Conditions: Pancreatic Cancer
Keywords: Cancer Advanced Pancreatic Cancer
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 45
Healthy volunteers: no

Brief summary:
This is a Phase 2 multicenter, open-label, non-randomized study to examine the safety and effectiveness of BPM31510 administered over 144-hours (two 72-hour 110mg/Kg doses) continuous intravenous (IV) infusion in combination with gemcitabine in advanced pancreatic cancer patients as 2nd / 3rd line therapy. The study will enroll up to 25 patients in the US and Europe.

Detailed description:
This is a Phase 2 multicenter, open-label, non-randomized study to examine the safety and effectiveness of BPM31510 administered over 144-hours (two 72-hour 110mg/Kg doses) continuous intravenous (IV) infusion in combination with gemcitabine in advanced pancreatic cancer patients as 2nd / 3rd line therapy.

Cycle 1 of therapy is 6 weeks in duration with BPM31510 administered twice weekly on Tuesdays and Fridays for 6 weeks plus gemcitabine administered on Mondays, Days 21, 28 and 35.

Cycles 2-12 are 4 weeks in duration with BPM31510 administered twice weekly on Tuesdays and Fridays for 4 weeks plus gemcitabine administered on Mondays, Days 7, 14 and 21. Response will be assessed after Cycle 2 (10 weeks) and patients who continue onto Cycles 2-12 will be assessed every 2 cycles (8 weeks).

Patients will continue BPM31510 in combination with gemcitabine, for a maximum of 12 cycles in the absence of intolerable toxicity and progression. If gemcitabine is discontinued due to chemotherapy-related toxicity, patients may continue to receive BPM31510 as monotherapy.

Patients who experience disease progression but are, in the opinion of the investigator, receiving clinical benefit may continue BPM31510 as a monotherapy or in combination with gemcitabine or as a monotherapy pending approval from the Sponsor.

Arms:
arm 1: BPM31510 Nanosuspension Injection (40 mg/mL) starting dose of 110 mg/kg administered IV over 144 hours as 2 consecutive 72-hour infusions per week (Tuesday-Friday and Friday-Monday).

Starting on Day 21-treatment with gemcitabine IV once weekly at a starting dose of 1000 mg/m2.

Cycle 1 of combination therapy is 6 weeks in duration for patients with BPM31510 administered twice weekly on Tuesdays and Fridays for 6 weeks and gemcitabine administered on Mondays, Days 21, 28 and 35. Cycles 2-12 are 4 weeks in duration with BPM31510 administered twice weekly on Tuesdays and Fridays for 4 weeks and gemcitabine administered on Mondays, Days 7, 14 and 21. arm 2: BPM31510 Nanosuspension Injection (40 mg/mL) starting dose of 110 mg/kg administered IV over 144 hours as 2 consecutive 72-hour infusions per week (Tuesday-Friday and Friday-Monday).

Interventions: intervention 1: BPM31510 Nanosuspension Injection intervention 2: Gemcitabine
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_000.pdf: 
 
 
 
 
BPM31510IV-05 
 
A Phase 2 Study of BPM31510 (
) 
Nanosuspension Injection Administered 
Intravenously with Gemcitabine as 2nd/3rdline 
therapy in Advanced Pancreatic Cancer Patients 
BERG PROTOCOL NUMBER: 
BPM31510IV-05 
PCRT PROTOCOL NUMBER: 
TRIAL DRUG: 
PCRT 15-002 
BPM31510 (
 Nanosuspension Injection  
IND NUMBER: 
EudraCT Number: 
108,093 
2017-001470- 42 
SPONSOR: 
BERG LLC                                        
500 Old Connecticut Path              
Building B                                      
Framingham, MA 01701 
ORIGINAL DATE: 
AMENDMENT 1: 
AMENDMENT 2: 
AMENDMENT 3: 
AMENDMENT 4: 
AMENDMENT 5: 
AMENDMENT 6: 
AMENDMENT 6.1 
AMENDMENT 7: 
20 November 2015 
01 April 2016 
20 April 2016 
03 October 2016 
27 January 2017 
16 June 2017 
19 August 2017     
05 January 2018 (UK Version only) 
25 August 2018 


Confidential Property of BERG, LLC 
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Protocol BPM31510IV-05 Amendment 7.0                                                                                          25 August 2018 
 
 
Clinical Trial Protocol Statement of Compliance 
 
This clinical trial shall be conducted in compliance with the protocol, as referenced 
herein, and all applicable local, national, and international regulatory requirements to 
include, but not be limited to: 
• 
International Conference on Harmonization (ICH) Guidelines on Good 
Clinical Practice (GCP) 
• 
Ethical principles that have their origins in the Declaration of Helsinki  
• 
Food and Drug Administration (FDA) Code of Federal Regulation (CFR): 
o Title 21CFR Part 50 & 45 CFR Part 46, Protection of Human Patients 
o Title 21CFR Part 54, Financial Disclosure by Clinical Investigators 
o Title 21CFR Part 56, Institutional Review Boards 
o Title 21CFR Part 312, Investigational New Drug Application 
o Title 45 CFR Parts 160, 162, and 164, Health Insurance Portability and 
Accountability Act (HIPAA) 
o Annex 1 of Directive 2001/83/EC 
o European Union (EU) clinical-trial legislation (Directive 2001/20/EC) 
o Clinical Trial Regulation (EU No 536/2014) 
 
As the Principal Investigator (PI), I understand that my signature on the protocol 
constitutes my agreement and understanding of PI responsibilities to conduct the clinical 
trial in accordance to the protocol and applicable regulations. Furthermore, it constitutes 
my understanding and agreement that any changes initiated by myself, without prior 
agreement in writing from the Sponsor, shall be defined as a deviation from the protocol, 
and shall be formally documented as such. 
As the Sponsor Representative, I understand that my signature constitutes agreement and 
understanding of acceptance of the defined and contracted Sponsor responsibilities to the 
CRO and the PI as defined by the protocol, applicable clinical trial agreements (CTA), 
and/or business contracts, but does not in any capacity relieve me of my responsibilities as 
the Sponsor. Additionally, my signature constitutes my understanding and agreement 
that any changes to the protocol, CTA, or contracts shall be implemented timely with my 
review and approval prior to implementation. 


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Protocol BPM31510IV-05 Amendment 7.0                                                                                          25 August 2018 
 
 
Clinical Trial Protocol Approval Page 
 
A Phase 2 Study of BPM31510 (
) Nanosuspension Injection Administered 
Intravenously with Gemcitabine as 2nd /3rd line therapy in Advanced Pancreatic Cancer 
Patients 
BERG Protocol Number: 
BPM31510IV-05 
PCRT Protocol Number:  
Trial Drug: 
PCRT 15-002 
BPM31510 (
 Nanosuspension Injection  
IND NUMBER: 
108,093 
DATE FINAL: 
20 November 2015 
AMENDMENT 1: 
01 April 2016 
AMENDMENT 2: 
AMENDMENT 3: 
AMENDMENT 4: 
AMENDMENT 5: 
AMENDMENT 6: 
AMENDMENT 6.1: 
AMENDMENT 7: 
20 April 2016 
03 October 2016 
27 January 2017 
16 June 2017 
19 August 2017    
05 January 2018 (UK Version Only) 
25 August 2018 
 
 
 
BERG CMO Name 
BERG Chief Medical Officer 
 Date 
 
 
 
 
 
 
 
BERG CSO Name 
BERG Clinical and Scientific Operations 
 Date 
 
 
 
 
 
 
Lead /Principal Investigator Name              Principal Investigator Signature                           Date 
 
 
 
 
 
 


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Protocol BPM31510IV-05 Amendment 7.0                                                                                          25 August 2018 
 
 
Clinical Trial Protocol Acceptance Form 
 
A Phase 2 Study of BPM31510 (
 Nanosuspension Injection Administered 
Intravenously with Gemcitabine as 2nd /3rd line therapy in Advanced Pancreatic Cancer 
Patients 
BERG Protocol Number: 
BPM31510IV-05 
PCRT Protocol Number:  
Trial Drug: 
PCRT 15-002 
BPM31510 
 
IND NUMBER: 
108,093 
DATE FINAL: 
20 November 2015 
AMENDMENT 1: 
01 April 2016 
AMENDMENT 2: 
AMENDMENT 3: 
AMENDMENT 4: 
AMENDMENT 5: 
AMENDMENT 6: 
AMENDMENT 6.1: 
AMENDMENT 7: 
20 April 2016 
03 October 2016 
27 January 2017 
16 June 2017 
19 August 2017   
05 January 2018 (UK Version Only)  
25 August 2018 
 
 
 
 
 
 
 
 
 
 
 
___________________________ ____________________________________________________ _____________ 
Principal Investigator Name 
Principal Investigator Signature 
Date 
 
 
 


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Protocol BPM31510IV-05 Amendment 7.0                                                                                          25 August 2018 
 
 
CLINICAL PROTOCOL BPM31510IV-05 SYNOPSIS 
Title of Trial: 
A Phase 2 Study of BPM31510 (
) Nanosuspension 
Injection Administered Intravenously with Gemcitabine as 2nd /3rd line 
therapy in Advanced Pancreatic Cancer Patients 
BERG Protocol 
Number: 
BPM31510IV-05 
Sponsor: 
BERG LLC                                                             
500 Old Connecticut Path                                   
Building B  
Framingham, MA 01701 USA                             
Trial Duration:  
The duration of the trial is 36 months. 
Phase of Trial: 2 
Trial Population 
and Trial Centers: 
The trial population is advanced pancreatic cancer patients who have received no more 
than 2 previous chemotherapy regimens.  
This is a multicenter trial to be conducted at up to 20 sites in the U.S. & Europe  
Objectives: 
Primary:  
Primary Objectives: 
Evaluate the Overall Response Rate in patients treated with the combination of 
BPM31510 with gemcitabine  
Secondary Objectives: 
Evaluate Overall Survival;  
Evaluate Progression-Free Survival overall and at around 10 weeks (equal to 2 cycles of 
treatment; cycle 1 = 6 weeks + cycle 2 = 4 weeks); 
Evaluate Time to Progression (TTP);  
Evaluate Tumor Response using Adaptive Molecular Responses (epi-genomic analysis 
(SNP or X-ome technology)) 
Determine the toxicity profile of BPM31510 in combination with gemcitabine when 
administered as a 144-hour (two 72-hr) intravenous (IV) infusion in patients with 
advanced pancreatic cancer.  
Evaluate change in CA 19-9 levels. 
Evaluate changes in patient reported Quality of Life at the end of Cycle 2, and at End of 
Study or early termination  
 
Primary Endpoint: 
Overall Response Rate.  A two-stage design will be used such that if one of the initial ten 
enrolled patients experiences a tumor response of Partial Response (PR) or better, based 
on RECIST 1.1 criteria, after 2 cycles of treatment, then the study will be expanded to 
enroll an additional 15 patients for a total of 25 evaluable patients. In the absence of at 
least one CR or PR, if at least 3 patients experience stable disease the Sponsor can choose 
to enroll the additional 15 patients into the expansion stage. 
 
Secondary Endpoints 
Efficacy: Best response, disease control rate (CR+PR+SD), Duration of Response, 
Overall Survival, Progression-Free Survival (PFS), Time to Progression, and CA 19-9 
level change.  
Quality of Life: FACT-HEP self-administered patient questionnaire 
 
Safety:  Laboratory results, adverse events, vital signs, concomitant medications, 
concomitant procedures and ECG.   


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Protocol BPM31510IV-05 Amendment 7.0                                                                                          25 August 2018 
 
 
Objectives (cont’d): 
Exploratory:  
The exploratory objectives are: 
• 
To evaluate the effects of BPM31510 on shifting tumors to aerobic respiration by 
18-FDG-PET imaging. 
• 
Tumor, plasma and urine samples will be assayed for levels of markers of 
BPM31510 activity using (but not limited to): 
o 
genomic (e.g. microarray, SAGE, northern blotting, gene expression), 
proteomic (e.g., LC/MS based analysis, 2DE-MS, MALDI TOF, antibody 
array, ELISA, immunohistochemistry, tissue microarray, flow cytometry, 
western blotting),  
o 
metabolomics (e.g., global analysis of metabolites in biological samples; 
identification of specific markers of energy metabolism e.g., pyruvate, 
lactate),  
o 
lipidomics (e.g., global analysis of lipid classes; identification of specific 
lipids e.g., derivatives of palmitate, linoleic acid, arachidonic acid).  
The objective of this integrative approach is to stratify patient populations based on 
phenotypic or molecular profiles for therapeutic benefit.  This includes assessing the 
patient’s biofluid as well as the tumor for markers of positive, stable or negative outcome 
allowing for guidance of selection of participants in future cohorts. 


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Protocol BPM31510IV-05 Amendment 7.0                                                                                          25 August 2018 
 
 
 
Trial Design: 
This is a Phase 2 multicenter, open-label, non-randomized study to examine the safety and 
effectiveness of BPM31510 administered over 144-hours (two 72-hour 110mg/Kg doses) 
continuous intravenous (IV) infusion in combination with gemcitabine in advanced 
pancreatic cancer patients as 2nd / 3rd line therapy.  
 
 
  
 
 
 
  
Toxicity will be graded according to National Cancer Institute Common Terminology 
Criteria for Adverse Events (CTCAE v4.02). Assessments of the antitumor activity of the 
combination will be performed at the end of Cycle 2 and every 2 cycles thereafter using 
standard techniques such as computerized tomography (CT) or magnetic resonance 
imaging (MRI) for patients with measurable disease. Response will be evaluated using 
Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 (Appendix E: RECIST 
Response Criteria for Solid Tumors).  
Patients who experience no unacceptable toxicity or disease progression, may receive 
additional 28-day cycles for up to 1 year.  
Patients will continue BPM31510 in combination with gemcitabine, for a maximum of 12 
cycles in the absence of intolerable toxicity and progression. If gemcitabine is 
discontinued due to chemotherapy-related toxicity, patients may continue to receive 
BPM31510 as monotherapy.  
Patients who experience disease progression but are, in the opinion of the investigator, 
receiving clinical benefit may continue BPM31510 as a monotherapy or in combination 
with gemcitabine pending approval from the Sponsor.  
 
 
Efficacy 
Assessments 
 
Efficacy measures will include: 
Overall Survival (OS) 
Overall Response Rate (ORR) 
Best Response 
Duration of Response 
Progression Free Survival (PFS) 
Clinical Benefit Rate (SD+PR+CR) 
CA 19-9 level change  
Quality of Life changes (FACT-Hep) 
 


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Protocol BPM31510IV-05 Amendment 7.0                                                                                          25 August 2018 
 
 
 
Safety Assessments 
 
Safety measures will include: 
AEs 
Hematology, clinical chemistry, and urinalysis 
Physical examination and vital signs 
Concomitant medications/procedures 
12-lead ECGs 
ECOG Performance Status 
Dose Modifications of protocol-specified treatment 
 
Exploratory 
Assessments 
 
• 
Assessment of tumor metabolic activity (18-FDG-PET/CT) will be done < 14 
calendar days prior to starting treatment with BPM31510 and repeated after the 
completion of Cycle 2, and then after every 2 Cycles (Cycle 4, 6, 8, …).  The PET 
scan will be performed to assess the effects of BPM31510 on the shifting tumors to 
aerobic respiration.  
• 
Plasma and urine samples will be assayed for levels of markers of BPM31510 
activity using (but not limited to): 
o 
genomic (e.g. microarray, SAGE, northern blotting, gene expression), 
proteomic (e.g., LC/MS based analysis, 2DE-MS, MALDI TOF, antibody 
array, ELISA, immunohistochemistry, tissue microarray, flow cytometry, 
western blotting),  
o 
metabolomics (e.g., global analysis of metabolites in biological samples; 
identification of specific markers of energy metabolism e.g., pyruvate, 
lactate),  
o 
lipidomics (e.g., global analysis of lipid classes; identification of specific 
lipids e.g., derivatives of palmitate, linoleic acid, arachidonic acid).  
The objective of this integrative approach is to stratify patient populations based on 
phenotypic or molecular profiles for therapeutic benefit.  This includes assessing the 
patient’s biofluid as well as the tumor for markers of positive, stable or negative outcome 
allowing for guidance of selection of participants in future cohorts. 
These exploratory data will be correlated with the secondary endpoints of PFS and TTP.  
 
Number of Patients: 
This study will occur in two parts. Part 1 of the study will enroll ten evaluable (10) 
patients in the BPM31510 plus gemcitabine (combination therapy arm). If at least one of 
ten patients treated experiences a Complete Response (CR) or Partial Response (PR), 
based on RECIST 1.1 criteria, after 2 cycles of treatment, then Part 2 of the study will 
enroll an additional 15 patients for a total of 25 evaluable patients. In the absence of at 
least one CR or PR if at least 3 patients experience stable disease, the Sponsor can choose 
to enroll 15 additional patients into the expansion stage. Patients who fail to complete at 
least 2 cycles of therapy will be replaced until a maximum of 25 evaluable patients have 
been treated.  


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Protocol BPM31510IV-05 Amendment 7.0                                                                                          25 August 2018 
 
 
 
Trial Drugs, Dose, 
and Mode of 
Administration: 
BPM31510 Nanosuspension Injection (40 mg/mL) will be administered IV over 144 
hours (two 72-hour 110 mg/Kg doses). Each patient will receive 2 consecutive 72-hour 
infusions per week (Tuesday-Friday and Friday-Monday). The dose for BPM31501 is 110 
mg/Kg. Patients will also be treated with gemcitabine IV once weekly (starting at week 3) 
at a starting dose of 1000 mg/m2. 
 
 
  
 
 
 
 
Duration of Therapy 
Patients may continue treatment for up to 12 cycles within their assigned treatment in the 
absence of progressive disease, unacceptable toxicity, or until any of the discontinuation 
criteria listed in Section 3.4 are met. Patients evaluated as having gemcitabine toxicity or 
disease progression may remain on monotherapy at the investigator’s discretion if 
experiencing clinical benefit and after consultation with the sponsor.   
 
Trial Drug Supply: 
Clinical trial supplies of BPM31510 will be provided by BERG LLC.  
The chemotherapy agent gemcitabine is commercially available and will be provided 
through commercial sources.  


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Protocol BPM31510IV-05 Amendment 7.0                                                                                          25 August 2018 
 
 
Inclusion Criteria: 
 
 
Patients must meet the following criteria in order to be included in the clinical trial: 
1. The patient has a histologically or cytologically confirmed metastatic pancreatic 
adenocarcinoma.  
2. The patient has received at least one, but no more than 2, prior standard or 
experimental therapies for metastatic pancreatic cancer*. If the patient has 
had prior gemcitabine treatment, the last date of gemcitabine administration-
should be ≥ 28 days prior to receiving study treatment. All patients who have 
previously received gemcitabine should be discussed with the medical 
monitor during screening 
.  
3. The patient is at least 18 years old. 
4. The patient has an ECOG 
 
 
5. Measurable tumor lesions according to RECIST 1.1 criteria 
 
6. In the opinion of the Investigator, the patient has a life expectancy of > 3 months. 
7. Sexually active patients and their partners agree to use an accepted method of 
contraception during the course of the study 
 
  
8. Female patients of childbearing potential must have a negative pregnancy test 
within 1 week prior to beginning study treatment. 
9. The patient has adequate organ and marrow function as follows:  
• 
ANC ≥ 1500 mm3, platelets ≥ 100,000/mm3, hemoglobin ≥ 9 g/dL,  
• 
serum creatinine ≤upper limit of normal (ULN) or calculated creatinine 
clearance > 50 ml/min;  
10. Total bilirubin ≤ 1.5 X ULN (unless related to Gilbert’s Syndrome); alanine 
aminotransferase (ALT), aspartate transaminase (AST) ≤ 2.5 times the upper limit 
of normal (ULN) if no liver involvement or ≤ 5 times the upper limit of normal 
with liver involvement. 
11. The patient has serum electrolytes (including calcium, magnesium, phosphorous, 
sodium and potassium) within normal limits (supplementation to maintain normal 
electrolytes is allowed). 
12. The patient has adequate coagulation: prothrombin time (PT) and an International 
Normalized Ratio (INR), and partial thromboplastin time (PTT) ≤ 1.5 times the 
upper limit of normal (ULN), 
13. In the opinion of the Investigator, the patient is capable of understanding and 
complying with the protocol and has signed the informed consent document. 
 
