the true 
PFS rate is >20% as the lower bound of 80% confidence interval (CI) is 20.7%. If 12 out of 
40 subjects achieve PFS at 16 weeks (observed PFS rate of 30%), there is 90% confidence 
that the true PFS rate is >20% as the lower bound of 80% CI is 20.5%. Thus, increasing 
sample size will allow a lower observed PFS rate with the lower bound of 80% CI to pass the 
20% bar. 
Table 1 summarizes the 95% and 80% exact CIs when observed PFS rate ranges between 
20% to 50%.  
Table 1: Observed Progression-free Survival Rate with Exact 95% and 80% Confidence Intervals 
 
N=20 
N=40 
Observed 
PFS Rate 
Number of 
PFS Subjects 
95% CI (%) 
80% CI 
(%) 
Number of 
PFS Subjects 
95% CI 
(%) 
80% CI 
(%) 
20% 
4 
5.7, 43.7 
9.0, 36.1 
8 
9.1, 35.6 
12.0, 30.4 
25% 
5 
8.7, 49.1 
12.7, 41.5 
10 
12.7, 41.2 
16.2, 35.9 
30% 
6 
11.9, 54.3 
16.6, 46.7 
12 
16.6, 46.5 
20.5, 41.2 
35% 
7 
15.4, 59.2 
20.7, 51.8 
14 
20.7, 51.7 
24.9, 46.3 
40% 
8 
19.1, 63.9 
24.9, 56.7 
16 
24.9, 56.7 
29.4, 51.4 
45% 
9 
23.1, 68.5 
29.3, 61.5 
18 
29.3, 61.5 
34.1, 56.3 
50% 
10 
27.2, 72.8 
33.8, 66.2 
20 
33.8, 66.2 
38.8, 61.2 
If 10 (50%) of 20 subjects experience Grade ≥3 treatment-emergent neuropathy, the 95% CI 
for incidence rate of Grade ≥3 neuropathy will be (27.2%, 72.8%) based on exact method. 
5. STUDY ENDPOINTS 
5.1 
Primary Endpoints 
• PFS rate at 16 weeks 
5.2 
Secondary Endpoints 
• PFS 
• Overall or Objective response rate (ORR) using Response Evaluation Criteria in Solid 
Tumors (RECIST) v1.1 
• Duration of Response (DOR) 
• Overall survival (OS) 


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• Incidence and severity of treatment-emergent adverse events (TEAEs) and their 
relationship to study drug; change from baseline in physical examinations, vital signs, 
12-lead electrocardiograms (ECGs), and clinical laboratory evaluations 
• Maximum observed concentration (Cmax), last observed quantifiable concentration 
(Clast), area under the concentration-time curve from time zero to time of last 
measurable concentration (AUClast) 
5.3 
Exploratory Endpoint 
• Untargeted metabolomics assessments that will include changes in isoleucine/leucine, 
tricarboxylic acid (TCA) cycle intermediates, short chain acyl carnitine, oxidative 
phosphorylation (OxPhos) biomarkers, and nucleotide and TCA cycle intermediates 
6. ANALYSIS  POPULATION 
• The Safety Population includes all subjects who receive at least 1 dose of ME-344. 
Safety analyses will be performed on the Safety Population. 
7. GENERAL STATISTICAL CONSIDERATIONS 
7.1 
Definition of Study Day 
Study day will be calculated in reference to the first dose date of study drug as follows: 
- Assessment/event date – first dose date of study drug + 1, if assessment/event date is on 
or after the first dose date; 
- Assessment/event date – first dose date of study drug, if assessment/event date is before 
the first dose date. 
Under the convention specified above, there will be no Study Day 0.  
7.2 
Baseline Definition 
Baseline value for any given parameter is defined as the last assessment obtained prior to the 
first dose of study drug.  
7.3 
Handling of Missing Data 
Missing values will not be assumed/imputed and only observed values will be used in data 
analyses and presentations unless otherwise stated. 