*For the purposes of this study, patients who have received at least one, but no more than 2, 
prior standard therapies for locally advanced pancreatic cancer and then transition to a 
diagnosis of metastatic pancreatic cancer ≤ 6 months post therapy may count the treatment 
for locally advanced cancer as 1st line treatment for metastatic cancer. 


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Protocol BPM31510IV-05 Amendment 7.0                                                                                          25 August 2018 
 
 
Exclusion Criteria: 
The patient will be excluded from study participation if any of the following criteria are 
met: 
1. The patient has uncontrolled intercurrent illness including, but not limited to 
uncontrolled infection, symptomatic congestive heart failure (NYHA class III and IV), 
uncontrolled cardiac arrhythmia, or psychiatric illness/social situations that would limit 
compliance with study requirements 
 
  
2. The patient has active heart disease including myocardial infarction within previous 3 
months, symptomatic coronary artery disease, arrhythmias not controlled by medication, 
unstable angina pectoris, or uncontrolled congestive heart failure (NYHA class III and 
IV) 
 
3. The patient has received chemotherapy within 2 weeks or radiotherapy within 4 weeks 
or has received nitrosoureas or mitomycin C within 6 weeks prior to the first dose of 
study drug. The patient must have recovered from treatment related toxicities to Grade 1 
or less (other than alopecia).  
4. Patients previously treated with gemcitabine:  who discontinued gemcitabine due to 
toxicity in the first 6 weeks of prior treatment or is/was unable to tolerate a dose of 800 
mg/m2 weekly at any point due to toxicity. 
5. The patient has received radiation to ≥ 25% of his or her bone marrow within 4 weeks 
of the first dose of study drug. 
6. The patient has received an investigational drug within 30 days of the first dose of 
study drug. 
7. Evidence of central nervous system (CNS) metastasis (negative imaging study, if 
clinically indicated, within 4 weeks of Screening Visit). 
8. History of other malignancies (except adequately treated Stage 1 cancer, cured 
basal cell carcinoma, superficial bladder cancer, breast ductal carcinoma in situ 
(DCIS) without invasive component, or carcinoma in situ of the cervix) unless 
documented free of cancer for ≥5 years. 
9. The patient has not recovered to grade ≤ 1 from adverse events (AEs) due to 
investigational drugs or other medications, which were administered more than 4 weeks 
prior to the first dose of study drug. 
10. The patient is pregnant or lactating. 
11. The patient is known to be positive for the human immunodeficiency virus (HIV). The 
effect of BPM31510 on HIV medications is unknown. Note: HIV testing is not required 
for eligibility, but if performed previously and was positive, the patient is ineligible for 
the study. 
 


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Protocol BPM31510IV-05 Amendment 7.0                                                                                          25 August 2018 
 
 
Exclusion Criteria 
(cont’d): 
12. The patient has an inability or unwillingness to abide by the study protocol or cooperate 
fully with the Investigator or designee. 
13. The patient is receiving digoxin, digitoxin, lanatoside C or any type of digitalis 
alkaloids. 
14. The patient has uncontrolled or severe coagulopathies or a history of clinically 
significant bleeding within the past 6 months, such as hemoptysis, epistaxis, 
hematochezia, hematuria, or gastrointestinal bleeding. 
15. The patient has a known predisposition for bleeding such as von Willebrand’s disease or 
other such condition. 
16. The patient requires therapeutic doses of any anticoagulant, including LMWH. 
Concomitant use of warfarin, even at prophylactic doses, is prohibited. 
Statistical 
Methodology: 
This phase 2 trial will examine the safety and efficacy of BPM31510 as a combination 
therapy with gemcitabine in advanced pancreatic cancer patients as 2nd/3rd line therapy. 
The primary safety endpoint is to determine the safety of BPM31510 as a combination 
therapy in this patient population.  The primary efficacy endpoint is overall response rate.  
This study will occur in two parts. Part 1 of the study will enroll ten (10) evaluable 
patients. If at least one of ten evaluable patients treated experience a Complete Response 
(CR) or Partial Response (PR), based on RECIST 1.1 criteria, after 2 cycles of treatment, 
then Part 2 of the study will enroll an additional 15 patients for a total of 25 evaluable 
patients. In the absence of at least one CR or PR, if at least 3 patients experience stable 
disease the Sponsor can choose to enroll the additional 15 patients into the expansion 
stage. 
Toxicity grading will be defined using CTCAE v4.02.  
Response rates will be summarized using frequency table techniques; exact 95% 
confidence intervals may be generated.  Safety observations and measurements including 
study drug exposure, adverse events, laboratory data, vital signs, and ECOG performance 
status will be summarized using descriptive statistics (number of patients, mean, median, 
standard deviation, minimum, and maximum) for continuous variables and using 
frequency and percentages for discrete variables. Adverse events and serious adverse 
events will be tabulated by system organ class and preferred terms and coded using 
MedDRA version 19.0 (or most current version). Laboratory test results will be 
summarized using values observed at each visit and shift from baseline values. 
Exploratory data will be collected on all patients to correlate with PD data and response. 
The objective of this integrative approach is to stratify patient populations based on 
phenotypic and/or molecular profiles for therapeutic benefit and outcomes.  This includes 
assessing the patient’s biofluid as well as the tumor for markers of positive, stable or 
negative outcome allowing for guidance of selection of participants in future cohorts. 
 
 
 
 


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Protocol BPM31510IV-05 Amendment 7.0                                                                                          25 August 2018 
 
 
 
CLINICAL TRIAL BPM31510IV-05 CONTACT INFORMATION: 
BERG Contact Information: 
BERG LLC 
500 Old Connecticut Path  
Building B 
Framingham, MA 01701 
Principal Investigator /Coordinating 
Investigator: 
 
 
 
Medical Monitor: 
 
  
 
Safety Surveillance / Pharmacovigilance 
 
 
 
 
 
 
BERG Clinical Operations  
 
 
 
 
BERG Clinical Operations 
 
 
 
 


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Protocol BPM31510IV-05 Amendment 7.0                                                                                          25 August 2018 
 
 
LIST OF ABBREVIATIONS 
AE 
adverse event 
ALT (SGPT) 
alanine aminotransferase 
ALP 
alkaline phosphatase 
ANC 
aPTT 
absolute neutrophil count 
activated partial thromboplastin time (commonly interchanged with PTT) 
AST (SGOT) 
aspartate aminotransferase 
ATP 
adenosine triphosphate 
AUC0-24hr 
area under the concentration-time curve from time 0 to 24 hrs. 
BPM 
BERG Molecule 
BUN 
blood urea nitrogen 
BWFI 
Bacteriostatic Water for Injection 
CA 
Competent Authorities 
CBC 
complete blood count 
CEA 
carcinoembryonic antigen 
CFR 
Code of Federal Regulations 
CHF 
congestive heart failure 
CL 
Clearance 
Cmax 
maximum concentration 
CMP 
comprehensive metabolic profile 
CNS 
central nervous system 
CP 
Cyclophosphamide 
CR 
complete response 
 
 
CRC 
Cohort Review Committee 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CRP 
C-reactive protein 
CSF 
colony-stimulating factor 
CT 
computerized tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
dose limiting toxicity 
DNA 
deoxyribonucleic acid 
EC 
Ethics Committee  
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
ED50 
dose required for 50% tumor inhibition 
EDC 
FACT-HEP 8.0 
Electronic Data Capture (system) 
Functional Assessment of Cancer Therapy – HEP 8.0 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 


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Protocol BPM31510IV-05 Amendment 7.0                                                                                          25 August 2018 
 
 
GLP 
Good Laboratory Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HNSTD 
highest non-severely toxic dose 
ICH 
International Conference on Harmonization 
IND 
Investigational New Drug 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board (or EC) 
IV 
intravenous(ly) 
LMWH 
Low molecular weight heparin 
LV 
Leucovorin 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
myocardial infarction 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NCI 
National Cancer Institute 
NYHA 
New York Heart Association 
ORR 
PD 
Overall Response Rate 
Pharmacodynamic 
PD  
progressive disease 
PDA 
PET 
pancreatic ductal adenocarcinoma 
Positron Emission Tomography 
PFS 
progression free survival 
PHI 
protected health information 
PK 
Pharmacokinetic 
PR 
partial response 
PT 
prothrombin time 
PTT 
partial thromboplastin time (commonly interchanged with aPTT) 
PVC 
polyvinyl chloride 
RECIST 
Response Evaluation Criteria in Solid Tumors (v1.1) 
RNA 
ribonucleic acid 
QA 
quality assurance 
SAE 
SUV 
serious adverse event 
standard uptake value (for PET scans) 
t1/2 
half-life 
tmax 
time to maximum concentration 
TTP 
time to progression 
ULN 
Vd 
Upper Limit of Normal 
volume of distribution 
VEGF 
vascular endothelial growth factor 
WBC 
white blood cell 
 
 


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Protocol BPM31510IV-05 Amendment7.0                                                                                       25 August 2018 
 
TABLE OF CONTENTS 
1 
INTRODUCTION............................................................................................... 20 
 
Background ............................................................................................... 20 
 
BPM31510 Nonclinical Pharmacology Studies........................................ 21 
1.2.1 
The Warburg Effect ..................................................................... 21 
 
BPM31510 Toxicology Studies ................................................................ 21 
 
BPM31510-IV First-in-Human Phase 1 Study in Solid Tumors 
(CTL0510) – Four Hour Infusion Study ................................................... 22 
1.4.1 
Rationale for 72-Hour Infusion Schedule ................................... 26 
 
In Vitro Data Supporting the Combination of 
BPM31510 & Chemotherapy ................................................................... 30 
1.7 Dose Selection for BPM31510 & Chemotherapy ........................................... 35 
2 
STUDY OBJECTIVES ....................................................................................... 36 
 
Primary Objective ..................................................................................... 36 
 
Secondary Objectives................................................................................ 36 
 
Exploratory Objectives ............................................................................. 36 
3 
STUDY POPULATION ..................................................................................... 37 
 
Number of Patients ................................................................................... 37 
 
Inclusion Criteria ...................................................................................... 37 
 
Exclusion Criteria ..................................................................................... 38 
 
Discontinuation from Trial Treatment ...................................................... 39 
3.4.1 
Pregnancy ................................................................................... 40 
4 
STUDY REGISTRATION ................................................................................. 41 
5 
STUDY DESIGN ................................................................................................. 41 
6 
ADMINISTRATION OF TREATMENT ......................................................... 42 
 
Combination BPM31510 and gemcitabine ............................................... 42 
 
Duration of Therapy .................................................................................. 44 
 
End of Study ............................................................................................. 44 
 
Concomitant Medications and Supportive Care ....................................... 44 
6.4.1 
Granulocyte Colony-Stimulating Factors ................................... 44 
6.4.2 
Other Cancer Treatments ........................................................... 44 
6.4.3 
Other Prohibited Medications .................................................... 44 
7 
DOSING AND DOSE MODIFICATIONS ....................................................... 44 
 
Calculation of BPM31510 Dose ............................................................... 44 
 
Infusion Rate and Loading Dose of BPM31510 ....................................... 45 
 
Missed Doses during Cycle 1 ................................................................... 45 
 
Dose Reduction during Cycles 2-12 ......................................................... 45 
7.4.1 
Guidelines for Dose Modification of BPM31510 ....................... 47 
7.4.2 
Guidelines for Dose Modification for 
Chemotherapy-Specific Toxicity ................................................. 47 
 
Dosing Delays during Cycles 2-12 ........................................................... 47 


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Protocol BPM31510IV-05 Amendment7.0                                                                                       25 August 2018 
 
 
Interruption of BPM31510 Due to Hemodynamic Instability .................. 47 
 
Dose Interruption Due to Infusion Pump Malfunction Outside 
of the Clinic............................................................................................... 48 
8 
STUDY TREATMENT ...................................................................................... 50 
 
Overview ................................................................................................... 50 
 
Screening................................................................................................... 50 
 
Treatment Period ....................................................................................... 51 
8.3.1 
Cycle 1 (Cycle = 6 weeks) .......................................................... 51 
8.3.2 
Cycles 2-12 (Cycle = 4 weeks) .................................................... 52 
 
Unscheduled Visits ................................................................................... 53 
 
End of Treatment/Early Termination (prior to completing 
Cycles 1 & 2) ............................................................................................ 54 
 
Laboratory Assessments ........................................................................... 55 
 
Pharmacodynamic Assessments ............................................................... 56 
8.7.1 
Blood Samples for Pharmacodynamic Analysis ......................... 56 
8.7.2 
Tumor Tissue Samples for Pharmacodynamic 
 
 
8.7.3 
Urine Samples for Pharmacodynamic Analysis.......................... 57 
9 
IDENTIFICATION OF STUDY TREATMENTS .......................................... 59 
 
BPM31510 ................................................................................................ 59 
 
Gemcitabine .............................................................................................. 59 
 
Labeling, Packaging and Supply of Study Treatments ............................. 60 
9.3.1 
BPM31510 .................................................................................. 60 
9.3.2 
Gemcitabine ................................................................................ 60 
 
Preparation and Administration of Study Treatments .............................. 61 
9.4.1 
BPM31510 .................................................................................. 61 
9.4.2 
Gemcitabine ................................................................................ 62 
 
Accountability of Study Treatments ......................................................... 62 
9.5.1 
BPM31510 .................................................................................. 62 
9.5.2 
Gemcitabine ................................................................................ 63 
 
Precautions and Risks Associated with Study Treatments ....................... 63 
9.6.1 
BPM31510 .................................................................................. 63 
9.6.2 
Gemcitabine ................................................................................ 64 
10 
RESPONSE EVALUATIONS AND MEASUREMENTS .............................. 66 
 
Baseline Eligibility.................................................................................... 66 
10.1.1 Guidelines for Evaluation of Measurable Disease ..................... 67 
10.1.2 Response Criteria ........................................................................ 68 
11 
STATISTICAL CONSIDERATIONS .............................................................. 69 
 
Overview ................................................................................................... 69 
 
Sample Size Considerations ...................................................................... 70 
 
Study Populations ..................................................................................... 70 
 
Study Design ............................................................................................. 70 
 
Efficacy Analysis ...................................................................................... 70 


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Overall Tumor Response .......................................................................... 70 
11.6.1 Progression Free Survival .......................................................... 71 
11.6.2 Time to Progression .................................................................... 71 
11.6.3 Overall Survival .......................................................................... 71 
11.6.4 Overall changes in patient reported quality of life ..................... 71 
11.6.5 Evaluation of Exploratory PD Parameters ................................. 71 
 
Planned Interim Analyses ......................................................................... 72 
 
Replacement of Patients ............................................................................ 72 
 
Data and Safety Monitoring Board ........................................................... 72 
 Steering Committee .................................................................................. 72 
12 
SAFETY REPORTING AND ANALYSES...................................................... 72 
 
Safety Review ........................................................................................... 72 
 
Safety Analyses ......................................................................................... 72 
 
Adverse Events ......................................................................................... 72 
12.3.1 Definitions of Adverse Events ..................................................... 72 
12.3.2 Assessing Severity of Adverse Events.......................................... 73 
12.3.3 Assessing Relationship to Trial Treatment ................................. 73 
12.3.4 Classification of Causality .......................................................... 74 
12.3.5 Recording of Adverse Events ...................................................... 75 
12.3.6 Abnormal Laboratory Values and Vital Signs ............................ 75 
12.3.7 Handling of Adverse Events ........................................................ 76 
 
Serious Adverse Events ............................................................................ 76 
12.4.1 Definitions of Serious Adverse Events ........................................ 76 
12.4.2 Serious Adverse Event Reporting by Investigator ...................... 77 
12.4.3 Reporting SAEs to BERG (or designee) ...................................... 77 
12.4.4 Reporting SAEs to IRBs/ECs ...................................................... 79 
12.4.5 BERG SAE Reporting Requirements........................................... 79 
 
Recording of Adverse Events and Serious Adverse Events ..................... 80 
12.5.1 Diagnosis vs. Signs and Symptoms ............................................. 80 
12.5.2 Persistent or Recurrent Adverse Events ..................................... 80 
12.5.3 Abnormal Laboratory Values and Vital Signs ............................ 80 
12.5.4 Deaths ......................................................................................... 81 
12.5.5 Hospitalization, Prolonged Hospitalization, or Surgery ............ 81 
12.5.6 Pre-Existing Medical Conditions ................................................ 81 
12.5.7 Pregnancy, Abortion, Birth Defects/Congenital Anomalies ....... 81 
12.5.8 New Cancers ............................................................................... 81 
12.5.9 Lack of Efficacy ........................................................................... 82 
12.5.10 BPM31510 Overdose .................................................................. 82 
 
Protocol-Defined Events of Special Interest ............................................. 82 
 
Monitoring Plan ........................................................................................ 82 
13 
ETHICAL, FINANCIAL, AND REGULATORY CONSIDERATIONS ...... 82 
 
IRB/EC Approval...................................................................................... 82 
 
Regulatory Approval ................................................................................. 83 
 
Insurance and Indemnity ........................................................................... 83 
 
Informed Consent...................................................................................... 83 


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Protocol BPM31510IV-05 Amendment7.0                                                                                       25 August 2018 
 
 
Confidentiality .......................................................................................... 84 
13.5.1 Patient Confidentiality ................................................................ 84 
13.5.2 Investigator and Staff Information .............................................. 85 
 
Financial Information................................................................................ 85 
14 
RECORD RETENTION AND DOCUMENTATION OF THE STUDY ...... 85 
 
Amendments to Protocol........................................................................... 85 
 
Documentation Required to Initiate Trial ................................................. 86 
 
Trial Documentation and Storage ............................................................. 86 
 
Quality....................................................................................................... 88 
14.4.1 Source Documents ...................................................................... 88 
14.4.2 Electronic Data Capture System ................................................. 88 
14.4.3 Data Monitoring Plan (DMP) .................................................... 88 
14.4.4 Centralized Monitoring ............................................................... 89 
14.4.5 Patient Enrollment Instructions .................................................. 89 
14.4.6 Data Submission Instructions ..................................................... 89 
 
Quality Assurance and Quality Control .................................................... 90 
 
Disclosure and Publication Policy ............................................................ 90 
15 
REFERENCES .................................................................................................... 92 
16 
APPENDICES ..................................................................................................... 94 
 
 




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Protocol BPM31510IV-05 Amendment7.0                                                                                       25 August 2018 
 
apoptotic bcl-2 proteins that cause death in oncotic cells with no change to normal fibroblasts, 
melanocytes and keratinocytes [Narain 2004b, 2006b, 2008; Persaud 2008, 2009]. 
 