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8. STATISTICAL ANALYSIS 
All data analyses will be conducted based on the Safety Population. 
Descriptive statistics for continuous data will include the number of observations (n), mean, 
standard deviation, median, minimum, first and third quartiles, and maximum. For discrete 
variables, descriptive analyses will be based on estimates of the number of subjects and related 
percentages. Unless otherwise stated, confidence intervals, when presented, are 2-sided with 
95% confidence level. 
All analyses will be performed using SAS® Version 9.4 (SAS Institute Inc., Cary NC).  
8.1 
Subject Disposition 
The following categories of subject disposition will be included: 
• Subjects who were treated with ME-344 
• Subjects who were treated with Bevacizumab 
• Subjects who discontinued from ME-344 
• Subjects who discontinued from the study 
For subjects who discontinued from the study, the primary reason for ending the study will be 
summarized. The number and percentage of subjects will be tabulated as appropriate. 
All deaths that occur on study will be reported in a subject listing, which will include the 
primary cause of death and the number of days between the date of the first (and last) dose of 
study drug and death.  
8.2 
Demographics and Baseline Characteristics  
Demographics and baseline characteristics will be summarized descriptively. Sex, race, 
ethnicity, baseline ECOG performance status, disease stage at diagnosis and prior lines of 
therapy (1-2 versus > 2) will be summarized with contingency tables. Age at informed consent 
(years), baseline weight and number of prior lines of therapy will be presented with descriptive 
statistics. 
8.3 
Exposure and Duration of Treatment 
Duration of treatment (DOT) will be summarized descriptively. Additionally, the swimmer 
plot of DOT will be generated. For subjects who either completed or discontinued the treatment 
by the EOS visit, DOT will be calculated as follows: 
DOT (months) = (Last Dose Date – First Dose Date + 1) / 30.4375 


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Number of ME-344 infusions will be presented with descriptive statistics. 
8.4 
Duration of Follow-up 
Duration of follow-up is calculated as (end of study date – first dose date + 1)/30.4375. 
Duration of follow-up will be summarized descriptively. 
 
8.5 
Efficacy Analyses 
8.5.1 Progression-Free Survival (PFS)  
PFS will be calculated from the day of first study drug dose to the first observation of 
progressive disease (PD) as assessed by the Investigator per RECIST v.1.1 or death from any 
cause. For the primary PFS analysis, subjects without a PD or death event will be censored at 
last adequate assessment date or first dose date if no adequate postbaseline assessment is 
available. For the exploratory analysis for PFS, subjects without a PD or death event will be 
censored at the end of treatment discontinuation date. 
PFS will be summarized descriptively using the Kaplan-Meier method. The Kaplan-Meier 
estimates of the median PFS and the corresponding 2-sided 95% confidence intervals, 
calculated using the method of Brookmeyer and Crowley, will be presented. Number of 
patients with PFS events and number of patients censored will be provided. Also, the Kaplan-
Meier estimates of PFS rates along with the corresponding 2-sided 95% confidence intervals 
will also be provided at 4 months, 6 months and 12 months. Plots of the Kaplan-Meier estimate 
of PFS rates will be generated with number of subjects at risk noted by 30 days intervals. 
8.5.2 Overall Survival (OS) 
OS is defined as the time from first study drug dose to death from any cause. Subjects without 
a death event will be censored at the last date when the subject was known to be alive. 
OS will be summarized descriptively using the Kaplan-Meier method. The Kaplan-Meier 
estimates of the median OS and the corresponding 2-sided 95% confidence intervals, 
calculated using the method of Brookmeyer and Crowley, will be presented. Number of 
patients with OS events and number of patients censored will be provided. Plots of the Kaplan-
Meier estimate of OS rates will be generated with number of subjects at risk noted by 30 days 
intervals. 


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8.5.3 Overall Response Rate (ORR) 
ORR will be derived by calculating the proportion of subjects with best response of 
Complete Response (CR) or Partial Response (PR) per RECIST v.1.1. The 2-sided exact 
95% CI based on the Clopper-Pearson method will be provided. 
8.5.4 Waterfall Plot 
Waterfall plot of best change in sum of target lesion size will be provided to present each 
subject’s best percent change from baseline in sum of target lesion size. 
 