BPM31510 Nonclinical Pharmacology Studies 
Nonclinical studies conducted at the University of Miami demonstrated significant in vivo 
inhibition of tumor growth with BPM31510 in mouse xenograft models. In efficacy studies, 
BPM31510 had significant effects on survival and health against pancreatic, lung, liver, and 
central nervous system (CNS) tumors. At 0.5 to 50 mg/kg, a dose-related improvement in 
mortality was observed in mice injected with pancreatic tumor cells (MiaPACA2). Survival and 
improved health was significantly increased at doses ≥5 mg/kg. Co-administration with 
doxorubicin resulted in a significant improvement in survival as well as the number of animals 
free of tumors [data on file].  
A dose-related increase in survival (0.5 to 50 mg/kg/day) compared to untreated controls was 
seen in rat xenograft models of various cancers including chloromas of lung and liver.   These 
studies included BPM 31510 alone or in combination with chemotherapy agents (data on file) 
that resulted in synergies in improving overall survival times of the treated cohort compared to 
untreated controls. 
1.2.1 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
BPM31510 Toxicology Studies  
Single Dose Toxicity Studies 
Toxicity associated with single IV doses of BPM31510 was characterized in range-finding 
studies in rats and dogs. Findings included dose-dependent changes in clinical signs, clinical 


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Protocol BPM31510IV-05 Amendment7.0                                                                                       25 August 2018 
 
pathology parameters reflective of effects on kidney, liver and hematopoietic tissues, and 
histopathological findings primarily in lymphoid and GI tract tissues. Phlebitis at the injection site 
(non-diluted formulation was administered), fluid in thoracic cavity and discolored internal 
gastrointestinal tract were observed in rats.  
No histopathological changes associated with BPM31510 administration were observed at the 
highest non-lethal doses in rats and dogs in these studies. Toxicokinetic analysis showed a slightly 
greater than dose proportional increase in the Cmax and AUC0-24h with increasing IV doses. 
There were no apparent gender-related differences in the PK of BPM31510. 
Repeat-Dose Toxicity Studies 
Good Laboratory Practice (GLP)-compliant 28-day repeat dose studies were conducted in rats 
and dogs, and a non-GLP study was performed in cynomolgus monkeys. In these studies 
BPM31510 was administered undiluted IV every other day (3 times per week) for 28 days. 
Findings included dose-dependent changes in clinical pathology parameters of the liver, kidney, 
organ weights, and tissue histomorphologic appearance of the liver. Safety signals included 
transient decreases in complete blood cell (CBC) and white blood cell (WBC) counts, phlebitis, 
diarrhea, minimal multifocal hepatocellular degeneration and necrosis with associated minimal 
reactive hepatitis (1 of 12 monkeys dosed with active BPM31510 product) and nephrotoxicity. 
There were no effects on electrocardiograms (ECG) in dogs, and no adverse clinical findings in 
the central nervous or respiratory systems of rats and dogs.  
Toxicokinetic evaluations in rats and dogs showed Cmax and AUC0-t increased with dose; there 
were no apparent gender difference in the PK of BPM31510 in the 28-day studies.  
  
 
BPM31510-IV First-in-Human Phase 1 Study in Solid Tumors (CTL0510) – Four 
Hour Infusion Study 
The first-in-human Phase 1 study with BPM31510 was conducted in 50 patients with advanced 
solid tumors. The objectives were to assess the safety, maximum tolerated dose, PK, and PD of 
BPM31510 
 
Plasma concentration profiles and PK 
parameters were determined from blood samples collected pre-dose and at intervals to 48 hours 
post-dose.  
Evaluation of the PK parameters indicated linear or close to linear dose-proportionality with the 
4-hour infusion schedule. As shown in Figure 1 the curves are similar for all doses. There was 
some evidence of non-linearity at the lowest dose levels. However, for doses of 22.5 mg/kg or 
higher, dose-proportionality appeared linear.  
Tmax and Cmax were generally associated with the end of the infusion. The t1/2 ranged from 2.18 to 
18.0 hours, with little or no dependence of t1/2 on dose. Considering all dose groups, there was no 
apparent accumulation with increasing duration of dosing.  
 
 




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Twenty patients died due to disease progression or intercurrent illness. Four patients 
discontinued treatment due to AEs reported as unrelated to treatment: grade 2 infection at the 
tumor site (1), grade 3 thrombocytopenia (2), and grade 4 AST increased (1). Three patients were 
actively being treated at the time of the study hold: 2 patients at the 104.3 mg/kg dose level and 1 
patient had received 2 doses at the 139 mg/kg dose level.   
Two SAEs were reported as possibly related to BPM31510: grade 3 APTT prolonged and grade 
3 hematuria. No clinically significant changes in vital signs or physical examination findings 
were observed. 
The best response to BPM31510 was stable disease in 23 of 50 patients (46%), One patient with 
a sarcoma had a partial response, and 15 patients (30%) had progressive disease. 
Please refer to the BPM31510 Investigator Brochure for further detail on relevant studies. The 
reference document for determination of expectedness of adverse events is the Investigator 
Brochure. 
BPM31510-IV Phase I study in Solid Tumors - A 144-hour continuous infusion study 
The second trial is a Phase 1a/b multicenter, open-label, non-randomized, dose-escalation study 
to examine the dose limiting toxicities (DLT) of BPM31510 administered as a 144-hour 
continuous intravenous (IV) infusion as monotherapy (treatment Arm 1) and in combination with 
chemotherapy consisting of gemcitabine, docetaxel, or 5FU (treatment Arm 2) in patients with solid 
tumors. In the Phase 1a portion of the trial, patients who meet eligibility parameters receive 2 
consecutive 72-hour infusions of BPM31510 twice weekly on Tuesday and Friday (i.e., Days 1, 
4, 8, 11, 15, 18, 22, and 25), essentially receiving BPM31510 treatment for 144 (72-hr x2) hours 
per week of each 28-day cycle. 
In the current open Phase I trial using BPM31510 in combination with gemcitabine for patients 
with solid tumors, 52 patients have been treated (31 with BPM31510 alone and 21 patients with 
BPM31510 in combination with gemcitabine.  Monotherapy dose levels are 66mg/kg, 88mg/kg, 
110mg/kg, 137mg/kg and 171mg/kg. BPM31510 dose levels in combination with gemcitabine 
are 50mg/kg, 66mg/kg, 88mg/kg, 110mg/kg, 137mg/kg and 171mg/kg. All combination therapy 
patients received a gemcitabine dose of 1000 mg/m² IV infusion.  
The number of patients treated in each group to date is in table below; 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  


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Protocol BPM31510IV-05 Amendment7.0                                                                                       25 August 2018 
 
As of 01 Apr 2016, 1134 adverse events have been reported; 401 events were reported in 
monotherapy patients and 733 events reported in BPM31510 / Gemcitabine combination therapy 
patients.  
75 events reported in 38 (73%) of the 52 patients (12 combo therapy and 26 monotherapy) were 
reported as serious.  Of the serious adverse events, 27 were not related, 1 was definitely related 
(APTT prolongation), and 1 was probably related (AST elevation), 8 were possibly related 
(anemia, thrombocytopenia, dysphagia with fatigue and weakness, nausea and vomiting, AST 
elevation, venous thrombosis, and ANC decreased) and 10 were unlikely related. There were no 
severe or serious events reported in more than one patient, in either arm, which were judged to 
be life threatening or resulted in death. No deaths occurred within 30 days of treatment were 
reported in this study to date.  
Table 2: Reported Serious Adverse Events  
 Treatment Arm 
Definitely 
Related 
Probably 
Related 
Possibly 
Related 
Unlikely 
Related 
Unrelated 
BMP31510 Monotherapy (n=31) 
1 
1 
5 
28 
22 
BPM31510 / Gemcitabine     
Combination therapy (n=21) 
0 
0 
3 
10 
5 
Totals (n=52) 
1 
1 
8 
38 
27 
A total of 595 events were identified as at least possibly related by the investigator.  Of these, 
375 (63%) were reported as mild, 161 (27%) moderate, 48 (8%) severe, and 11 (2%) life 
threatening. 


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Protocol BPM31510IV-05 Amendment7.0                                                                                       25 August 2018 
 
Table 3: Adverse Events that occur with a frequency of ≥7%. 
Event 
Grade 
#Occurrences/percent 
BPM31510 Monotherapy 
Occurrences/percent 
BPM31510 / Gemcitabine 
Elevated INR 
Grade 1 & 2 
 38 (24%) 
74 (43%) 
Elevated APTT 
Grade 1, 2 & 3  
 34 (21%) 
66 (43%) 
Anemia 
Grade 2,3 & 4* 
 32 (18%) 
74 (39%) 
*Grade 4 anemia recovered with sequelae after blood transfusion 
The majority of AEs (95%) reported during the study were CTCAE Grade 1 or 2, with the most 
common non-laboratory AEs (all causalities combined) being fatigue; nausea; dyspnea; 
abdominal pain, fever, vomiting, anorexia, edema, constipation, pleural effusion anxiety and 
arthralgia. The most common related adverse events that were identified as possibly, probably, or 
definitely related to the study drug are thrombocytopenia, anemia, elevated PT/PTT/INR and 
elevated LFT/AST/ALT/LDH.  The majority of the events resolved with treatment. 
The most common laboratory AEs experienced by patients in both arms (all causalities 
combined) were: INR elevated (7%), anemia (7%), PTT prolonged (7%), PT prolonged (6%), 
thrombocytopenia 5(%), and AST increased (4%). 
Of these laboratory AEs, those judged to be BPM31510-related included INR elevated (16%),  
PTT prolonged (13%), PT prolonged (13%), anemia (9%, platelet count decreased (9%), AST 
increased (4%), and hypertriglyceridemia (4%).  
In all 67 patients’ experienced abnormal INR values. In 23 of these patients (34%) the increased 
INR was considered related to BPM31510 alone while in the 42 patients (63%) enrolled in the 
combo-therapy arm the increased INR was considered related.   
Increased INR was clinically significant in 1 of the monotherapy patients having increased to 
grade 3 or caused a bleeding event. When Vitamin K was administered, all INRs decreased to 
grade 1 or resolved.  
Six patients (4 monotherapy and 2 combination therapy) died due to disease progression or 
intercurrent illness. None of the deaths occurred within 30 days of treatment and none of the 
deaths were deemed related to BPM31510. 
1.4.1 
 
 
 
 
 
 
 
 


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Protocol BPM31510IV-05 Amendment7.0                                                                                       25 August 2018 
 
a continuous infusion over a 48 hours period with a total of two 48 hour infusion over a duration 
 
 
 
  
 
 
 
In all cancer cell lines tested as described in the Figure 2 below, decrease in cell viability in 
response to BPM31510 was evident as early as 24 hours and increased progressively between 48 
and 72 hours.  There was a consistent decrease in cell viability in the cancer cell lines tested 
independent of the mutational status.  In each of the cell lines, extent of BPM31510 effect on cell 
viability was associated with duration of exposure, with some cell lines exhibiting higher 
sensitivity at 48 hours times while in other cancer cell lines decrease in cell viability was observed 
at 72 hours.  This data suggest that duration of exposure, an indirect measure of drug-cell contact 
is an important and critical component of BPM31510 effect on viability of cancer cells of different 
lineage.  In an effort to extend these finding in the preclinical animal models, several studies were 
undertaken wherein different dosing regimens were tested to determine correlates to the dose 
(concentration in mg/kg body weight) and dosing regimen and its association to overall clinical 
presentation and outcomes.   
 
Figure 2: Effect of BPM31510 on viability of cancer cells lines.  Each of the cell lines was treated with a fixed 
dose (100µM) of BPM31510 and cell viability measured between 24 and 72 hours duration.  The data represents 
cell viability in the absence and presence of BPM31510 at 48 or 72 hours exposures.  
Note: All treatments had readouts at 24, 48 and 72h cell viability.  The figure describes maximal responses in each 
of cell line that was observed – in cell lines described in figure, this was either at 48 or 72 hour. 


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Protocol BPM31510IV-05 Amendment7.0                                                                                       25 August 2018 
 
The Table below describes a study investigating three different dosing regimens for BPM31510 
in a pancreatic cancer xenograph model established using human derived MIA-PACA-2 cell 
lines introduced into the pancreas of hairless nude mice. 
Table 4: BPM31510 in a pancreatic cancer xenograph model 
 
Effect of BPM31510 alone or in combination with gemcitabine on total survival in preclinical 
animal model of pancreatic cancer.  The table describes the three regimens utilized for the study 
which included once/daily, twice/daily or thrice/daily dosing of BPM31510 either 50 mg/kg body 
weight (Regimen 1 & Regimen 20) and inclusion of 75 mg/kg body weight in Regimen 3 alone 
or in combination with a fixed dose gemcitabine (150 mg/kg body weight). 
Each group of animals received chemotherapeutic treatment for a minimum of three cycles and 
was maintained to determine outcomes.  
In each of the cohorts tested, BPM31510 alone was associated with increase in survival of animals 
compared to untreated or treated with chemotherapy alone (Figure 3 below).  Of interest is the 
observation that BPM31510 when added to gemcitabine chemotherapy had an additive effect, with 
better results observed than for either BPM31510 or chemotherapy alone. 
 
 


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Protocol BPM31510IV-05 Amendment7.0                                                                                       25 August 2018 
 
 
Figure 3: Effect of gemcitabine, BPM31510 (50 mg/kg body weight dose) and combination of 
gemcitabine + BPM31510 on survival in pancreatic cancer model.  The panel of figures above 
describes survival profiles of animals treated with once/daily BPM31510 (left figure), or the 
same total daily dose of BPM31510 divided for twice/daily dosing (middle figure) or thrice/daily 
dosing (right figure) of BPM31510 alone or in combination with gemcitabine.  The left and 
middle figures additionally provide the survival profiles of animals treated with gemcitabine 
alone, as comparison control for the animals treated with BPM31510 monotherapy or 
combination therapy of BPM31510 with gemcitabine. 
The Figure above provides evidence that increasing doses of BPM31510 from once/daily dosing 
to three times per day was associated with significant improvement in duration of survival along 
with decrease in tumor size and histopathology.  This observation suggests that the 50 mg/kg body 
weight dose of BPM31510 distributed over 24 hour duration in three separate dosing regimen is 
associated with significant improvement compared to administration of identical dose as a single 
once/daily administration.  Thus, the improvement in and maintenance of animals administered 50 
mg/kg dose of BPM31510 in multiple bolus may be due to a relatively constant level of BPM31510 
in the blood for longer duration that can be potentially achieved compared to a single daily 
administration. 
 
 
Figure 4: Effect of continuous infusion of increasing concentrations of BPM31510 on the 
duration of survival of animal model of pancreatic cancer.  An infusion pump was surgically 
installed in the animals to facilitate continuous infusion of BPM31510 at dose of 25 mg/kg, 50 
mg/kg and 100 mg/kg body weight per day respectively. 


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Protocol BPM31510IV-05 Amendment7.0                                                                                       25 August 2018 
 
A continuous infusion protocol was implemented to determine the effect of constant BPM31510 
administration on endpoints in animal model of cancer.  The Figure above describes the effect of 
continuous infusion of increasing concentrations of BPM31510 on duration of survival in an 
animal model of pancreatic cancer. 
Continuous infusion of BPM31510 at a dose of 25 mg/kg body weight per day was associated with 
increase in duration of survival compared to the animal cohort administered 50 mg/kg body weight 
in three divided doses.  Thus, continuous infusion of BPM31510 administration at the 25 mg/kg 
body weight dose over a 24 hour duration was associated with better survival compared to 
administration of the aforementioned regimen. 
The observed improvement in animal cohorts administered BPM31510 as a continuous infusion 
is recapitulated in other animal models of cancer.  Figure 4 describes the duration of survival in 
prostate cancer model of animals administered BPM31510 using two treatment regimen.  The 
cohorts treated with BPM31510 administered 75 mg/kg body weight distributed over 24 hours 
demonstrated overall significantly positive results.  In contrast, the animal cohorts administered 
BPM31510 at the same dose as a continuous infusion demonstrated an even greater positive effect 
when compared to the multiple bolus regimen.   
In summary, the data presented provides support that both dose and dosing schedule are potentially 
critical parameters associated with survival outcomes in preclinical model of cancer tested.  
Increased dose of BPM31510 is associated with significant improvement in duration of survival 
in the animal models.  Furthermore, the data presented provide evidence that continuous infusion 
of BPM31510 is associated with significant improvement in the overall endpoints in a cancer 
model.  Thus, the ability to maintain a higher relatively constant blood concentration of BPM31510 
that can potentially be achieved using a continuous infusion protocol appears to be an important 
determinant in the improvement of overall survival and slowing of clinical deterioration effects in 
this cancer model. 
 
In Vitro Data Supporting the Combination of BPM31510 & Chemotherapy 
The combination of chemotherapeutic agents in the treatment of cancers is supported by the 
rationale that a mixture of agents with differing mechanisms of action (and dose limiting toxicities) 
provides a broader range of cytotoxic coverage to the heterogeneous population of cancer cells 
and minimizes the incidence of drug resistance in cancer. The mechanisms of action of 
chemotherapeutic agents in eliciting anti-cancer effects converge on their individual or combined 
abilities to activate the process of apoptosis. 
Significant progress has been made toward understanding the mechanism(s) influencing life/death 
pathways and the centrality of mitochondria and metabolic regulatory networks in dictating 
survival outcomes. The role of the Bcl-2 family of proteins in regulating the survival/death balance 
is well understood and has been investigated for utility in the clinics. Recently, Davids and Letai 
(2012) suggested that chemotherapeutic agents “push” cancer cells towards the commitment of 
apoptosis, the extent of the “push” beyond a threshold is essential for commitment to the apoptotic 
process. Since the apoptotic process is governed at the level of the mitochondria, a “mitochondrial 
priming” event should increase the sensitivity of cancer cells to the cytotoxic potential of 
chemotherapeutic agents (Chonghaile 2011). BPM31510 influences the metabolic network in 
cancer cells, effecting a shift from glycolysis to mitochondrial oxidative phosphorylation and re-
educating cancer cells to undergo apoptosis. In addition, the central role of 
 in arbitrating 


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Protocol BPM31510IV-05 Amendment7.0                                                                                       25 August 2018 
 
mitochondrial-centric bioenergetics network is indicative of its potential utility in “priming” the 
cancer cells to the cytotoxic effects of chemotherapy agents.  
Experiments were designed to characterize (a) the effect of combining BPM31510 with 
chemotherapy agents on the cytotoxic response in cancer cell lines and (b) the effect of pre-
treatment of cancer cells with BPM31510 followed by combination with chemotherapy agents on 
the sensitivity of cancer cells to the cytotoxic effects of chemotherapy agents. The data presented 
below indicate that pretreatment with BPM31510 alone and in combination with gemcitabine, 5-
FU or docetaxel is associated with an increase in the cytotoxic potential compared to chemotherapy 
treatment alone, suggesting the utility of BPM31510 in effectuating “priming” of certain cancer 
cells to the cytotoxic effects of standard of care chemotherapy agents. The cancer cell lines used 
in the experiments are shown in the following table. 
 
Table 5: The cancer cell lines used in the experiments 
 
In the pretreatment protocol, cancer cells were pretreated with BPM31510 (100 μM) alone for 6 
hours. This was followed by exposure to BPM31510 (100 μM) in combination with increasing 
doses of the chemotherapy agent. The concentrations of chemotherapy agents were empirically 
established using dose-response experiments prior to implementation of this protocol.  
For all cell lines tested, the combination phase of treatment was 48 hours. The summary below 
provides data specific to the effect of BPM31510 alone or in combination for testing on the 
pancreatic cancer model, using the MiaPaCa-2 cultured cell line and either gemcitabine or 5-FU.  
The data presented in Figures 2 and 3 represent examples of the cytotoxic response in cancer cell 
lines that were pretreated with BPM31510 (100 μM) for 6 hours (left panels) followed by the 
combination of BPM31510 (100 μM) with gemcitabine, 5-FU or docetaxel for 48 hours. The right 
panels of each figure represent cytotoxic response in cancer cells treated with the combination of 
BPM31510 (100 μM) with chemotherapy agents for 48 hours (no pretreatment). Data is expressed 
in terms of relative live cell counts determined using trypan blue exclusion as criteria for cell 
viability determination and compared to total cell counts (Stoddard 2011).  


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Protocol BPM31510IV-05 Amendment7.0                                                                                       25 August 2018 
 
Cancer cell lines treated with 100 μM BPM31510 were associated with decreases in relative live 
cell counts (i.e., cytotoxic response) reaching variable levels of significance (p<0.05 or greater) 
compared to the respective chemotherapeutic agent alone (Figure 2 and 3). Pretreatment of cancer 
cells with BPM31510 (100 μM) was associated with a dose-dependent cytotoxic response at lower 
doses of chemotherapy, particularly in pancreatic and lung cancer treated with gemcitabine (Figure 
2) or 5-FU (Figure 3).  In the rest of the pretreatment groups, the cytotoxic response elicited by 
BPM31510 appeared to be maximal with no additive effect observed in the presence of increasing 
concentrations of chemotherapy agent e.g., colorectal cancer treated with 5-FU (Figure 3). In a 
few instances, a particular chemotherapy treatment in a particular cancer cell line required 
significant dose escalations to observe dose response. However, introduction of 100 µM 
BPM31510 (as combination) produced a cytotoxic response at very low dose spectrum of 
chemotherapy, hence the lack of dose dependence e.g., in colorectal cancer co-treatment panel 
(Figure 3). The addition of BPM31510 produced a cytotoxic response in the presence of 0.1 µM 
5-FU that was almost equipotent to that observed with 1µM 5-FU, although 5-FU by itself did not 
show much difference at eliciting a cytotoxic response between the 2 doses. 
In the combination treatment regimen, pancreatic cancer treated with BPM31510/5-FU 
combination demonstrated variability in cytotoxic response. In contrast, pancreatic cancer cells 
exhibited a dose-dependent decrease in live cell count treated with a combination of 
BPM31510/gemcitabine. Similarly, lung cancer treated with BPM31510 in combination with 
gemcitabine (Figure 5) demonstrated a trend towards dose-dependent decrease in live cell counts 
reaching variable levels of significance (p < 0.05 or greater) at specific doses compared to 
chemotherapy alone. Similar to observations in the pretreatment group, the cytotoxic response 
elicited by BPM31510 appeared to be maximal with no additive effect observed in the presence of 
increasing concentrations of chemotherapy agent e.g., colorectal cancer treated with 5-FU (Figure 
6). Overall, data suggests that pretreatment with BPM31510 and/or the combination of BPM31510 
with chemotherapy improves cytotoxicity with low doses of chemotherapy agent in most cancer 
cell lines, the extent of differential response in pretreatment or combination groups reaching 
variable significance of p < 0.05 or greater depending on cell line, treatment protocol and dose. 
 
 


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Figure 5: Effect of BPM31510 Alone or in Combination with Gemcitabine in Pancreatic 
and Lung Cancer Cells  
 
(* P<0.05; ** P<0.01; *** P<0.001) 
 
 
 
 


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Figure 6: Effect of BPM31510 Alone or in Combination with 5-FU in Colorectal and 
Pancreatic Cancer Cells 
 
(* P<0.05; ** P<0.01; *** P<0.001) 
 
1.6 Sensitization of pancreatic cancer by BPM31510 pretreatment 
 
The efficacy of BPM31510 continuous infusion for 60 days followed by treatment with 
gemcitabine in pancreatic cancer xenograft model was compared to treatment regimens of 
BPM31510 alone or BPM31510 – gemcitabine combination therapy initiated Day1. 
 
 
Figure 7: Effect of BPM31510 alone, in combination with gemcitabine therapy initiated 
Day 1 and BPM31510 treatment for 60 days as continuous infusion followed by 
combination with gemcitabine in pancreatic cancer xenograft model. 
 


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Protocol BPM31510IV-05 Amendment7.0                                                                                       25 August 2018 
 
Continuous infusion of BPM31510 alone or in combination with gemcitabine was associated 
with increase in duration of survival in pancreatic cancer xenograft mice model.  Interestingly, a 
60 day treatment of BPM31510 as a single agent followed by incorporation of gemcitabine as a 
combination cytotoxic chemotherapy agent was associated with improvement in duration of 
survival (Figure 7above).  The data suggests that extended infusion of BPM31510 (the duration 
in this study is almost equivalent to two cycles of monotherapy in the clinical trial) followed by 
gemcitabine improves duration of survival.  
The preclinical animal data along with in vitro demonstration that BPM31510 and gemcitabine 
induce activation of apoptotic pathways in MIA-PACA2 cells by two independent mechanisms 
that convergence at the mitochondria in a synergistic manner suggests that the observed 
improvement in duration of survival in the 60 day BPM31510 treatment followed by 
gemcitabine is suggestive of sensitization and mechanism based synergy. 
1.7 Dose Selection for BPM31510 & Chemotherapy 
Results from the on-going BPM31510IV-04 Phase 1 clinical study, started in 2013, have 
demonstrated the safety of BPM31510 up to a dose of 110 mg/kg IV when given in combination 
with gemcitabine and up to 171 mg/kg when given as monotherapy.  Furthermore, data from 
preclinical studies in xenograft models for pancreatic cancer suggest that higher doses of 
BPM31510 alone or in combination with gemcitabine was associated with improved duration of 
survival. The combination of safety (observed in human trials) and efficacy (observed in 
preclinical studies) results encouraged the Sponsor to perform further clinical studies and to 
explore efficacy of IV BPM31510 alone and in combination with gemcitabine in the treatment of 
advanced pancreatic cancer.  
Additional information about the product, including pharmacology, toxicology, and prior human 
use experience is contained in the Investigator’s Brochure (IB). All combination therapy patients 
will receive a gemcitabine dose of 1000 mg/m² IV infusion which is the recommended starting 
dosage for patients being treated for recurring pancreatic cancer. 
 


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2 
STUDY OBJECTIVES 
 
Primary Objective 
The primary objective of this study is: 
• To evaluate the Overall Response Rate in patients treated with the combination of 
BPM31510 with gemcitabine. 
 
Secondary Objectives 
The secondary objectives of this study are:  
• Evaluate Overall Survival; 
• Evaluate Progression-Free Survival—overall and at around 10 weeks 
 
 
• Evaluate Time to Progression (TTP); 
• Evaluate Tumor Response using Adaptive Molecular Responses (epi-genomic analysis 
(SNP or X-ome technology)); 
• Determine the toxicity profile of BPM31510 in combination with gemcitabine when 
administered as a 144-hour (two 72-hr) intravenous (IV) infusion in patients with advanced 
pancreatic cancer. 
• Evaluate Change in CA 19-9 levels. 
• Evaluate changes in patient reported Quality of Life using the validated FACT-HEP 
patient-reported outcomes instrument specific for patients with hepatobiliary and 
pancreatic cancers at the end of Cycle 2 and at End of Study or Early Termination  
 
Exploratory Objectives 
The exploratory objectives of this trial are: 
• To evaluate the effects of BPM31510 on shifting tumors to aerobic respiration by PET 
imaging. 
• Plasma and urine samples will be assayed for levels of markers of BPM31510 activity 
using (but not limited to): 
o genomic (e.g. microarray, SAGE, northern blotting, gene expression), proteomic 
(e.g., LC/MS based analysis, 2DE-MS, MALDI TOF, antibody array, ELISA, 
immunohistochemistry, tissue microarray, flow cytometry, Western blotting),  
o metabolomics (e.g., global analysis of metabolites in biological samples; 
identification of specific markers of energy metabolism e.g., pyruvate, lactate),  
o lipidomics (e.g., global analysis of lipid classes; identification of specific lipids 
e.g., derivatives of palmitate, linoleic acid, arachidonic acid).  
The objective of this integrative approach is to stratify patient populations based on phenotypic 
or molecular profiles, with the aim of correlating these profiles with patient outcomes to 
facilitate prediction of therapeutic benefit to aid in future patient selection.  This includes 


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assessing the patient’s biofluid as well as the tumor for markers of positive, stable or negative 
outcome allowing for guidance of selection of participants in future cohorts.   
3 
 
STUDY POPULATION 
3.1 
Number of Patients 
This study will occur in two parts. Part 1 of the study will enroll ten (10) evaluable patients. If at 
least one of ten patients treated experiences a Complete Response (CR) or Partial Response (PR), 
based on RECIST v1.1 criteria, after 2 cycles of treatment, then Part 2 of the study will enroll an 
additional 15 patients for a total of 25 evaluable patients. In the absence of at least one CR or PR, 
if at least 3 patients experience stable disease following the first 2 cycles of treatment the 
Sponsor can choose to enroll the additional 15 patients into the expansion stage. 
3.2 
Inclusion Criteria 
Patients must meet the following criteria in order to be included in the clinical trial: 
1. The patient has a histologically or cytologically confirmed metastatic pancreatic
adenocarcinoma.
2. The patient has received at least one but no more than 2 prior, standard or
experimental therapies for metastatic pancreatic cancer*. If the patient has had prior
gemcitabine treatment, the last date of gemcitabine administration-should be ≥ 28
days prior to receiving study treatment. All patients who have previously received
gemcitabine should be discussed with the medical monitor during screening.
3. The patient is at least 18 years old.
4. The patient has an ECOG performance status 0 - 1 
5. Measurable tumor lesions according to RECIST 1.1 criteria 
6. In the opinion of the Investigator, the patient has a life expectancy of > 3 months.
7. Sexually active patients and their partners agree to use an accepted method of
contraception during the course of the study 
8. Female patients of childbearing potential must have a negative pregnancy test within 1
week prior to beginning study treatment.
9. The patient has adequate organ and marrow function as follows:
ANC ≥ 1500 mm3, platelets ≥ 100,000/mm3, hemoglobin ≥ 9 g/dL, serum creatinine
≤ULN or calculated creatinine clearance > 50 ml/min;
10. Total bilirubin ≤ 1.5 X ULN (unless related to Gilbert’s Syndrome); alanine
aminotransferase (ALT), aspartate transaminase (AST) ≤ 2.5 times the upper limit of
normal if no liver involvement or ≤ 5 times the upper limit of normal with liver
involvement.
11. The patient has serum electrolytes (including calcium, magnesium, phosphorous, sodium
and potassium) within normal limits (supplementation to maintain normal electrolytes is
allowed).




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9. The patient has not recovered to Grade ≤ 1 from adverse events (AEs) due to 
investigational drugs or other medications, which were administered more than 4 weeks 
prior to the first dose of study drug. 
10. The patient is pregnant or lactating. 
11. The patient is known to be positive for the human immunodeficiency virus (HIV).   The 
effect of BPM31510 on HIV medications is unknown. Note: HIV testing is not required 
for eligibility, but if performed previously and was positive, the patient is ineligible for 
the study. 
12. The patient has an inability or unwillingness to abide by the study protocol or cooperate 
fully with the Investigator or designee. 
13. The patient is receiving digoxin, digitoxin, lanatoside C or any type of digitalis alkaloid. 
14. The patient has uncontrolled or severe coagulopathies or a history of clinically significant 
bleeding within the past 6 months, such as hemoptysis, epistaxis, hematochezia, 
hematuria, or gastrointestinal bleeding. 
15. The patient has a known predisposition for bleeding such as von Willebrand’s disease or 
other such condition. 
16. The patient requires therapeutic doses of any anticoagulant, including LMWH. 
Concomitant use of warfarin, even at prophylactic doses, is prohibited. 
 
Discontinuation from Trial Treatment 
Permanently discontinue BPM31510 treatment if any of the following conditions are met: 
• 
Documented progressive disease* 
• 
Occurrence of a ≥ grade 2 INR increased associated with clinically significant 
bleeding, or with no bleeding but does not normalize with Vitamin K, cryoprecipitate 
or fresh frozen plasma within 7 calendar days. 
• 
Occurrence of a second asymptomatic grade 3 INR. 
• 
Grade 3 PTT abnormalities (with or without bleeding) or ≥ grade 2 elevations in PTT 
with clinically significant bleeding. 
• 
Treatment delay of greater than 14 calendar days (without sponsor approval).  
• 
Patient withdrawal of consent for study participation at any time.  
• 
Withdrawal of a patient at the Investigator’s discretion for any reason that the 
Investigator believes continuation of study drug therapy would not be in the patient’s 
best interest. The reason for the patient’s discontinuation must be recorded on the Case 
Report Form (CRF). 
• 
An intercurrent illness which, in the opinion of the Investigator, would prevent 
completion of study-related evaluations. 
• 
Pregnancy (
 
• 
Patient noncompliance with study or follow-up procedures. 
• 
Termination of the study by BERG. 
• 
The patient exhibits signs of anaphylaxis. 


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*Patients who experience disease progression but are, in the opinion of the investigator, 
receiving clinical benefit may continue BPM31510 as a monotherapy or in combination 
with gemcitabine or as a monotherapy with approval from the Sponsor.  
The study may be terminated at any time by the Sponsor for safety concerns or if in the 
Sponsor's judgement there are no further benefits to be expected from the study.  In such a case, 
the Sponsor or delegate will inform the study investigators, institutions, and all Regulatory 
Authorities. The study can also be terminated by the Regulatory Authority for any reason. 
An excessive rate of patient withdrawals can render the study uninterpretable; therefore, every 
reasonable effort will be made to keep the patient in the study. Patients that are withdrawn for 
any reason prior to completing at least 2 cycles of treatment will be replaced until no more than 
25 evaluable patients have been treated under this protocol. 
If a patient is withdrawn from treatment, the Investigator will make every effort to complete all 
final evaluations and laboratory tests required by the protocol. The reason(s) for study 
termination must be clearly documented on the CRF.  
After withdrawal from protocol treatment, patients must be followed for AEs for 30 calendar 
days after their last dose of BPM31510. All new AEs occurring during this period must be 
reported and followed until resolution, unless, in the opinion of the Investigator, these values are 
not likely to improve because of the underlying disease. In this case, the Investigators must 
record his or her reasoning for this decision in the patients’ medical records and as a comment on 
the CRF. 
All patients who have CTCAE grade 3 or 4 laboratory abnormalities at the time of treatment 
discontinuation must be followed until the laboratory values have returned to grade 1 or 2 unless 
in the opinion of the Investigator it is not likely that these values are to improve because of the 
underlying disease. In this case, the Investigator must record his or her reasoning for making this 
decision in the patients’ medical records and as a comment on the CRF. 
3.4.1 
Pregnancy 
During the course of the trial, all female patients of childbearing potential (definitions listed in 
 must contact the treating 
Investigator immediately if they suspect that they may be pregnant (a missed or late menstrual 
period should be reported to the treating Investigator).  
If an Investigator suspects that a patient may be pregnant prior to administration of BPM31510, 
BPM31510 must be withheld until the result of the pregnancy test is confirmed. If a pregnancy is 
confirmed, the patient must not receive any BPM31510, and must be discontinued from the trial.  
If an Investigator suspects that a patient may be pregnant after the patient has been receiving 
BPM31510, BPM31510 must immediately be withheld until the result of the pregnancy test is 
confirmed. If a pregnancy is confirmed, BPM31510 must be immediately and permanently 
stopped, the patient must be discontinued from the trial, and the Investigator must notify the 
BERG study chair as soon as possible. If a patient becomes pregnant while enrolled in the trial, a 


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Pregnancy Form (a paper report form, not available within the Electronic Data Capture (EDC) 
system should be completed
 
 
 
4 
STUDY REGISTRATION 
Human protection committee approval of this protocol and consent form is required. Eligible 
patients who wish to participate in the trial must provide informed consent prior to enrollment. 
Informed consent for this trial includes education about the procedures to be followed, the 
experimental nature of the treatment, as well as the potential benefits, alternatives, side-effects, 
risks and discomforts of treatment.  
The sample size of this study will be a maximum of 25 evaluable patients. This study will occur 
in two parts. Part 1 of the study will enroll 10 evaluable patients..  If a response of Complete 
Response (CR) or Partial Response (PR) is not observed in the first 10 patients two cycles of 
treatment, enrollment may be terminated.  If at least one response of CR or PR is observed in the 
first 10 patients after two cycles of treatment, Part 2 of the study will enroll an additional 15 
patients for a total of 25 patients. In the absence of at least one CR or PR, if at least three patients 
experience stable disease, the Sponsor can choose to enroll the additional 15 patients into the 
expansion stage.  
Both Screening and Enrollment Registration is via the study EDC system and must occur prior to 
the initiation of protocol therapy. The Screening Registration will consist of submitting relevant 
information collected on the study specific eCRF pages to verify the patient’s eligibility. Once 
these forms are complete, the site’s Principal Investigator will review the data for eligibility 
determination and assign a treatment regimen to the patient.  
Patients registered to screening into the EDC system will be automatically assigned a unique 
Patient ID number, comprised of the four-digit site number and a unique four-digit sequential 
number per site.  Investigators will be able to view the total number of patients that are currently 
enrolled in each arm in the EDC system.  In addition, the Sponsor will require Investigational 
sites to provide information on the eligibility of the patient to a specific treatment arm prior to 
registering patients in enrollment in the EDC system.  The Sponsor will provide written 
confirmation to the Investigator that the patient enrollment to arm requested by the 
Investigational site is allowable and the arm of the study has not met capacity. 
Once the eligibility for the patient is confirmed, the Patient ID number will follow the patient’s 
treatments and outcomes throughout the trial. If the patient is a screen failure, the specific Patient 
ID number assigned to this subject will not be used again in the study.  
5 
STUDY DESIGN 
This is a Phase 2 multicenter, open-label, non-randomized study to examine the safety and 
effectiveness of BPM31510 administered in combination with gemcitabine as a 144-hour (two 
72-hour) continuous intravenous (IV) infusion in advanced pancreatic cancer patients as 2nd/ 3rd 
line therapy.   


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This study will occur in two parts. Part 1 of the study will enroll ten (10) evaluable patients If at 
least one of ten patients treated experiences a Complete Response (CR) or Partial Response (PR), 
based on RECIST 1.1 criteria, after 2 cycles of treatment, then Part 2 of the study will enroll an 
additional 15 patients for a total of 25 patients. In the absence of at least one CR or PR, if at least 
3 patients experience stable disease following the first two treatment cycles the Sponsor can 
choose to enroll the additional 15 patients. 
This study is multinational. 
  
Cycle 1 is 6 weeks in duration with BPM31510 administered twice weekly on Tuesdays and 
Fridays for 6 weeks. Each 110 mg/Kg dose is administered over 72-hours. Patients will also be 
treated with gemcitabine administered on Mondays, on Days 21, 28 and 35.  
Cycles 2-12 are 4 weeks in duration with BPM31510 administered twice weekly on Tuesdays 
and Fridays for 4 weeks. Patients will be treated with gemcitabine administered on Mondays, 
Days 7, 14 and 21 of each cycle. Toxicity will be graded according to National Cancer Institute 
Common Terminology Criteria for Adverse Events (CTCAE v4.02). Safety oversight will be 
provided by the Medical Monitor  
Assessments of the antitumor activity of BPM31510 will be performed at the end of Cycle 2 and 
every 2 cycles thereafter using standard techniques such as computerized tomography (CT) or 
magnetic resonance imaging (MRI) for patients with measurable disease. Response will be 
evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 
 Patients who experience no 
unacceptable toxicity or disease progression, may continue to receive additional 28-day cycles 
for up to 1 year.  
Patients will continue to receive BPM31510 in combination with gemcitabine, for a 
maximum of 12 cycles in the absence of intolerable toxicity and progression. If 
gemcitabine  is discontinued due to chemotherapy-related toxicity, patients may continue to 
receive BPM31510 as monotherapy if, in the opinion of the investigator, the patient may 
continue to receive clinical benefit from continuing use of study drug.  
An 18-fluorodeoxyglucose (18-FDG) PET scan will be performed < 14 days prior to starting 
treatment, at the end of Week 2 and then again after 10 weeks of treatment (end of treatment 
cycle 2) and then after every additional 2 cycles of completed treatment. This exploratory data 
will be correlated with the secondary endpoints of PFS and TTP.  
6 
ADMINISTRATION OF TREATMENT 
 
Combination BPM31510 and gemcitabine 
BPM31510 Nanosuspension Injection (40 mg/mL) will be administered IV over 144 hours; each 
patient will receive 2 consecutive 72-hour infusions (of 110 mg/Kg) per week (Tuesday-Friday 
and Friday-Monday). Patients will be subsequently treated with gemcitabine IV once weekly at a 
starting dose of 1000 mg/m2, as outlined below, starting 3 weeks after initiation of treatment with 
BPM31510. 


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Protocol BPM31510IV-05 Amendment7.0                                                                                       25 August 2018 
 
Cycle 1 of therapy is 6 weeks in duration for patients with BPM31510 administered twice 
weekly on Tuesdays and Fridays for 6 weeks. Patients will be treated with gemcitabine 
administered on Mondays, Days 21, 28 and 35 during the first treatment cycle.  
Response will be assessed after Cycle 2 (10 weeks) and patients who continue onto Cycles 3-12 
will be assessed every 2 cycles (8 weeks). Cycles 2-12 are 4 weeks in duration with BPM31510 
administered twice weekly on Tuesdays and Fridays for 4 weeks and gemcitabine administered 
on Mondays, Days 7, 14 and 21 of each treatment cycle. 
Alternate dosing schedules are allowed with pre-approval from the study sponsor. For patients 
receiving an alternate dosing schedule, the gemcitabine chemotherapy treatment will be given 
after the completion of the sixth infusion (three weeks following initiation of BPM31510 
treatment).  
If the gemcitabine component of combination therapy is discontinued due to chemotherapy-
related toxicity, patients may continue to receive BPM31510 as monotherapy at the 
investigator’s discretion.  