8.6 
Safety Analyses 
Safety will be assessed and relevant parameters will include AEs, serious adverse events 
(SAEs), and laboratory safety tests including hematology (complete blood count [CBC]), and 
serum chemistry. 
Safety analyses in general will be presented in tabular format with the appropriate summary 
statistics.  
8.6.1 Adverse Events (AE) 
A TEAE is defined as an AE starting or worsening per CTCAE grade after the first dose until 
30 days after the last dose of study drug or start of new anticancer therapy, whichever is 
earlier. Safety will be assessed through the analysis of the reported incidence, severity, and 
relationship of TEAEs, including SAEs, AEs leading to withdrawal of study drug, and AEs 
related to study treatment. 
AEs will be summarized by MedDRA coded Preferred Term (PT).  
The number and percentage of subjects with TEAEs will be summarized by PT and Grade. 
Treatment-related TEAEs, treatment-emergent SAEs, and TEAEs leading to discontinuation 
of study drug will be summarized by PT. For these summaries, subjects with multiple adverse 
events will be counted only once per PT.   
8.6.2 Clinical Laboratory Tests  
Hematology parameters including Hemoglobin, Lymphocyte count, Neutrophil count, Platelet, 
and Leukocytes and Chemistry parameters including AST, ALT, Total Bilirubin, and Alkaline 
Phosphatase will be assigned toxicity grades, using NCI CTCAE v5.0.  
The number and percentage of subjects with laboratory abnormalities (any grade) will be 
presented for the above mentioned hematology and chemistry laboratory parameters by grade.  


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9. APPENDIX: TLF SHELL


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Table 1 Disposition Summary - Safety Population 
Characteristic 
Total (N=23) 
n(%) 
 
Total Patients Treated With ME-344 [b] 
23 
 
Discontinued From ME-344 
21 
 Completed treatment as defined in protocol 
0 
 Adverse Event 
2 (8.7) 
 Death 
0 
 Lost To Follow-Up 
0 
 Physician's Decision 
2 (8.7) 
 Pregnancy 
0 
 Progressive Disease 
15 (65.2) 
 Non-Compliance 
0 
 Site Terminated by Sponsor 
0 
 Study Terminated By Sponsor 
0 
 Withdrawal by Subject 
2 (8.7) 
 New Anti-Cancer Therapy 
0 
 Other 
0 
 
Did Not Discontinue From ME-344 [c] 
2 
 
Total Patients Treated With Bevacizumab [d] 
23 
 Discontinued From Study 
11 
 Lost To Follow-up 
0 


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Characteristic 
Total (N=23) 
n(%) 
 Progressive Disease 
1 (4.3) 
 New Anti-Cancer Therapy 
0 
 Non-Compliance 
0 
 Withdrawal by Subject 
1 (4.3) 
 Site Terminated by Sponsor 
0 
 Study Terminated By Sponsor 
0 
 Death 
9 (39.1) 
 Other 
0 
 
Did Not Discontinue From Study [e] 
12 
 
 
Percentage is based on the number of subjects in the safety population.  
[b] Patients who received at least one dose of ME-344. 
[c] Patients without a reason for ME-344 discontinuation. 
[d] Patients who received at least one dose of bevacizumab 
[e] Patients without a reason for study discontinuation 
 
 
 
 
 


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Table 2 Summary of Demographics and Baseline Characteristics - Safety Population 
 
Total 
 (N=23) 
 
 
 
Sex 
 
 
 
  Female 
12 (52.2) 
 
 
  Male 
11 (47.8) 
 
 
 
 
 
 
Race 
 
 
 
  American Indian or Alaska Native 
0 
 
 
  Asian 
3 (13.0) 
 
 
  Black or African American 
2 (8.7) 
 
 
  Native Hawaiian or Other Pacific Islander 
0 
 
 
  White 
18 (78.3) 
 
 
  Other 
0 
 
 
 
 
 
 
Ethnicity 
 
 
 
  Hispanic or Latino 
1 (4.3) 
 
 
  Not Hispanic or Latino 
22 (95.7) 
 
 
 
 
 
 
Age at Informed Consent (Years) 
 
 
 
  n 
23 
 
 
  Mean (Standard Deviation) 
59.1 (11.10) 
 
 
  Median 
58.0 
 
 
  Min, Max 
43, 83 
 
 
  First,Third Quartile (Inter-Quartile Range) 
50.0, 65.0 (15.0) 
 
 
Baseline ECOG Performace Status 
 
 0 
13 (56.5) 


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Total 
 (N=23) 
 
 
 1 
9 (39.1) 
 2 
1 (4.3) 
 
Baseline Weight (kg) 
 
 n 
23 
 Mean (Standard Deviation) 
81.57 (16.178) 
 Median 
82.20 
 Min, Max 
44.4, 109.7 
 First,Third Quartile (Inter-Quartile Range) 
73.0, 96.2 (23.2) 
 
Disease Stage at Diagnosis 
 
 Stage 2 
2 (8.7) 
 Stage 3 
9 (39.1) 
 Stage 4 
12 (52.2) 
 
 
 
 


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Table 3 Summary of Prior Therapies - Safety Population 
Total 
(N=23) 
 