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Duration of Therapy 
Patients who experience no unacceptable toxicity or disease progression while on BPM31510 for 
2 cycles of therapy (10 weeks) may receive additional 28-day cycles of their current treatment 
for up to 1 year (12 cycles) or until any of the discontinuation criteria listed in 
 are 
met.  
Patients who experience disease progression but are, in the opinion of the investigator, receiving 
clinical benefit may continue BPM31510 as a monotherapy or in combination with gemcitabine 
with approval from the Sponsor.  
 
End of Study 
The study will end at the conclusion of the enrollment period plus a 12-month follow up period 
for all patients, or until the last patient enrolled in the study has finished the study, has 
withdrawn, or expired, whichever occurs first.  
 
Concomitant Medications and Supportive Care 
Supportive measures including analgesics, blood transfusions, and antimicrobials are permitted 
throughout the trial.  
Prophylactic Vitamin K will be given to all patients prior to the beginning of every week of 
therapy, unless contraindicated as determined by the Investigator. Additional Vitamin K (oral, 
IM, IV), cryoprecipitate or fresh frozen plasma is to be administered, at the investigators 
discretion,  if the patient has a ≥ grade 2 INR value. 
Several other types of therapy may be allowed or prohibited as specified below. 
6.4.1 
Granulocyte Colony-Stimulating Factors 
Prophylactic use of colony stimulating factors is permitted. Hematopoietic colony stimulating 
factors are allowed to treat cytopenias at the discretion of the Investigator. 
6.4.2 
Other Cancer Treatments 
Therapeutic administration of anticancer therapies including radiation, biologics, or other 
investigational cytotoxic agents is not permitted without Sponsor’s prior approval.  
Palliative radiotherapy is permitted with the Sponsor’s prior approval. 
6.4.3 
Other Prohibited Medications 
The following medications may not be taken concomitantly with BPM31510: 
• 
Digoxin, digitoxin, lanatoside C or any type of digitalis alkaloids. 
• 
Systemic use of anticoagulants, including LMWH. Concomitant use of warfarin, even 
at prophylactic doses, is prohibited. Use of heparin for the purposes of line preparation 
/ flushing is allowed. 
7 
DOSING AND DOSE MODIFICATIONS 
 
Calculation of BPM31510 Dose 
The calculation of the dose of BPM31510 should be based on the patient’s weight in kilograms. 
For obese patients with a Body Mass Index > 30, the dose should be calculated using the 


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patient’s Adjusted Body Weight 
 
 
 
 
Infusion Rate and Loading Dose of BPM31510 
For the first dose of each week, a loading dose (approximately 8.2 % of the total volume) will be 
infused over 1 hour with the remainder of the dose volume infused over approximately 71 hours 
as indicated.  Patients will be monitored closely during the loading dose procedures and during 
the transition to ambulatory infusion while at the research site. Per protocol section 7.6, 
Interruption of BPM31510 due to Hemodynamic Instability; patients will undergo study 
evaluations including AE and vital sign assessments to evaluate the patient’s tolerance for 
BPM31510 and for the treatment administration process. Upon successful infusion of the loading 
dose, the remainder of the 72-hour infusion will be completed on an outpatient basis. 
If the patient exhibits signs of hemodynamic instability at any time during the BPM31510 
infusion (loading dose or ambulatory infusion), the infusion will be stopped and the patient’s 
vital signs monitored closely. If hemodynamic instability does not resolve within 2 hours, the 
infusion will not be restarted.  Patients should be directed to report signs and symptoms 
indicative of vital sign changes to their research site should they become aware of any of these 
signs and symptoms. The study site should take the appropriate steps for follow up. 
If the patient’s vital signs stabilize within 2 hours, the infusion can be restarted at ½ the rate and 
vital signs will be monitored every 10-15 minutes for at least 30 minutes before increasing the 
administration rate. Vital signs will then be monitored every 10-15 minutes for at least 30 
minutes before discharging the patient. 
Patients will be instructed on potential signs and symptoms commonly associated with 
hemodynamic instability and will be directed to contact their research site or contact emergency 
services as required. 
If the pump cannot be programmed to administer the total volume of BPM31510 over 71 hours 
exactly on the first dose of each week or 72 hours exactly on the second dose of each week, 
please be sure to document the change in duration on the dosing log eCRF and collect PD 
specimens based on the end of infusion time.  
 
Missed Doses during Cycle 1 
The dose of BPM31510, defined as 110 mg/Kg over a 72-hour infusion, may be interrupted due 
to BPM31510 related clinically significant toxicity. BPM31510 dose reductions are not allowed. 
No more than 3 doses (in total) may be missed during Cycle 1 unless approved by Sponsor. 
Removal from the study will be at the Investigator’s discretion based on whether the subject is 
experiencing clinical benefit from treatment or it is in the best interest of the subject to continue 
study treatment.   
Doses that are missed will not be made-up. If the first dose of the week is missed or held, the 
second dose will still be given over 72 hours with no loading dose.  
 
Dose Reduction during Cycles 2-12 


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Hematologic Toxicity  
The Baseline Laboratory Requirements are ANC ≥ 1500 mm3, platelets ≥ 50,000/mm3, 
hemoglobin ≥ 9 g/dL and INR < 1.5 X UNL. Hematology and chemistry should be assessed 
weekly and coagulation labs should be repeated within 24-72 hours prior to initiation of each dose. 
BPM31510 must be held for any grade 3 or 4 hematologic toxicity that is at least possibly drug-
related. Any grade 3 or 4 hematologic toxicity must return to a grade 1 or be resolved with the 
exception of INR which must be < 1.5 X UNL prior to continuing administration of 
BPM31510.  
To monitor and mitigate BPM31510-associated coagulopathies, PT, PTT, INR and platelet 
counts must be assessed prior to administering each dose of BPM31510. Prophylactic Vitamin K 
will be given to all patients prior to the beginning of every week of therapy, unless 
contraindicated as determined by the Investigator. Vitamin K formulation, dosing and frequency 
of dosing is at the Investigators discretion. Additional Vitamin K should be given as needed. An 
INR value of ≥ grade 2 requires immediate treatment with Vitamin K, cryoprecipitate or fresh 
frozen plasma as clinically indicated.  Any AE must decrease to ≤ grade 1 and the INR must be < 
1.5 X UNL before resuming BPM31510 treatment.  
If a second adverse event of ≥ grade 3 INR elevations occurs, permanently discontinue 
BPM31510. 
 
 
Non-Hematologic Toxicity 
A grade 3 or 4 non-hematologic toxicity that is at least possibly drug-related must return to 
grade 1 or resolve prior to continuing administration of BPM31510.  Grade 3 fasting lipid 
abnormalities are an exception in the absence of clinical signs or symptoms. BPM31510 causes a 
false positive fasting lipid elevation. Abnormal fasting lipid profiles should be monitored closely, 
however BPM31510 may continue in the absence of clinical signs or symptoms. 
 
 




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evaluate the patient’s tolerance for BPM31510 and for the treatment administration process. 
Upon successful infusion of the loading dose, the remainder of the 72 hour infusion will be 
completed on an outpatient basis. 
If the patient exhibits signs of hemodynamic instability at any time during the BPM31510 
infusion (loading dose or ambulatory infusion), the infusion will be stopped and the patient’s 
vital signs monitored closely. If hemodynamic instability does not resolve within 2 hours, the 
infusion should not be restarted. 
If the patient’s vital signs stabilize within 2 hours, the infusion can be restarted at ½ the rate and 
vital signs will be monitored every 10-15 minutes for at least 30 minutes before increasing the 
administration rate. Vital signs will then be monitored every 10-15 minutes for at least 30 
minutes before discharging the patient. 
Patients will be instructed on potential signs and symptoms commonly associated with 
hemodynamic instability and will be directed to contact their research site or contact emergency 
services as required. 
 
Dose Interruption Due to Infusion Pump Malfunction Outside of the Clinic 
Study drug administration will be started and completed only at research / treatment facilities 
authorized by BERG, LLC on the completed Enrollment Authorization Form. Once the infusion 
has started, patients will continue study drug administration via ambulatory pump. Use of 
ambulatory pump allows patients to continue infusion at home and to have mobility in 
completing daily activities with limited restrictions. The ambulatory pumps being used are 
validated for, and marketed in the EU and US for this purpose. Patients will return to their 
research /treatment facility 1-2 hours before infusion end to complete the infusion and to have 
study procedures (including vital sign and AE assessments) completed per protocol. 
If problems are encountered during infusion of BPM31510 outside of the clinic, the following 
steps should be taken: 
• 
If a malfunction occurs after clinic hours, the patient should turn the pump off and call 
the helpline phone number listed on the pump.  
• 
If the pump cannot be restarted with the assistance of the helpline, the patient should 
return to the outpatient clinic the following day.  
• 
The clinic staff will determine the length of time the infusion was stopped by 
calculating the volume of BPM31510 remaining in the cassette/bag, the start time of 
the infusion, and infusion rate on the pump. The dosing interruption will be captured 
on the dose eCRF as a pump malfunction and the delay will be recorded. 
• 
If the clinic staff is able to resume the infusion after a delay, this information will be 
captured. Data regarding the exact amount infused, the duration of any stoppage, and 
the volume remaining in the cassette at the time the infusion was discontinued will be 
recorded on the eCRF. 






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Assessments to be performed < 7 calendar days prior to the first day of study treatment are listed 
below. If any of these assessments are performed more than 7 calendar days prior to the first 
dose of BPM 31510, they should be repeated on Cycle 1, Day 1 prior to administration of study 
drug:  
• 
Physical examination. 
• 
Weight. 
• 
Height (does not have to be repeated if >7 days before C1D1 of treatment). 
• 
Vital signs (5-minute sitting blood pressure, pulse, respiratory rate, oral temperature). 
• 
ECOG performance status 
 
• 
FACT-HEP survey administered and completed by patient. 
• 
Pregnancy test (urine or serum) in women of childbearing potential 
 Guidelines Regarding Women of Childbearing Potential). 
• 
Hematology 
 
• 
PT/PTT/INR and platelets* 
• 
Serum chemistry panel, including CMP and serum lipids (Table 6) 
• 
C - reactive protein.  
• 
Vitamin K levels*These assessment results must meet the Inclusion Criteria prior to 
Cycle 1 Day 1 dosing.  
 
Treatment Period 
8.3.1 
Cycle 1 (Cycle = 6 weeks) 
Safety assessments will be performed prior to administration of each dose of BPM31510. 
Prophylactic Vitamin K will be given to all patients prior to the beginning of each week of 
therapy, unless contraindicated as determined by the Investigator.  Vital signs will be assessed 
prior to each dose in Cycles 1-12.  
The following assessments will be performed during Cycle 1 (within ± 3 days unless noted 
otherwise): 
• Day 1: Physical examination and weight. 
• Day 1: ECG pre-dose and at 24 hours post start of infusion (90% of Cmax). 
• Day 1: CA 19-9 value (or CEA or CA 125 if patient does not express CA 19-9). 
• Days 1, 8, 15, 22, 29, 36 and 39: Vital signs prior to each dose, 1 hour post start of 
infusion and prior to discharge (unless discharge is ≤30 minutes from 1-hr post vital 
sign collection).  Prior to discharge, the patient will receive instructions to call the 
research site if they have any signs or symptoms related to potential vital sign changes 
(shortness of breath, racing heartbeat, dizziness, skin flushing, chills, fever, etc.) or any 
other side effects they may experience during or after study drug administration. 
Concomitant Medications are reviewed. Assess for Adverse Events prior to start of 
infusion and before patient is discharged. Hematology, serum chemistry panel 
[including CMP and serum lipids], PT/PTT/INR, platelets and urinalysis ≤ 24-72 hours 
prior to each week’s first dose on Tuesday. Patients should not be dosed until those are 
within normal limits (with the exception of PT/PTT/INR which must be < 1.5X ULN, 


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or have returned to grade 1 or resolved from previous elevations. Patients will be 
provided with instructions on reporting of adverse events to site personnel during and 
following study drug administration.  
• Day 1: Pharmacodynamic samples (PD Blood and Urine are collected pre-dose 
• Day 2: PD Blood & Urine are collected (24 hours after dose start). Vital signs (5-
minute sitting blood pressure, pulse, respiratory rate, oral temperature) are assessed and 
adverse events are collected. 
• 
Day 4, 11, and 18: PD Blood and Urine samples collected EOI (between the two 
infusions) 
• Days 8, 15, 22, 29 and 36: PD Blood and Urine samples are collected pre-dose ( 
within 30 mins prior to start of new infusion) 
• Day 25: C-Reactive Protein  
• Days 4, 11, 18, 25, 32, 39: Vital signs prior to each dose and 1 hour post start of 
infusion or prior to discharge, whichever comes first. Assess for Adverse Events prior 
to start of infusion and before patient is discharged. Prior to discharge, the patient will 
receive instructions to call the research site if they have any signs or symptoms related 
to potential vital sign changes (shortness of breath, racing heartbeat, dizziness, skin 
flushing, chills, fever, etc.) or any other side effects they may experience during or 
after study drug administration. PT/PTT/INR and platelets ≤ 24-72 hours prior to each 
dose. Note: laboratory assessment of PT/PTT/INR and platelets can be conducted 
Monday for the Tuesday dose, but must be conducted on Friday before the dose is 
administered. Patients should not be dosed until INR and PTT are within < 1.5X ULN.  
• End of Week 2: 18-FDG-PET scan (between Day 10- and prior to dosing on day15) 
• Days 21, 28, and 35 Gemcitabine dosing days (Mondays). Vital signs prior to each 
dose, 1-hr post start of infusion and prior to discharge. Assess for Adverse Events prior 
to start of infusion and before patient is discharged. 
• Day 21: ECG before patient is discharged. 
• As needed: Laboratory testing for any ≥ grade 2 prolonged INR to determine the 
underlying cause. The workup should include: LFTs, levels of vitamin-K dependent 
coagulation factors (II, VII, IX, X), Protein C, and Protein S. If ≥ grade 2 INR is not 
corrected following administration of Vitamin K, additional tests such as mixing 
studies, fibrinogen level, D-dimer and fibrin split products should be performed. 
Additional coagulation testing does not need to be completed more than once per 
patient. 
8.3.2 
Cycles 2-12 (Cycle = 4 weeks) 
• 
Day 1: Physical examination, weight, CA 19-9 Value, ECOG performance status 
 and pregnancy test (urine or serum) 
in women of childbearing potential (within 24-72 hours prior to Day 1). 
 


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• 
Days 1, 8, 15, and 22: Adverse Events and Concomitant Medications reviewed. 
Assess for Adverse Events prior to start of infusion and before patient is discharged. 
Hematology, serum chemistry panel [including CMP and serum lipids], PT/PTT/INR, 
platelets and urinalysis ≤ 24-72 hours prior to each Tuesday dose. Patients should not 
be dosed until those are within normal limits or have returned to grade 1 or resolved 
from previous elevations with the exception of PT/PTT/INR which must be < 1.5 X 
UNL.  
• Day 25: C-Reactive Protein  
• Days 1, 4, 8, 11, 15, 18, 22, and 25: Vital signs prior to each dose, 1-hr post start of 
infusion and prior to discharge (unless discharge is ≤30 minutes from 1-hr post vital 
sign collection). Prior to discharge, the patient will receive instructions to call the 
research site if they have any signs or symptoms related to potential vital sign changes 
(shortness of breath, racing heartbeat, dizziness, skin flushing, chills, fever, etc.) or any 
other side effects they may experience during or after study drug administration. 
Assess for Adverse Events prior to start of infusion and before patient is discharged. 
PT/PTT/INR and platelets ≤ 24-72 hours prior to each dose. Note: laboratory 
assessment of PT/PTT/INR and platelets can be conducted Monday for the Tuesday 
dose, but must be conducted on Friday before the dose is administered. Patients should 
not be dosed until INR is within or below normal limits from previous elevations.  
• 
End of Week 10: 18-FDG PET scan and FACT-HEP questionnaire completed by 
patient. 
• End of Cycle 2 and every 2 cycles thereafter:  Tumor response assessment 
 and ECG if clinically indicated. 
• Days 1and 15:  PD Blood and Urine samples are collected pre-dose (within 30 mins 
prior to start of new infusion).  
• Day 28: PD Blood and Urine samples are collected EOI 
• Days 7, 14 and 21: Gemcitabine dosing days (Mondays). Assessment of vital signs 
prior to each dose, 1-hr post start of infusion and prior to discharge. Assess for 
Adverse Events prior to start of infusion and before patient is discharged. 
• As needed: Laboratory testing for any ≥ grade 2 prolonged INR to determine the 
underlying cause. The workup should include: LFTs, levels of vitamin-K dependent 
coagulation factors (II, VII, IX, X), Protein C, and Protein S. If ≥ grade 2 INR is not 
corrected following administration of Vitamin K, cryoprecipitate or fresh frozen 
plasma, additional tests such as mixing studies, fibrinogen level, D-dimer and fibrin 
split products should be performed. Additional coagulation testing does not need to be 
completed more than once per patient. 
 
 
Unscheduled Visits  
If additional Unscheduled Visits are required, the following evaluations will be performed at the 
discretion of the Investigator: 


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• Physical examination 
• Weight 
• Vital signs (5-minute sitting blood pressure, pulse, respiratory rate, oral temperature) 
• ECOG performance status 
 
• Hematology (Table 6) 
• PT/PTT/INR and platelets. 
• Serum chemistry panel (including CMP and serum lipids) (Table 6) 
• C-Reactive Protein (optional, only in patients with a history of CHF or chronic 
inflammatory conditions such as arthritis and psoriasis) 
• Urinalysis (Table 6) 
• Laboratory testing as needed for any patient who develops ≥ grade 2 prolonged INR to 
determine the underlying cause. The workup should include: LFTs, levels of Vitamin-
K dependent coagulation factors (II, VII, IX, X), Protein C, and Protein S. If ≥ grade 2 
INR is not corrected following administration of Vitamin K, additional tests such as 
mixing studies, fibrinogen level, D-dimer and fibrin split products should be 
performed. Additional coagulation testing does not need to be completed more than 
once per patient. 
• Concomitant medications 
• Adverse events 
 
End of Treatment/Early Termination (prior to completing Cycles 1 & 2)  
End of Treatment assessments 
 
Therapy) will be performed within 30 days after the last dose of BPM31510 on the basis of 
completion of the planned trial treatment period, disease progression, or for any of the reasons 
. After withdrawal from or completion of protocol treatment, patients must 
be followed for adverse events for at least 30 calendar days, and follow Serious Adverse Events 
until resolution or stabilization, after the last dose of trial drug, unless unlikely to further improve 
based on underlying disease in the opinion of the Investigator. 
The Investigator must make every effort to complete all End-of-Treatment assessments as 
follows: 
• Physical examination 
• Weight 
• Vital signs (5-minute sitting blood pressure, pulse, respiratory rate, oral temperature) 
• CA 19-9 value (or CEA or CA 125 if patient does not express CA 19-9) 
• ECG 
• ECOG performance status (Appendix A: ECOG Performance Status Criteria) 
• 
FACT-HEP questionnaire completed by patient. 
• Hematology (Table 6) 
• PT/PTT/INR and platelets 
• Serum chemistry panel (including CMP and serum lipids) (Table 6) 


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• C - reactive protein.  
• Urinalysis  
• Tumor assessment 
• Concomitant medications 
• Adverse events 
All patients who are treated under this protocol, and who come off study for any reason (i.e. 
disease progression, start a new therapy, other) will be followed for survival every 3 months for a 
minimum of 12 months, or until the study closes, whichever occurs first. Sites are expected to 
attempt to contact the patient, or caregiver to obtain patient status. On site visits are not required.  
At least 3 attempts should be made to contact patients who early term or fail to complete the 
clinical study. The patient should be documented via EDC as “lost to follow-up” if all attempts 
fail. Contact attempts should be documented in the patients study file. 
 
Laboratory Assessments 
Local laboratories will perform all laboratory tests and results and lab normal reference range for 
each test will be provided to the Investigator for entry into the eCRF. Blood and urine samples 
for hematology, coagulation, serum chemistry, and urinalysis will be prepared for analysis using 
standard procedures. Laboratory panels are defined in Table 6. Vitamin K and advanced 
coagulation testing (for Grade 2 increases in INR) may be performed through local laboratory or 
through the central laboratory contracted by the Sponsor to provide this service. 
Table 6: 
Laboratory Panels 
Hematology  
CBC with differential, platelets  
Coagulation 
PT/PTT/INR (Screening only: Vitamin K) 
Serum Chemistry 
Albumin, alkaline phosphatase, ALT, AST, blood urea nitrogen (BUN), calcium, 
carbon dioxide, chloride, creatinine, gamma-glutamyl transferase (GGT), glucose, 
lactate dehydrogenase, phosphorus, potassium, sodium, total bilirubin, total protein, 
serum magnesium, cholesterol, triglycerides 
Urinalysis 
Appearance, color, pH, specific gravity, ketones, protein, glucose, bilirubin, 
nitrite, urobilinogen, and occult blood (microscopic examination of sediment will 
be performed only if the results of the urinalysis dipstick evaluation are positive) 
Laboratory work-up for 
any ≥ grade 2 INR 
LFTs, levels of Vitamin-K dependent coagulation factors (II, VII, IX, X), Protein C, 
and Protein S. If ≥ grade 2 INR is not corrected following administration of Vitamin K, 
cryoprecipitate or fresh frozen plasma, additional tests such as mixing studies, 
fibrinogen level, D-dimer and fibrin split products should be performed.  Additional 
coagulation testing does not need to be completed more than once per patient. 
 
Abnormalities in clinical laboratory tests that are considered clinically significant by the 
Investigator will be recorded on the AE CRF page. If values meet criteria defining them as 
serious, they must be reported as serious adverse events (SAEs) 
 Special 
Instructions Regarding Coagulation Assessments Prior to Each BPM31510 Dose  


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Protocol BPM31510IV-05 Amendment7.0                                                                                       25 August 2018 
 
• 
Prophylactic Vitamin K will be given to all patients prior to the beginning of each 
week of therapy, unless contraindicated as determined by the Investigator. Additional 
Vitamin K may be given as needed and at the Investigator’s discretion. 
• 
Prior to administering each dose of BPM31510, the PT/PTT, INR and platelet count 
must be assessed and any clinically significant abnormal result reported to both the 
primary Investigator and BERG.  
• 
BPM31510 may be administered if the INR, PT, and PTT are ≤ 1.5 times the upper 
limit of normal and the platelet count is ≥ 50,000/mm3.  
• 
Any PTT or INR value ≥ grade 2 requires immediate treatment with Vitamin K (oral, 
IV, IM, or SC), cryoprecipitate or fresh frozen plasma as clinically indicated and 
BPM31510 will be held until the abnormal lab returns to normal limits  (≤ 1.5 x UNL) 
from previous elevations.  
• Patients who develop ≥ grade 2 INR any time during the study should undergo 
laboratory testing to determine the underlying cause. The workup should include: 
LFTs, levels of Vitamin K-dependent coagulation factors (II, VII, IX, X), Protein C, 
and Protein S. If the ≥ grade 2 INR is not corrected following administration of 
Vitamin K, cryoprecipitate or fresh frozen plasma, as noted above, additional tests 
such as mixing studies, fibrinogen level, D-dimer and fibrin split products should be 
performed.   Additional coagulation testing does not need to be completed more than 
once per patient. 
 
 
Pharmacodynamic Assessments 
8.7.1 
Blood Samples for Pharmacodynamic Analysis 
Blood samples will be collected during BPM31510 therapy, according to the schedule in Table 7. 
If the pump cannot be programmed to administer the total volume of BPM31510 over 72 hours 
exactly, please be sure to document the start and end of infusion times on the dosing log eCRF 
and collect PD specimens based on the end of infusion time. 
Detailed preparation, storage, and shipping instructions for PD samples are provided in the Study 
Laboratory Manual. 
Blood samples will be assayed for levels of PD markers of BPM31510 activity using the 
techniques described in Section 11.6.5. The analyses are essential based on nonclinical data 
demonstrating the ability of BPM31510 to influence gene, protein, metabolite and lipid anabolic 
and catabolic pathways including but not limited to areas of apoptosis, angiogenesis, cell cycle 
regulation, bioenergetics, metabolism, lipid homeostasis, and serum proteins.  
All samples will be discarded after the studies are complete and will not be stored for future 
genetic analysis. 
 
 




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array, ELISA, western blotting), metabolomics (e.g., global analysis of metabolites in biological 
samples; identification of specific markers of energy metabolism e.g., pyruvate, lactate), 
lipidomics (e.g., global analysis of lipid classes; identification of specific lipids e.g., derivatives 
of palmitate, linoleic acid, arachidonic acid). 
The analyses are essential based on in vitro and nonclinical data demonstrating the ability of 
BPM31510 to influence gene, protein, metabolite and lipid anabolic and catabolic pathways 
including, but not limited to, areas of apoptosis, angiogenesis, cell cycle regulation, 
bioenergetics, metabolism, lipid homeostasis, and serum proteins. All samples will be discarded 
after the studies are completed and will not be stored for future genetic analysis. 
Spot samples for urine PD will be collected at the times shown in Table 7, Schedule of Blood 
and Urine Samples for Pharmacodynamics, in Section 8.7.1 above.  
Detailed preparation, storage, and shipping instructions for PD urine samples are provided in the 
Study Laboratory Manual. 
 
 




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Labeling, Packaging and Supply of Study Treatments 
9.3.1 
BPM31510 
BERG will provide the Investigator with an adequate supply of BPM31510 Nanosuspension 
Injection. BPM31510 will be supplied
 
 
Table 10: 
Composition of Sterile BPM31510 Nanosuspension Injection (40 mg/mL) 
Ingredient 
Vial Volume 
Concentration 
API Theoretical 
Quantity per vial 
BPM31510 
100 mL 
40 mg/mL 
4000 mg 
The labeling and packaging of BPM31510 will be in accordance with Good Manufacturing 
Practice (GMP) Annex 13 and any other local applicable regulatory requirements. The 
immediate packaging will also contain a statement to conform with FDA Investigational New 
Drug (IND) requirements as follows: Caution: New Drug - Limited by Federal (or United States) 
law to investigational use or the statement “for clinical trial use only” to meet the requirements 
for use under the Investigational Medicinal Product Dossier IMPD submitted in European 
Union Member States 
BPM31510 is an investigational new drug. Accordingly, all drug handling and disposal 
procedures for investigational drugs should be performed by qualified personnel as documented 
by the American Hospital Formulary Service (AHFS) or other recognized formulary 
requirements.  
 
 
Inventory of the investigational drug supplies must be performed according to applicable state 
and federal regulations. BERG or its representatives must be granted access on reasonable 
request to check drug storage, dispensing procedures and accountability records.  
9.3.2 
Gemcitabine 
Gemcitabine is a commercially available product and is being used for the indication for which it 
has been labeled.  Gemcitabine for this study and will be provided by the clinical site or by the 
Sponsor per clinical trial agreement. For the purposes of this study, Gemcitabine is considered 
investigational.  
Storage conditions for these chemotherapy agents are provided in the gemcitabine Package 
Insert/SmPC. The expiration date on the label of each drug product must not be exceeded. 
Please refer to the Package Insert/SmPC for detailed information on the properties of 
gemcitabine drug product and Section 12.0 Safety Reporting and Analyses for the reporting of 
adverse events and product complaints.  


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Inventory of the investigational drug supplies must be performed according to applicable local 
regulations. BERG or its representatives must be granted access on reasonable request to check 
drug storage, dispensing procedures and accountability records.  
 
Preparation and Administration of Study Treatments 
9.4.1 
BPM31510 
BPM31510 Nanosuspension Injection (40 mg/mL) will be administered IV over 144 hours (two 
72 hour 110 mg/Kg doses). Doses will be prepared and administered at the clinical site. The 
volume of each dose will be based on the patient’s weight in kilograms.  
Instructions for preparing undiluted BPM31510 drug product for administration as a single 72-
hour continuous infusion are as follows (see also storage and administration instructions with 
drug product and infusion sets).  
Note:
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 




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returned to BERG (or designee). Clinical trial supplies may be destroyed on-site when prior 
approval has been granted by BERG or its representative. 
9.5.2 
Gemcitabine 
There are no protocol requirements for accountability of gemcitabine other than those required 
by the policies and procedures of the study site. Lot numbers for gemcitabine administered to 
patients in this study will be recorded in the study EDC system. 
 
Precautions and Risks Associated with Study Treatments 
9.6.1 
BPM31510 
In animals receiving lethal doses of BPM31510, toxicity was rapid in onset (within 15 
minutes). In the event of clinical toxicity during infusion, stop the infusion and take appropriate 
resuscitative measures.  
To monitor and mitigate BPM31510-associated coagulopathies, the PT, PTT, INR and platelet 
count must be assessed prior to each dose of BPM31510. Prophylactic Vitamin K will be given 
to all patients prior to the beginning of each week of therapy, unless contraindicated as 
determined by the Investigator. An INR ≥ grade 2 requires immediate treatment with Vitamin K 
as clinically required. An abnormal INR, PTT, and PT must return to normal (≤ 1.5 X UNL) and 
platelets must be ≥ 50,000/mm3 prior to treating with BPM31510. Additional Vitamin K should 
be administered as needed when PT/PTT/INR are abnormal. 
 
 
 
  
 
  
 
 
  
 
 
 
 
 
  
 
 
 


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Protocol BPM31510IV-05 Amendment7.0                                                                                       25 August 2018 
 
 
 
9.6.2 
Gemcitabine 
Refer to the Package Insert/SmPC for detailed information on the risks associated with the use of 
gemcitabine. The following adverse effects have been reported: 
Hematologic: myelosuppression (dose-limiting); anemia, leukopenia, thrombocytopenia; 
infections (common); sepsis (rare); petechiae; hemorrhage (mild)  
Gastrointestinal: nausea and vomiting (common); diarrhea; stomatitis  
Hepatic: transient elevations of serum transaminases (common); hepatotoxicity including 
liver failure and death (rare) 
Renal: proteinuria and hematuria (mild, common); Hemolytic Uremic Syndrome (HUS) 
(rare, serious); elevated serum creatinine or BUN  
Skin: rash (common); pruritus; alopecia (common)  
Pulmonary: dyspnea, bronchospasm (occasional, serious)  
Flu-like Symptoms: fever (common); asthenia, anorexia, headache, cough, chills, and 
myalgia (common); insomnia, rhinitis, sweating, and malaise (infrequent) 
Neurotoxicity: paresthesias (mild, common); severe paresthesias (rare) 
Allergic: bronchospasm (rare); anaphylactoid reaction (rare) 
Cardiovascular: myocardial infarction, cerebrovascular accident, arrhythmia, and 
hypertension (rare); edema, peripheral edema (common); generalized edema (rare). 
Hepatic Toxicity, Drug-induced liver injury, including liver failure and death, has been reported 
in patients receiving Gemcitabine alone or in combination with other potentially hepatotoxic 
drugs. Administration of Gemcitabine in patients with concurrent liver metastases or a pre-
existing medical history of hepatitis, alcoholism, or liver cirrhosis can lead to exacerbation of the 
underlying hepatic insufficiency. Investigators should assess hepatic function prior to initiation 
of Gemcitabine and periodically during treatment. Discontinue Gemcitabine in patients that 
develop liver toxicity and/or severe liver injury. 
 
 
 
 
 
 
 
 


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Ultrasound: 
When the primary trial endpoint is objective response, ultrasound should 
not be used to measure tumor lesions. It is, however, a possible alternative 
to clinical measurements of superficial palpable lymph nodes, 
subcutaneous lesions, and thyroid nodules. Ultrasound may also be useful 
to confirm the complete disappearance of superficial lesions usually 
assessed by clinical examination. 
Endoscopy and Laparoscopy: 
Use of endoscopy and laparoscopy for objective tumor evaluation has not 
yet been fully and widely validated. Therefore, use of these techniques for 
objective tumor response should be restricted to validation purposes in 
specialized centers. Such techniques can be useful in confirming complete 
pathological response when biopsies are obtained. 
Tumor Markers: 
Tumor markers alone cannot be used to assess response. If markers are 
initially above the upper limit of normal, they must normalize for a patient 
to be considered in complete clinical response when all lesions have 
disappeared. 
Cytology and Histology: 
Cytology and histology can be used to differentiate between PR and CR in 
rare cases (e.g., after treatment to differentiate between residual benign 
lesions and residual malignant lesions in tumor types such as germ cell 
tumors). 
10.1.2 
Response Criteria 
Evaluation of Target Lesions 
Complete Response (CR): 
Disappearance of all target lesions.  
Partial Response (PR): 
At least a 30% decrease in the sum of the longest diameter (LD) of target 
lesions, taking as reference the baseline sum LD. 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest (nadir) sum LD since the 
treatment started. 
Progressive Disease (PD): 
At least a 20% increase in the sum of the LD of target lesions, taking as 
reference the smallest (nadir) sum since the treatment started, or the 
appearance of one or more new lesions. Requires not only 20% increase, 
but absolute increase of a minimum of 5 mm over sum. 
Evaluation of Non-Target Lesions 
Complete Response (CR): 
Disappearance of all non-target lesions and normalization of tumor 
markers. All lymph nodes must be non-pathological in size (<10 mm short 
axis). 
Non-CR/Non-PD: 
Persistence of one or more non-target lesions and/or persistence of tumor 
marker level above the normal limits. 
Progressive Disease (PD): 
Appearance of one or more new lesions and/or unequivocal progression of 
existing non-target lesions. When the patient also has measurable disease, 
to achieve “unequivocal progression” on the basis of the non-target 
disease, there must be an overall level of substantial worsening in non-
target disease such that, even in presence of SD or PR in the target disease, 
the overall tumor burden has increased sufficiently to merit discontinuation 
of therapy. 
 
 


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Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). In general, the patient’s best response 
assignment will depend on the achievement of both measurement and confirmation criteria.  
Per RECIST, confirmation of response (by repeat scans after 4 weeks or as specified in the 
protocol) is required for this study in which response rate is the primary endpoint.  
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
NO 
CR 
CR 
NON-CR/NON-PD 
NO 
PR 
CR 
NE 
NO 
PR 
PR 
NON-PD OR NE 
NO 
PR 
SD 
NON-PD OR NE 
NO 
SD 
PD 
ANY 
YES OR NO 
PD 
ANY 
PD 
YES OR NO 
PD 
ANY 
ANY 
YES 
PD 
In some circumstances, it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of a CR depends upon this determination, it is recommended that the 
residual lesion be investigated by fine needle aspirate or biopsy to confirm the CR status.  
When nodal disease is included in the sum of target lesions, and the nodes decrease to “normal” 
size (<10 mm), they may still have a measurement reported on scans. This measurement should 
be recorded even though the nodes are normal in order not to overstate progression, should it be 
based on increase in size of the nodes. As noted earlier, this means that patients with CR may not 
have a total sum of “zero” on the Case Report Form (CRF). 
11 
STATISTICAL CONSIDERATIONS 
 
Overview 
This is a Phase 2 multicenter, open-label, non-randomized study to examine the safety and 
efficacy of BPM31510 with gemcitabine in advanced pancreatic cancer patients as 2nd /3rd line 
therapy.  
Data will be summarized by treatment arm using descriptive statistics (number of patients, mean, 
median, standard deviation, minimum, and maximum) for continuous variables and using 
frequency and percentages for discrete variables. Exact 95% confidence intervals may be 
generated using the Clopper-Pearson method for selected efficacy, safety and exploratory variables.  
Time-to-event endpoints will be assessed using the Kaplan-Meier method 
  
Medians and proportions event-free at specified time points will be estimated using the Kaplan 
and Meier method; 95% confidence intervals for median PFS and OS may be generated using the 
Brookmeyer-Crowley method. 


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Additional details regarding statistical analyses will be described in the Statistical Analysis Plan 
(SAP). 
 
Sample Size Considerations 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
Study Populations 
The Safety Population will consist of all patients treated with at least one dose of BPM31501 or 
gemcitabine. The Efficacy Population will consist of all patients who complete at least one cycle 
of therapy.  
 
Study Design 
  
 
 
 
 
. 
 
Efficacy Analysis  
Assessments based on response will include best response, objective response rate (ORR: 
CR+PR), disease control rate (DCR: CR+PR+SD), Progression-Free Survival (PFS) and Time to 
Progression (TTP).  Patients without a post-baseline tumor assessment will be analyzed as non-
responders in the analysis of ORR and DCR.   
 
Overall Tumor Response 
Objective responses will be evaluated using the Response Evaluation Criteria In Solid Tumors 
1.1 (RECIST 1.1). Changes (i.e. improvements) in tumor measurements from baseline values 
will be assigned a status of CR or PR or SD. Objective response measurements will comprise the 
sum of CR plus PR. The overall response rate (CR+PR), the disease control rate (CR+PR+SD) as 


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well as the rates for the individual categories of response (i.e. CR, PR, SD, and PD), will be 
analyzed.   When a CR or PR is documented, a confirmatory CT or PET scan will be obtained 
per RECIST guidelines. 
11.6.1 
Progression Free Survival 
Progression-free survival (PFS) is defined as the number of days from the first dose of study 
drug to the first documentation of progression or death due to any cause.  Patients who remain 
alive without progression will be censored for PFS at the date of their last tumor assessment. 
11.6.2 
Time to Progression 
Time to Progression (TTP) is defined as the number of days from the first dose of study drug to 
the first documentation of progression.  Patients without progression will be censored for PFS at 
the date of their last tumor assessment. 
11.6.3 
Overall Survival 
Overall survival is defined as the number of days from the first dose of study drug to the date of 
death due to any cause.  Patients alive at the time of analysis will be censored at the date of last 
contact.  
11.6.4 
Overall changes in patient reported quality of life  
Patient-reported outcomes for quality of life (QOL) measures will be  assessed using the self-
administered Functional Assessment of Cancer Therapy validated patient questionnaire tailored 
for patients with hepatobiliary and pancreatic cancers, FACT-HEP, which asks patients to 
consider, rate, and score their treatment- and disease-related symptoms and general quality of life 
across a spectrum of categories. Changes in QOL scores from baseline values during treatment 
and follow-up will be assessed. Patient entered scores for each questionnaire item will be 
summed for each category, multiplied by the number of items, and divided by the number of 
items answered in the category, according to the instructions provided. The overall quality of life 
score will comprise the sum of values for each category (Physical, Social, Emotional and 
Functional Well-being and Additional Concerns specific to Pancreatic Cancer patients). Overall 
QOL and categorical assessment changes will be analyzed.    
11.6.5 
Evaluation of Exploratory PD Parameters 
Blood samples will be collected for PD during BPM31510 treatment. PET scans performed will 
be evaluated for the Warburg effect by BPM31510 in the tumors.  
Exploratory PD analyses will be performed on blood and urine samples and assayed for markers 
of BPM31510 activity using (but not limited to) genomic (e.g., microarray, SAGE, northern 
blotting, gene expression), proteomic (e.g., LC/MS based analysis, 2DEMS, MALDI TOF, 
antibody array, ELISA, immunohistochemistry, flow cytometry, western blotting), metabolomics 
(e.g., global analysis of metabolites in biological samples; identification of specific markers of 
energy metabolism e.g., pyruvate, lactate), lipidomics (e.g., global analysis of lipid classes; 
identification of specific lipids e.g., derivatives of palmitate, linoleic acid, arachidonic acid). 


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The exploratory endpoints are defined by molecular characteristics of patient populations that 
demonstrate predictive power in associating a profile of response, stable design, or lack of 
efficacy to guide clinical decision making. 
 
Planned Interim Analyses 
No formal interim analysis is planned excepting for the analysis of the first 10 evaluable patients 
enrolled as described above.  These separate analyses will be triggered as soon as the last patient 
to be enrolled (of the ten) has completed the first two treatment cycles. 
 
Replacement of Patients 
Patients who are enrolled into the study, but fail to receive at least two cycles (10 weeks) of 
BPM31510 will be replaced. 
 