Number of Prior Lines of Therapy Regimens 
 
 n 
23 
 Mean (Standard Deviation) 
4.39 (1.828) 
 Median 
4.00 
 Min, Max 
1.0, 8.0 
 
Number (%) of Patients Receiving 
 
 1 - 2 Prior lines of therapy 
4 (17.4) 
 > 2 Prior lines of therapy 
19 (82.6) 
 
 
 


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Table 4 ME-344 Exposure - Safety Population 
Total 
(N=23) 
 
Duration of Treatment (Days) 
 
 n 
23 
 Mean (Standard Deviation) 
59.52 (44.442) 
 Median 
44.00 
 Min, Max 
8.0, 156.0 
 First,Third Quartile (Inter-Quartile Range) 
29.0, 106.0 (77.0) 
 
Number of ME-344 Infusions 
 
 n 
23 
 Mean (Standard Deviation) 
7.09 (4.242) 
 Median 
6.00 
 Min, Max 
2.0, 18.0 
 First,Third Quartile (Inter-Quartile Range) 
4.0, 9.0 (5.0) 
 
 
 


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Table 5 Summary of Duration of Follow-up - Safety Population 
 
Total 
(N=23) 
 
Follow-up Time (Months) 
 
 n 
23 
 Mean (Standard Deviation) 
4.04 (1.686) 
 Median 
4.01 
 Min, Max 
0.5, 7.0 
 First,Third Quartile (Inter-Quartile Range) 
3.1, 5.2 (2.1) 
 
 
 


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Table 6.1 Summary of Progression Free Survival (Primary Analysis) - Safety Population 
Characteristic 
Number (%) of patients [a] 
(N=23) 
 
Number of patients with events 
17 (73.9) 
 
Number of patients censored[1] 
6 (26.1) 
 
Median Time to Event (95% CI)[2] 
1.89 (1.61, 5.19) 
 
Event Rates 
 
 
 4 months (95% CI) 
31.17 (13.51, 50.71) 
 
 6 months (95% CI) 
0.00 (., .) 
 
 12 months (95% CI) 
0.00 (., .) 
 
[a]N=Number of subjects; the denominator for % calculations should be N for each column (number in study part or total). 
Note: PFS is defined as the time from first dose of study drug (Day 1) until first disease progression or death from any cause. 
Note: Percentages are based on the number of overall subjects (N). 
[1] Censored at the last disease assessment or first dose date if no progression, or death. 
[2] Kaplan-Meier estimate with 95% CI based on Brookmeyer-Crowley log(-log) transformation. 
 


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Table 6.2 Summary of Progression Free Survival (Exploratory Analysis) - Safety Population 
Characteristic 
Number (%) of patients [a] 
(N=23) 
 
Number of patients with events 
17 (73.9) 
 
Number of patients censored[1] 
6 (26.1) 
 
Median Time to Event (95% CI)[2] 
1.89 (1.61, 5.19) 
 
Event Rates 
 
 
 4 months (95% CI) 
31.17 (13.51, 50.71) 
 
 6 months (95% CI) 
0.00 (., .) 
 
 12 months (95% CI) 
0.00 (., .) 
 
[a]N=Number of subjects; the denominator for % calculations should be N for each column (number in study part or total). 
Note: PFS is defined as the time from first dose of study drug (Day 1) until first disease progression or death from any cause. 
Note: Percentages are based on the number of overall subjects (N). 
[1] Censored at the end of treatment discontinuation date if no progression, or death. 
[2] Kaplan-Meier estimate with 95% CI based on Brookmeyer-Crowley log(-log) transformation. 
 
 


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Table 7 Summary of Overall Survival - Safety Population 
Characteristic 
Number (%) of patients 
[a] 
(N=23) 
 
Number of patients with events 
8 (34.8) 
 
Number of patients censored 
15 (65.2) 
 
Median Time to Event (95% CI)[1] 
6.67 (3.42, NA) 
 
[a]N=Number of subjects; the denominator for % calculations should be N for each column (number in study part or total). 
Note: OS is defined as the time from first dose of study drug (Day 1) until death from any cause. 
Note: Percentages are based on the number of overall subjects (N). 
[1] Kaplan-Meier estimate with 95% CI based on Brookmeyer-Crowley log(-log) transformation. 
 
 
 
 


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Table 8 Summary of Disease Response - Safety Population 
 
Characteristic 
Number (%) of patients 
[a] 
(N=23) 
 
Best Overall Response 
0 
   Complete Response 
0 
   Partial Response 
0 
   Stable Disease 
10 (43.5) 
   Progressive Disease 
9 (39.1) 
   Not Evaluable 
0 
   Not Available 
4 (17.4) 
 
Overall Response Rate (Complete Response + Partial Response) 
0 
   95% CI (LCL, UCL) 
(0.0, 14.8) 
 
 
[a]N=Number of subjects; the denominator for % calculations should be N for each column (number in study part or total). 
[b] 2-sided exact 95% confidence interval (CI) based on the Clopper-Pearson method; LCL – Lower confidence limit; UCL – Upper confidence limit. 


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Table 9 Subject Incidence of TEAEs by Grade - Safety Population 
 
 
All Subjects (N=23) 
 
 
 
 
N(%)  
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
All Grade 
Subjects with at least one TEAE 
17 (73.9) 
14 (60.9) 
15 (65.2) 
1 (4.3) 
1 (4.3) 
21 (91.3) 
Fatigue 
4 (17.4) 
2 (8.7) 
3 (13.0) 
0 
0 
9 (39.1) 
Abdominal pain 
3 (13.0) 
3 (13.0) 
2 (8.7) 
0 
0 
8 (34.8) 
Diarrhoea 
2 (8.7) 
4 (17.4) 
1 (4.3) 
0 
0 
7 (30.4) 
Constipation 
4 (17.4) 
1 (4.3) 
0 
0 
0 
5 (21.7) 
Blood sodium decreased 
2 (8.7) 
2 (8.7) 
0 
0 
0 
4 (17.4) 
Nausea 
2 (8.7) 
1 (4.3) 
1 (4.3) 
0 
0 
4 (17.4) 
Vomiting 
2 (8.7) 
1 (4.3) 
1 (4.3) 
0 
0 
4 (17.4) 
Blood bilirubin increased 
1 (4.3) 
0 
2 (8.7) 
0 
0 
3 (13.0) 
Dehydration 
0 
0 
3 (13.0) 
0 
0 
3 (13.0) 
Hypertension 
0 
1 (4.3) 
2 (8.7) 
0 
0 
3 (13.0) 
Leukocytosis 
0 
0 
3 (13.0) 
0 
0 
3 (13.0) 
Non-cardiac chest pain 
3 (13.0) 
0 
0 
0 
0 
3 (13.0) 
Abdominal pain upper 
1 (4.3) 
1 (4.3) 
0 
0 
0 
2 (8.7) 
Aspartate aminotransferase increased 
2 (8.7) 
0 
0 
0 
0 
2 (8.7) 
 
If a patient had multiple events with same preferred term and different grades, the event will be shown in the highest grade of the table.  
If a patient had multiple events with different preferred terms, these events will be shown in the corresponding highest grades of the table. 
 


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Table 10 Subject Incidence of Serious Adverse Events (SAE) by Preferred Term - Safety Population 
Total 
(N=23) 
Subjects with at least one SAE 
11 (47.8) 
 Dehydration 
3 (13.0) 
 Abdominal Pain 
2 (8.7) 
 Pulmonary Embolism 
2 (8.7) 
 Sepsis 
2 (8.7) 
 Atrial Fibrillation 
1 (4.3) 
 Blood Bilirubin Increased 
1 (4.3) 
 Cholecystitis 
1 (4.3) 
 Decreased Appetite 
1 (4.3) 
 Diarrhoea 
1 (4.3) 
 Fall 
1 (4.3) 
 Gastritis 
1 (4.3) 
 Haematochezia 
1 (4.3) 
 Hepatic Failure 
1 (4.3) 
 Hyponatraemia 
1 (4.3) 
 Large Intestinal Obstruction 
1 (4.3) 
 Rectal Haemorrhage 
1 (4.3) 
 Urinary Retention 
1 (4.3) 
 Vomiting 
1 (4.3) 
 
 


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Table 11 Subject Incidence of Related TEAEs by Preferred Term - Safety Population 
Total 
(N=23) 
Subjects with at least one Related TEAE 
14 (60.9) 
 Fatigue 
8 (34.8) 
 Abdominal Pain 
3 (13.0) 
 Diarrhoea 
2 (8.7) 
 Headache 
2 (8.7) 
 Hypertension 
2 (8.7) 
 Leukocytosis 
2 (8.7) 
 Peripheral Sensory Neuropathy 
2 (8.7) 
 Vomiting 
2 (8.7) 
 Abdominal Pain Upper 
1 (4.3) 
 Arthralgia 
1 (4.3) 
 Asthenia 
1 (4.3) 
 Atrial Fibrillation 
1 (4.3) 
 Blood Sodium Decreased 
1 (4.3) 
 Chills 
1 (4.3) 
 Constipation 
1 (4.3) 
 Decreased Appetite 
1 (4.3) 
 Hyponatraemia 
1 (4.3) 
 Nausea 
1 (4.3) 
 