Data and Safety Monitoring Board 
The trial will not utilize the services of a Data and Safety Monitoring Board.  
 
Steering Committee 
The trial will not utilize the services of a Steering Committee. 
12 
SAFETY REPORTING AND ANALYSES 
 
Safety Review 
All patients who receive any amount of BPM31510 or gemcitabine will be included in the safety 
analyses, which will be based on the following: 
• 
The incidence, severity, duration, causality, seriousness, and type of AEs, changes 
in the patient’s physical examination, vital signs, and clinical laboratory results.  
• 
The incidence of death. 
• 
Use of concomitant medications. 
 
Safety Analyses 
Safety assessments will consist of monitoring and recording protocol-defined adverse events 
(AEs) and serious adverse events (SAEs); measurement of protocol-specified hematology, 
coagulation, clinical chemistry, and urinalysis variables; measurement of protocol-specified vital 
signs; and other protocol-specified tests that are deemed critical to the safety evaluation of the 
trial drug.  Selected laboratory measurements will be graded using CTCAE criteria.  Adverse 
Events will be coded using MedDRA 19.0 or version specified by the study safety management 
plan. 
 
Adverse Events 
The Investigator is responsible for recognizing and reporting serious adverse events promptly to 
BERG, LLC and/or its Pharmacovigilance (PV) service provider. If not delegated to another 
entity, it is BERG’s responsibility to report relevant SAEs to the applicable local, national, or 
international regulatory body. 
12.3.1 
Definitions of Adverse Events 


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Adverse Event (AE): Any untoward medical occurrence or deterioration of a pre-existing 
medical condition in a patient or clinical investigation subject following or during exposure to an 
investigational product. An AE does not necessarily have a causal relationship with the 
medicinal product. For this study, the medicinal product is BPM31510 and its combination with 
gemcitabine. 
An undesirable medical condition can include symptoms (e.g., nausea, chest pain), signs (e.g., 
tachycardia, enlarged liver), or the abnormal results of an investigation (e.g., laboratory 
findings).  
The criteria for identifying AEs are: 
• 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product. 
• 
Any new disease or exacerbation of an existing disease. 
• 
Any deterioration in non-protocol-required measurements of laboratory value or other 
clinical test (e.g., ECG or X-ray) that results in symptoms, requires treatment, results 
in a change in study drug treatment, or discontinuation from study drug. 
• 
Recurrence of an intermittent medical condition (e.g., headache) not present at 
Baseline. 
12.3.2 
Assessing Severity of Adverse Events 
The NCI CTCAE v4.02 will be used to assign the following severity scale to AEs.  
• 
Grade 1 = Mild 
• 
Grade 2 = Moderate 
• 
Grade 3 = Severe 
• 
Grade 4 = Life Threatening 
• 
Grade 5 = Death 
AEs that are not defined in the NCI CTCAE should be evaluated for severity according to the 
following scale: 
• 
Grade 1 = Mild 
• 
Grade 2 = Moderate 
• 
Grade 3 = Severe 
In addition, all AEs reported using the NCI CTCAE classification and graded as 4 or 5 are to be 
considered serious. 
The criteria for assessing severity are different than those used for seriousness. 
12.3.3 
Assessing Relationship to Trial Treatment 
Items to be considered when assessing the relationship of an AE to BPM31510 or gemcitabine 
therapy are: 
• 
Temporal relationship of the onset of the event to the initiation of the study treatment. 


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• 
The course of the event, considering especially the effect of discontinuation of study 
treatment or reintroduction of study treatment, as applicable. 
• 
Whether the event is known to be associated with the study treatment, or with other 
similar treatments. 
• 
The presence of risk factors in the study patient known to increase the occurrence of 
the event. 
• 
The presence of non-study treatment related factors which are known to be associated 
with the occurrence of the event. 
12.3.4 
Classification of Causality 
Causality is a determination of whether there is a reasonable possibility that the study drug may 
have caused or contributed to an adverse event. It includes assessing temporal relationships, 
dechallenge/rechallenge information, association (or lack of association) with underlying 
diseases, and the presence (or absence) of one or more likely causes. 
The Investigator will give his or her opinion as to the relationship of the adverse event to trial 
drug treatment (i.e., whether the event is related or unrelated to trial drug administration). The 
Investigator or physician designee is responsible for verifying and providing source 
documentation for all adverse events and assigning the attribution for each event for all patients 
enrolled on the trial.  
The Investigator must attempt to determine whether an adverse event is in some way related to 
the use of the study drug. This relationship should be described as follows: 
Not Related: A causal relationship between the study treatment and the AE is not a reasonable 
possibility. Related: A causal relationship between the study treatment and the AE is a 
reasonable possibility. The Investigator must further qualify the degree of certainty of 
relatedness as follows: 
Unlikely: The event is clearly due to causes distinct from the use of the study drug, such as a 
documented pre-existing condition, the effect of a concomitant medication, or a new condition 
that, based on the pathophysiology of the condition and the pharmacology of the study drug, is 
unlikely to be related to the use of the study drug. 
Possible: The event follows a reasonable temporal sequence from administration of the study 
drug or the event follows a known response pattern to the study drug, but the event could have 
been produced by a concomitant medication or an intercurrent medical condition which, based 
on the pathophysiology of the condition and the pharmacology of the study drug, is unlikely to 
be related to the use of the study drug.  
Probable: The event follows a reasonable temporal sequence from administration of the study 
drug, and the event follows a known response pattern to the study drug, and the event cannot be 
reasonably explained by an intercurrent medical condition, or the event cannot be the effect of a 
concomitant medication. 


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Definite: The event follows a reasonable temporal sequence from administration of the study 
drug, the event follows a known response pattern to the study drug, and based on the known 
pharmacology of the study drug, the event is clearly related to the effect of the study drug. 
Unknown: Based on the evidence available, causality cannot be ascribed. 
12.3.5 
Recording of Adverse Events 
All adverse events (AEs) of any patient enrolled in the trial will be reported in the electronic case 
report form (eCRF). All AEs, regardless of relationship to study drug or procedure, should be 
collected beginning at patient consent and continue through thirty days after the last dose of 
study drug. Patients with AEs that are ongoing at the patient’s last study visit must be followed 
until resolution or for 30 days after the patient’s last dose of study drug, whichever comes first. 
AEs should be reported as SAEs if they become serious and fit the criteria for SAEs. AEs that 
cause interruption or discontinuation of investigational product, or AEs that are present at the 
end of their participation in the study must be followed until resolution or for 30 days after the 
patient’s last dose of study drug, whichever comes first. Such patients should receive post-
treatment follow-up as appropriate.  
If the adverse event is serious, it should be immediately entered into the eCRF, by first entering 
it into the Adverse Events eCRF and then completing the SAE report form, which should be 
signed by the PI or authorized designee. Upon completion, the Medical Monitor will be notified 
by email to review.  
12.3.6 
Abnormal Laboratory Values and Vital Signs 
The reporting of abnormalities of vital signs as adverse events should be avoided. Abnormalities 
of vital signs should not be reported unless any criterion for an SAE is fulfilled, the vital signs 
abnormalities cause the patient to discontinue trial treatment, requires a medical intervention 
(e.g., IV fluid administration for hypotension) or they are determined by the investigator to be 
clinically significant and which does not rise to the level of fulfilling SAE criteria or the 
Investigator decides that the abnormality should be reported as an AE.  
A laboratory result should be considered by the Investigator to be an adverse event if it: 
• 
Is any grade 3 or 4 laboratory abnormality or any clinically significant grade 1 or 2 
hematology or biochemistry laboratory value.  
• 
Results in the withdrawal of study treatment. 
• 
Results in withholding of study treatment pending some investigational outcome. 
• 
Results in the initiation of an intervention (e.g., potassium supplement for 
hypokalemia). 
• 
Increases in severity compared to Baseline by ≥ 2 NCI grades, with the exception of 
lymphocytes, albumin, cholesterol, glucose, and electrolytes. For these tests, a change 
of ≥ 2 grades will be evaluated by the Investigator to determine if they are of clinical 
significance and if so, will be considered an adverse event. 


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Abnormal laboratory values should not be listed as separate AEs if they are considered to be part 
of the clinical syndrome that is being reported as an AE. Any laboratory abnormality considered 
to constitute an AE should be reported on the Adverse Event CRF. 
If an abnormal laboratory value or vital sign is associated with clinical signs and/or symptoms, 
the sign or symptom should be reported as an AE, and the associated laboratory value or vital 
sign should be considered additional information that must be collected on the relevant CRF or 
EDC. 
12.3.7 
Handling of Adverse Events 
All adverse events resulting in discontinuation from the trial should be followed until resolution 
or stabilization. Patients must be followed for AEs for 30 calendar days after discontinuation or 
completion of protocol-specific treatment (e.g., chemotherapy, radiation, oral medications, 
targeted therapy, surgery, etc.). All new AEs occurring during this period must be reported and 
followed until resolution unless, in the opinion of the Investigator, these values are not likely to 
improve because of the underlying disease. In this case, the Investigator must record his or her 
reasoning for this decision in the patient’s medical record and as a comment on the CRF or EDC. 
After 30 days, only AEs, SAEs, or deaths assessed by the Investigator as treatment related are to 
be reported. 
 
Serious Adverse Events 
12.4.1 
Definitions of Serious Adverse Events 
The definitions of SAEs are given below. The PI is responsible for ensuring that all staff 
involved in the trial is familiar with the content of this section. 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either 
the Investigator or the Sponsor, it results in any of the following outcomes:  
• 
Death (NOTE: death due to disease progression is a study outcome endpoint, will be 
recorded on the CRF, and does not need to be reported as an SAE). 
• 
A life-threatening adverse drug experience—any adverse experience that placed the 
patient, in the view of the initial reporter, at immediate risk of death from the adverse 
experience as it occurred. It does not include an adverse experience that, had it 
occurred in a more severe form, might have caused death. 
• 
Requires at least a 24-hour inpatient hospitalization or prolongation of existing 
hospitalization. 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
• 
A congenital anomaly/birth defect. 
• 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or may require medical 
or surgical intervention to prevent one of the outcomes listed in this definition.  




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causality, within 24-hours of the first knowledge of the event by the treating physician or 
research personnel.  
When the adverse event is serious, it should be immediately entered into the Adverse Events 
eCRF, and then the SAE report form should be completed and signed by the PI or designee. 
Upon completion of the SAE report form, 
 
within 24-hours of becoming aware of the event, for initial review and classification. Additional 
details on SAE reporting can be found in the BPM31510IV-05 Safety Manual provide to your 
site. 
• 
All life-threatening or fatal events that are unexpected and related to the study drug 
must have a written report submitted within 24 hours (next working day) of knowledge 
of the event to the Sponsor.  
• 
An Unexpected Adverse Event is one that is not listed in the current Clinical 
Investigator Brochure (CIB)/Package Insert or that differs from the event mentioned in 
the CIB/Package Insert because of greater severity or specificity. 
• 
All SAEs and medically confirmed deaths (regardless of causality assessment) 
occurring on trial treatment or within 30 days of last trial treatment must be reported to 
BERG’s pharmacovigilance service provider as SAEs using the SAE report form and 
followed until resolution (with autopsy report if applicable). (NOTE: death due to 
disease progression is a study outcome endpoint, will be recorded on the CRF, and 
does not need to be reported as an SAE). 
• 
Deaths occurring within 30 days after last trial treatment that are deemed ‘possibly’, 
‘probably’ or ‘definitely’ related to BPM31510 must be reported as SAEs on the SAE 
report form (with an autopsy report if available). 
• 
Deaths occurring within 30 days after last trial treatment and not attributed to trial 
treatment (e.g., disease progression) need not be reported as SAEs, but simply captured 
on the appropriate eCRF. 
• 
Additionally, any serious adverse events that occur after the 30 day time period that 
are related to the study treatment must be reported to BERG. This may include the 
development of a secondary malignancy. 
• 
NOTE: SAEs occurring in patients registered to the trial but not receiving study drug 
(i.e., occurring before protocol treatment) do not require reporting. 


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To report an SAE, the SAE eCRF should be completed with the necessary information after the 
AE eCRF is completed in the EDC. Additional eCRF pages that need to be completed and are 
required for SAE reporting include those that collect: 
• 
Adverse Event  
• 
Study drug (BPM31510) and gemcitabine dosing and administration 
• 
Concomitant Medications 
• 
Demographics 
• 
Baseline Abnormalities/Medical History 
The site PI/Coordinator will submit the SAE using the SAE Report Form. Once received by 
the Medical Monitor, BERG and the CRO Project Managers will be notified via e-mail. 
The site coordinator/PI must complete the AE eCRF and SAE Report Form within 24-hours after 
the site becoming aware of the SAE. 
Follow-up information for SAEs and information on non-serious AEs that become serious should 
also be reported as soon as it is available using the same reporting system; these reports should 
be submitted using the SAE Report Form. The detailed SAE reporting process will be provided 
to the sites in the Safety Manual. 
 
 
 
12.4.4 
Reporting SAEs to IRBs/ECs 
All events occurring during the conduct of a protocol and meeting the definition of an SAE must 
be reported to the IRB/EC in accordance with the site’s IRB/EC standard operating procedures 
and timeframes. Unless stated otherwise in the protocol, all SAEs, expected or unexpected, must 
be reported to the Sponsor regardless of attribution within 24 hours of knowledge of the event. 
12.4.5 
BERG SAE Reporting Requirements 
Berg must inform Investigators and regulatory authorities, including the FDA and EMA, of 
reportable events in compliance with applicable regulatory requirements on an expedited basis 
(i.e., within specific timeframes). For this reason, it is imperative that investigational sites 
provide complete SAE information in the manner described above. 
BERG is responsible for reporting relevant SAEs to the competent authority, other applicable 
regulatory authorities, and participating Investigators, in accordance with ICH guidelines, FDA 
regulations (21 CFR 312.32), ICH E2A Clinical Safety Data Management and/or local regulatory 
requirements.  
BERG or designee is responsible for reporting unexpected fatal or life-threatening events 
associated with the use of trial drugs to the regulatory agencies via telephone, on-line or by fax 
within 7 calendar days after being notified of the event. BERG will report all related but 
unexpected SAEs including non-death/non-life-threatening related but unexpected SAEs 
associated with the use trial medications to the appropriate authorities (according to local 


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guidelines), Investigators, and central IRBs/IECs (except in the United States where 
Investigators are responsible for reporting to their IRBs per local requirements) by a written 
safety report within 15 calendar days of notification. 
 
Recording of Adverse Events and Serious Adverse Events 
Investigators should use correct medical terminology/concepts when recording AEs or SAEs on 
the SAE Report Forms and AE CRF. Avoid colloquialisms and abbreviations. 
All AEs, including those that meet SAE reporting criteria, should be recorded on the AE CRF; 
AEs that meet the definition of an SAE should additionally be reported following the procedures 
 
12.5.1 
Diagnosis vs. Signs and Symptoms 
All AEs should be recorded individually in the patient’s own words (verbatim) unless, in the 
opinion of the Investigator or designated physician, the AEs constitute components of a 
recognized condition, disease, or syndrome. In the latter case, the condition, disease, or 
syndrome should be named rather than each individual sign or symptom. If a constellation of 
signs and/or symptoms cannot be medically characterized as a single diagnosis or syndrome at 
the time of reporting, each individual event should be recorded as an AE or SAE as appropriate 
on the relevant form(s) (SAE Report Form and/or AE CRF). If a diagnosis is subsequently 
established, it should be reported as follow-up information is available. If a diagnosis is 
determined subsequent to the reporting of the constellation of symptoms, the signs/symptoms 
should be updated to reflect the diagnosis. 
12.5.2 
Persistent or Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution, between patient evaluation 
time points. Such events should only be recorded once on the SAE Report Form and/or the AE 
CRF. If a persistent AE becomes more severe or lessens in severity, it should be recorded on a 
separate SAE Report Form and/or AE CRF.  
A recurrent AE is one that occurs and resolves between patient evaluation time points and 
subsequently recurs. All recurrent AEs should be recorded on an SAE Report Form and/or AE 
CRF. 
12.5.3 
Abnormal Laboratory Values and Vital Signs 
Any grade 3 or 4 laboratory abnormality or any clinically significant grade 1 or 2 hematology or 
biochemistry laboratory value should be recorded as an AE. If an abnormal laboratory value or 
vital sign is associated with clinical signs and/or symptoms, the sign or symptom should be 
reported as an AE, and the associated laboratory value or vital sign should be considered 
additional information that must be collected on the relevant CRF/ EDC. If the laboratory value 
or vital sign abnormality is a sign of a disease or syndrome, only the diagnosis needs to be 
recorded on the SAE Report Form or AE CRF. 


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12.5.4 
Deaths 
Deaths that occur during the protocol-specified AE reporting period that are attributed by the 
Investigator solely to progression of cancer will be recorded on the “Trial Discontinuation” CRF. 
All other on-trial deaths, regardless of attribution, will be recorded on an SAE Report Form and 
expeditiously reported to the BERG or designee. 
When recording a serious adverse event with an outcome of death, the event or condition that 
caused or contributed to the fatal outcome should be recorded as the single medical concept on 
the SAE Report Form and Adverse Event page of the CRF/EDC system. If the cause of death is 
unknown and cannot be ascertained at the time of reporting, record “Death NOS” on the CRF or 
Adverse Event page of the EDC system. During post-trial survival follow-up, deaths attributed to 
progression of cancer will be recorded only on the “After Progressive Disease Follow-Up” CRF. 
12.5.5 
Hospitalization, Prolonged Hospitalization, or Surgery 
Any AE that results in hospitalization of more than 24 hours or prolonged hospitalization should 
be documented and reported as an SAE unless specifically instructed otherwise in this protocol. 
There are some hospitalization scenarios that do not require reporting as an SAE when there is 
no occurrence of an AE 
 
12.5.6 
Pre-Existing Medical Conditions 
A pre-existing medical condition is one that is present at the start of the trial. Such conditions 
should be recorded on the Medical History CRF. A pre-existing medical condition should be 
recorded as an AE or SAE only if the frequency, severity, or character of the condition worsens 
during the trial. When recording such events on an SAE Report Form and/or AE CRF, it is 
important to convey the concept that the pre-existing condition has changed by including 
applicable descriptors. 
12.5.7 
Pregnancy, Abortion, Birth Defects/Congenital Anomalies 
If a patient becomes pregnant while enrolled in the trial, a Pregnancy Form (a paper report form) 
should be completed and faxed to 
 Pharmacovigilance department or designee. 
The pharmacovigilance department should be notified expeditiously, irrespective of whether or 
not it meets the criteria for expedited reporting. Abortions (spontaneous, accidental, or 
therapeutic) must also be reported to the BERG Clinical Operations or designee. 
Congenital anomalies/birth defects always meet SAE criteria and should therefore be 
expeditiously reported as an SAE, using the previously described process for SAE reporting. A 
Pregnancy Form should also have been previously completed, and will need to be updated to 
reflect the outcome of the pregnancy. 
12.5.8 
New Cancers 
The development of a new primary cancer should be regarded as an AE and will generally meet 
at least one of the serious criteria 
New primary cancers are those that are 
not the primary reason for the administration of the clinical trial treatment and have developed 


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after the inclusion of the patient into the trial. They do not include metastases of the original 
cancer. Symptoms of metastasis or the metastasis itself should not be reported as an AE/SAE as 
they are considered to be disease progression. 
12.5.9 
Lack of Efficacy 
When there is deterioration in the condition for which the clinical trial treatment is being used, 
there may be uncertainty as to whether this is lack of efficacy or an AE. In such cases, unless the 
Sponsor or reporting physician considers the trial treatment contributed to the deterioration of the 
condition, the deterioration should be considered lack of efficacy and not an AE. 
12.5.10 
BPM31510 Overdose 
Symptomatic and non-symptomatic overdose must be reported in the CRF. Any accidental or 
intentional overdose with the trial treatment that is symptomatic, even if not fulfilling a serious 
criterion, is to be reported to 
 Pharma’s Pharmacovigilance department or designee 
immediately (within 1 working day) using the appropriate AE eCRF pages, and following the 
same process described for SAE reporting 
 if the overdose is symptomatic. 
An overdose is defined as any dose that exceeds the dosage or frequency prescribed by the 
protocol. For information on how to manage an overdose of BPM31510, see the Investigator 
Brochure. 
 