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Table 12 Subject Incidence of TEAEs Leading to Study Discontinuation by Preferred Term - Safety Population 
 
Total 
(N=23) 
Subjects with AE leading to study discontinuation 
2 (8.7) 
 Fatigue 
1 (4.3) 
 Sepsis 
1 (4.3) 
 
 
 


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Table 13 Summary of Decreased Haematology Parameters - Safety Population 
Total 
(N=23) 
 
Hemoglobin 
22 
   Grade  1 
11 (47.8) 
   Grade  2 
7 (30.4) 
   Grade  3 
0 
 
Lymphocyte Count 
22 
   Grade  1 
4 (17.4) 
   Grade  2 
6 (26.1) 
   Grade  3 
3 (13.0) 
   Grade  4 
1 (4.3) 
 
Neutrophils count 
22 
   Grade  1 
0 
   Grade  2 
1 (4.3) 
   Grade  3 
0 
   Grade  4 
0 
 
Platelet 
22 
   Grade  1 
3 (13.0) 
   Grade  2 
0 


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Total 
(N=23) 
   Grade  3 
0 
   Grade  4 
1 (4.3) 
 
Leukocytes 
22 
   Grade  1 
2 (8.7) 
   Grade  2 
1 (4.3) 
   Grade  3 
0 
   Grade  4 
0 
 


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Table 14 Summary of Elevated Chemistry Parameters - Safety Population 
 
Total 
(N=23) 
 
AST 
22 
   Grade  1 
7 (30.4) 
   Grade  2 
3 (13.0) 
   Grade  3 
1 (4.3) 
   Grade  4 
0 
 
ALT 
22 
   Grade  1 
6 (26.1) 
   Grade  2 
0 
   Grade  3 
1 (4.3) 
   Grade  4 
0 
 
Total Bilirubin 
22 
   Grade  1 
4 (17.4) 
   Grade  2 
0 
   Grade  3 
2 (8.7) 
   Grade  4 
1 (4.3) 
 
Alkaline Phosphatase 
22 
   Grade  1 
2 (8.7) 


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Total 
(N=23) 
   Grade  2 
2 (8.7) 
   Grade  3 
1 (4.3) 
   Grade  4 
0 
 


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Figure 1 Swimmer Plot – Safety Population 
 
 
 


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Figure 2.1 
Kaplan-Meier Curve for Progression-Free Survival (Primary Analysis) - Safety Population 
 
 
Programming note: For the primary PFS analysis, subjects without a PD or death event will be censored at last adequate assessment 
date or first dose date if no adequate postbaseline assessment is available. 
 


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Figure 2.2 
Kaplan-Meier Curve for Progression-Free Survival (Exploratory Analysis) - Safety Population 
 
 
Programming note: For the exploratory PFS analysis, subjects without a PD or death event will be censored at last adequate 
assessment date or first dose date if no adequate postbaseline assessment is available.


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Figure 3 Kaplan-Meier Curve for Overall Survival – Safety Population 
 


 
 
 
Figure 4 Waterfall Plot of Best Change in Sum of Target Lesion Size - Safety Population 
 
 
 


 
 
 
 
Listing 1. Subjects who died in Study ME-344-003 
Subject ID 
Sex 
Age 
Primary Cause of Death 
Last ME-344-003
Dose Date (Day) Death Date (Day) 
AE 
Preferred 
Term
(if Died due to AE) 
Relationship 
to Drug 
0037_009 
Male 
74 
Adverse Event 
9 Mar 2020 (456) 31 Mar 2020 (478) 
Corona virus infection 
Not-Related 
0102_004 Female 
44 
Disease Progression 
2 Aug 2019 (19) 
11 Aug 2019 (28) 
4005_002 
Male 
79 
Unknown 
22 Mar 2019 (639) 20 Jun 2019 (729) 
41007-001 Female 
50 
Adverse Event 
27 Mar 2020 (15) 10 Apr 2020 (29) 
Tumour lysis syndrome 
Related 
41008-001 
Male 
78 
Disease Progression 
22 Dec 2019 (110) 14 Jan 2020 (133)