Protocol-Defined Events of Special Interest 
Protocol-defined events of special interest related to the safety profile of BPM31510 should be 
reported expeditiously to the Sponsor 
 These events include the following: 
• 
Increased PT/PTT/INR 
• 
Bleeding events 
• 
≥ Grade 3 increased LFTs considered related to BPM31510. 
 
Monitoring Plan 
Site monitoring shall be conducted to ensure the human patient protection, trial procedures, 
laboratory, investigational product administration, and data collection and evaluation processes 
are of high quality and meet Sponsor, GCP/ICH and regulatory guidelines. The Monitoring Plan 
shall define aspects of the monitoring process. 
13 
ETHICAL, FINANCIAL, AND REGULATORY CONSIDERATIONS 
This trial will be conducted in accordance with the International Conference on Harmonization 
(ICH) guideline on Good Clinical Practice (GCP) (E6), Title 21 of the Code of Federal 
Regulations (CFR) parts 50, 54, 56 and 312, applicable government regulations, institutional 
research policies and procedures, and any other applicable local regulatory requirements. 
 
IRB/EC Approval 
The trial protocol, ICF, IB, available safety information, patient documents (e.g., trial diary), 
patient recruitment procedures (e.g., advertisements), information about payments (i.e., PI 


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payments) and compensation available to the patients and documentation evidencing the PI’s 
qualifications should be submitted to the IRB/EC for ethical review and approval if required by 
local regulations, prior to the trial start.  
The PI, BERG and/or designee will follow all necessary regulations to ensure appropriate, initial, 
and ongoing IRB/EC trial review. The PI, BERG or designee (as appropriate) must submit and, 
where necessary, obtain approval from the IRB/EC for all subsequent protocol amendments and 
changes to the informed consent document. Investigators will be advised by BERG or designee 
whether an amendment is considered substantial or non-substantial and whether it requires 
submission for approval or notification only to an IRB/EC. 
Safety updates for BPM31510 will be prepared by the Sponsor or its representative as required 
for submission to the relevant IRB/EC. 
 
Regulatory Approval 
As required by local regulations, BERG will ensure all legal aspects are covered and approval of 
the appropriate regulatory bodies is obtained prior to trial initiation. If required, BERG will also 
ensure that the implementation of substantial amendment to the protocol and other relevant trial 
documents happen only after approval by the relevant regulatory authorities. 
Safety updates for BPM31510 will be prepared by BERG or its representative as required for 
submission to the relevant regulatory authority. 
 
Insurance and Indemnity 
Details of insurance and/or indemnity will be contained within the written agreement between 
the PI or site and BERG. 
 
Informed Consent 
Informed consent is a process by which a patient voluntarily confirms his or her willingness to 
participate in a particular trial, after having been informed of all aspects of the trial that are 
relevant to the patient's decision to participate. Informed consent is documented by means of a 
written, signed and dated informed consent form. 
The informed consent form will be submitted for approval to the IRB/EC that is responsible for 
review and approval of the trial. Each consent form must include all of the relevant elements 
currently required by the FDA, as well as local county authority or state regulations and national 
requirements. 
Before recruitment and enrollment into the trial, each prospective candidate will be given a full 
explanation of the trial. Once the essential information has been provided to the prospective 
candidate and the Investigator is sure that the individual candidate understands the implications 
of participating in this trial, the candidate will be asked to give consent to participate in the trial 
by signing an informed consent form. A notation that written informed consent has been 
obtained will be made in the patient’s medical record. A copy of the informed consent form, to 
include the patient’s signature, will be provided by the Investigator to the patient.  


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If an amendment to the protocol substantially alters the trial design or the potential risks to the 
patients, the patient’s written re-consent to continue participation in the trial should be obtained. 
 
Confidentiality 
13.5.1 
Patient Confidentiality 
Confidentiality of the patient’s personal data will be protected in accordance with the Health 
Insurance Portability and Accountability Act of 1996 (HIPPA), General Data Protection 
Regulations 2018 (GDPR) and country specific national data protection laws, as applicable. 
HIPAA regulations require that, in order to participate in the trial, a patient must sign an 
authorization from the trial that he or she has been informed of the following:  
• 
What protected health information (PHI) will be collected from patients in this trial; 
• 
Who will have access to that information and why; 
• 
Who will use or disclose that information;  
• 
That health information may be further disclosed by the recipients of the information, 
and that if the information is disclosed the information may no longer be protected by 
federal, state or regional privacy laws; 
• 
The information collected about the research trial will be kept separate from the 
patient’s medical records, but the patient will be able to obtain the research records 
after the conclusion of the trial; 
• 
Whether the authorization contains an expiration date; and 
• 
The rights of a research patient to revoke his or her authorization.  
In the event that a patient revokes authorization to collect or use his or her PHI, the Investigator, 
by regulation, retains the ability to use all information collected prior to the revocation of patient 
authorization. For patients that have revoked authorization to collect or use PHI, attempts should 
be made to obtain permission to collect at least vital status (i.e., that the patient is alive) at the 
end of their scheduled trial period. 
In compliance with ICH GCP guidelines and applicable parts of 21 CFR it is a requirement that 
the Investigator and Study Site permit authorized representatives of BERG, the regulatory and 
competent authorities, and the IRB/EC direct access to review the patient’s original medical 
records at the site for verification of trial-related procedures and data. 
Measures to protect confidentiality include:  
• 
Only a unique trial number and initials will identify patients on the CRF or other 
documents submitted to BERG.  
• 
This information, together with the patient’s date of birth, will be used in the database 
for patient identification.  
• 
Patient’s name and address will not be entered in the CRF or database.  
• 
No material bearing a patient’s name will be kept on file by BERG.  
• 
Patients will be informed of their rights within the ICF. 


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13.5.2 
Investigator and Staff Information 
Personal data of the Investigators and sub-Investigators may be included in the BERG database, 
and shall be treated in compliance with all applicable laws and regulations. When archiving or 
processing personal data pertaining to the Investigator or sub-Investigator, BERG shall take all 
appropriate measures to safeguard and prevent access to this data by any unauthorized party. 
 
Financial Information 
BERG is sponsoring this trial. BERG will provide funding and the trial drug BPM31510 for all 
trial participants for the duration of the trial. The physicians participating in this trial will receive 
compensation from BERG, LLC. 
14 
RECORD RETENTION AND DOCUMENTATION OF THE STUDY 
 
Amendments to Protocol 
Amendments to the protocol shall be planned, documented and signature authorized prior to 
implementation.  
If an amendment to the protocol is required, the amendment will be originated and documented 
by BERG. The written amendment must be reviewed and approved by BERG, and submitted to 
the IRB at the Investigator’s facility for the Board’s approval. 
Items requiring a protocol amendment with IRB/EC and/or FDA/CA approval include, but are 
not limited to, the following: 
• 
Change to trial design  
• 
Change in risk to patient 
• 
Increase of the dose or patient exposure to drug  
• 
Patient number increase  
• 
Addition or removal of tests and/or procedures  
• 
Addition/removal of a new Investigator  
The amendment will be submitted formally to the FDA or other Regulatory /Competent 
authorities by BERG after IRB/EC approval and specifically when an increase to dosing or 
patient exposure and/or patient number has been proposed, or when the addition or removal of an 
Investigator is necessitated. 
It should be further noted that, if an amendment to the protocol substantially alters the trial 
design or the potential risks to the patients, the informed consent form must be updated 
accordingly, and their consent to continue participation in the trial should be obtained. 


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Documents at a minimum required to begin a trial include, but are not limited to, the following: 
•
A signature-authorized protocol and contract;
•
A copy of the official IRB/EC approval of the trial and the IRB/EC members list (or
statement of assurance);
•
Current Curricula Vita and Current Medical License/Certifications for the principal
Investigator who will be involved in the trial;
•
Indication of appropriate accreditation for any laboratories to be used in the trial and a
copy of the normal ranges for tests to be performed by that laboratory;
•
Original Form FDA 1572 (Statement of Investigator), appropriately completed and
signed;
•
A copy of the IRB/EC-approved consent form containing permission for audit by
representatives of BERG, the IRB/EC, and regulatory authorities;
•
Financial disclosure forms for all Investigators listed on Form FDA 1572 or
Investigator Agreement;
•
Site qualification reports, where applicable;
•
Verification of Principal Investigator acceptability from local and/or national
debarment list(s).
Trial Documentation and Storage
The PI must maintain a list of appropriately qualified persons to whom he/she has delegated trial 
duties and should ensure that all persons assisting in the conduct of the trial are informed of their 
obligations. All persons authorized to make entries and/or corrections on the CRFs are to be 
included on this document. All entries in the patient’s CRF are to be supported by source 
documentation where appropriate. 
Source documents are the original documents, data, records and certified copies of original 
records of clinical findings, observations and activities from which the patient’s CRF data are 
obtained. These can include, but are not limited to, hospital records, clinical and office charts, 
laboratory, medico-technical department and pharmacy records, diaries, microfiches, ECG 
tracings, copies or transcriptions certified after verification as being accurate and complete, 
photographic negatives, microfilm or magnetic media, X-rays, and correspondence. 


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The PI and research staff are responsible for maintaining a comprehensive and centralized filing 
system (Site Trial File/SSF or ISF) of all trial-related (essential) documentation, suitable for 
inspection at any time by representatives from BERG and/or applicable regulatory authorities. 
The ISF/SSF must consist of those documents that individually or collectively permit evaluation 
of the conduct of the trial and the quality of the data produced. The ISF/SSF should contain at a 
minimum all relevant documents and correspondence as outlined in ICH GCP Section 8 and 21 
CFR Part 312.57, including key documents such as the IB and any amendments, protocol and 
any amendments, signed ICFs, copies of completed CRFs, IRB approval documents, Financial 
Disclosure forms, patient identification lists, enrollment logs, delegation of authority log, staff 
qualification documents, laboratory normal ranges, records relating to the trial drug including 
accountability records. Drug accountability records should, at a minimum, contain information 
regarding receipt, shipment, and disposition. Each form of drug accountability record, at a 
minimum, should contain PI name, date drug shipped/received, date, quantity and batch/code, or 
lot number for identity of each shipment. In addition, all original source documents supporting 
entries in the CRF must be maintained and be readily available. 
BERG shall maintain adequate investigational product records and financial interest records as per 
21CFR Part 54.6 and Part 312.57 for no less than 2 years after the last marketing application has 
been approved by FDA; or, in the event that the marketing application has not been approved by 
FDA, for no less than 2 years after the last shipment/delivery of the drug for investigational use is 
discontinued and FDA has been notified of the discontinuation. The IRB/EC shall maintain 
adequate documentation/ records of IRB/EC activities as per 21CFR Part 56.115 or local/regional 
requirements for at least 3 years after completion of the research. 
The Investigator shall maintain adequate records of drug disposition, case histories and any other 
trial-related records as per 21 CFR Part 312.62 for no less than 2 years after the last marketing 
application has been approved by FDA; or, in the event that the marketing application has not 
been approved by FDA, for no less than 2 years after the last shipment/delivery of the drug for 
investigational use is discontinued and FDA has been notified of the discontinuation. 
To enable evaluations and/or audits from regulatory authorities or from BERG or its 
representative, the Investigator additionally agrees to keep records, including the identity of all 
participating patients (sufficient information to link records e.g., eCRFs and medical records), all 
original, signed informed consent forms, and copies of all eCRFs, SAE Report Forms, source 
documents, detailed records of treatment disposition, and related essential regulatory documents. 
The documents listed above must be retained by the Investigator for as long as needed to comply 
with national and international regulations (generally 2 years after discontinuing clinical 
development or after the last marketing approval). BERG or its representative will notify the 
investigator(s)/Study Site(s) when the trial-related records are no longer required.  
If the Investigator relocates, retires, or for any reason withdraws from the trial, both BERG and 
its representative should be prospectively notified. The trial records must be transferred to an 
acceptable designee, such as another Investigator, another Study Site, or BERG. The Investigator 
must obtain the Sponsor’s written permission before disposing of any records, even if retention 


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requirements have been met. All trial files will be maintained by BERG or its representative 
throughout the trial, and will be transferred to BERG at the conclusion of the trial. 
 
 Quality 
14.4.1 
Source Documents 
Source data/records, are those data elements that represent the first recording of study data. 
Examples of Source documents are 1) patient information used in a clinical trial whether 
collected on paper or electronically at the time of the subject’s visit, 2) certified copies of 
original records, 3) observations, and 4) laboratory data from clinical laboratories. Clinical 
Investigators maintain control over source data from inception and until the end of the regulatory 
retention period. The Investigator must permit access to these data during sponsor monitoring 
visits, audits, IRB reviews and regulatory inspections. Per GDPR requirements in the European 
Union, certain individuals from BERG or their designee, and regulatory organizations may look 
at patient medical and research records to check the accuracy of the research study. BERG will 
only receive information without any identifying information. The people who analyze the 
information will not be able to identify patients and will not be able to find out patient name, 
medical record /insurance numbers or contact information. 
14.4.2 
Electronic Data Capture System 
Personnel at the study site will enter all required clinical trial data into the study Electronic Data 
Capture (EDC) system, a validated 21 CFR Part 11 compliant Internet-based EDC system. Site 
personnel will be expected to enter data in English and manage all changes to the clinical trial 
data, through the EDC system’s change management functionality that is subject to a full audit 
trail.  
Site Investigators and staff will be provided training on the use of the EDC system prior to 
enrollment of the first subject. 
maintains a list of authorized users and grants role-based 
access to the EDC system only after ensuring that site personnel have received system training. 
BERG restricts access to the EDC database only to authorized personnel.  
At the end of the study, the monitor will contact the clinical Investigator or authorized sub-
Investigator and provide him/her the "Principal Investigator's Sign off Form" for eCRFs 
submitted for each subject enrolled.  At the end of the trial, and after all approval forms have 
been signed off by the clinical Investigator and confirmed by the monitor, 
 will provide 
each site with an electronic file containing all eCRF records for all subjects.  
14.4.3 
Data Monitoring Plan (DMP) 
The DMP identifies the monitoring schedule and the rationale for the frequency and type of 
monitoring visits. The DMP also provides details with regard to the use of risk-based monitoring 
and source document verification. If the monitor is not allowed access to any e-source records 
during source document verification, certified printouts provided by sites can be used. In 
addition to on-site monitoring, monitors and/or Data Managers will perform central (i.e., remote) 
monitoring, electronically reviewing data in near real-time. 
Data monitoring procedures will be carried out by Cancer Research And Biostatistics 
 




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be retained by the Investigators as part of the patient’s study file.  
 
Quality Assurance and Quality Control 
In addition to the Clinical Monitoring component of this protocol, BERG shall establish an 
Auditing Plan document separate from the protocol to establish the criteria by which independent 
auditing shall be conducted during the conduct of the trial to assess compliance with GCP and 
applicable regulatory requirements. The Audit Plan may be developed in coordination with 
BERG’s QA, or independently, if so desired by BERG. Data or documentation audited shall be 
assessed for compliance to the protocol, accuracy in relation to source documents and 
compliance to applicable regulations. 
Each trial site shall be required to have Standard Operating Procedures (SOPs) to define and 
ensure quality assurance/control processes for trial conduct, data generation and collection, 
recording of data/documentation and reporting according to the protocol, GCP and any 
applicable local, national or international regulations. 
 
Disclosure and Publication Policy 
All information provided regarding the trial, as well as all information collected/documented 
during the course of the trial, will be regarded as confidential. BERG reserves the right to release 
literature publications based on the results of the trial. Results from the trial will be 
published/presented as per BERG’s publication strategy. 
The financial disclosure information will be provided to BERG prior to trial participation from 
all PIs and sub-Investigators who are involved in the trial and named on the FDA 1572 form. 
BERG will register the trial on www.clinicaltrials.gov. In addition, BERG will publish the 
results of the trial. 
Inclusion of the Investigator in the authorship of any multicenter publication will be based upon 
substantial contribution to the design, analysis, interpretation of data, drafting and/or critically 
revising any manuscript(s) derived from the trial. The Investigator acknowledges that the trial is 
part of a multicenter trial and agrees that any publication by the Investigator of the results of the 
trial conducted at the research site shall not be made before the first multicenter publication. In 
the event there is no multicenter publication within fifteen (15) months after the trial has been 
completed or terminated at all trial sites, and all data has been received, the Investigator shall 
have the right to publish its results from the trial, subject to the notice requirements described 
herein and subject to acknowledgement of BERG as appropriate. Investigator shall provide 
BERG thirty (30) days to review a manuscript or any poster presentation, abstract or other 
written or oral material which describes the results of the trial for the purpose only of 
determining if any confidential or patentable information is disclosed thereby. If BERG requests 
in writing, the Investigator shall withhold any publication or presentation an additional sixty (60) 
days solely to permit BERG to seek patent protection and to remove any BERG Confidential 
Information from all publications. 
Confidentiality Disclosure Agreements (CDAs) shall be executed between BERG and Study 
Sites. The document shall address areas of confidentiality, like patents that may result as part of 


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the trial, but it is intended to address confidentiality of the protocol, the drug, and 
findings/results. 
Clinical Trial Agreement (CTA) shall be executed between BERG and Study Site. The document 
shall address any offers, especially monetary offers, by BERG to the Study Site for 
services/results with acceptance by all involved. 
 


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15 
REFERENCES 
American Cancer Society. Facts & Figures 2015. Atlanta: American Cancer Society. 2015; p 19-
20. 
Assaf E, Verlinde-Carvalho M, Delbaldo C, Grenier J, Sellam Z, Pouessel D, Bouaita L, 
Baumgaertner I, Sobhani I, Tayar C, Paul M, Culine S. 5-Fluorouracil/Leucovorin Combined 
with Irinotecan and Oxaliplatin (FOLFIRINOX) as Second-Line Chemotherapy in Patients with 
Metastatic Pancreatic Adenocarcinoma. Oncology 2011;80:301-306 (DOI: 10.1159/000329803) 
Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, 
Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Von Hoff DD. 
Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients 
with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997 Jun; 15(6):2403-13. 
Chonghaile TN, Sarosiek KA, Vo T-T, Ryan JA et al. Pretreatment mitochondrial priming 
correlates with clinical response to cytotoxic chemotherapy. Science 334: 1129, 2011. 
Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul J-L, 
Gourgou-Bourgade S, de la Fouchardière C, Bennouna J, Bachet J-B, Khemissa-Akouz F, Péré-
Vergé D, Delbaldo C, Assenat E, Chauffert B, Michel P, Montoto-Grillot C, Ducreux M. 
FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 
2011;364:1817-1825 
Davids MS, Letail A. Targeting the B-cell lymphoma/leukemia-2 family in cancer. J Clin Oncol. 
30: 3127, 2012. 
Dragovich T: Pancreatic Cancer. eMedicine.Medscape.Com, 2012. Available from: 
http://emedicine.medscape.com/article/280605. 
Eisenhauer EA, P. Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. (2009). New 
response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J 
Cancer. 45:228-247. 
Gandhi V, Estey E, Du M, et al (1997). Minimum dose of fludarabine for the maximal 
modulation of 1-beta-D-arabinofuranosylcytosine triphosphate in human leukemia blasts during 
therapy. Clin Cancer Res. 3:1539-1545. 
Gandhi V, Estey E, Keating MJ, et al (1993). Fludarabine potentiates metabolism of cytarabine 
in patients with acute myelogenous leukemia during therapy. J Clin Oncol. 11:116-124. 
Heinemann V, Boeck S, Hinke A, Labianca R, Louvet C. Meta-analysis of randomized trials: 
evaluation of benefit from gemcitabine-based combination chemotherapy applied in advance 
pancreatic cancer. BMC Cancer. 2008;28:82. DOI: 10.1186/1471-2407-8-82 
Ji Y, Li Y, Bekele B. (2007a). Dose-finding in phase I clinical trials based on toxicity probability 
intervals. Clin Trials. 4: 235-244. 
Ji Y, Liu P, Li Y, and Bekele BN. (2010) A modified toxicity probability interval method for 
dose-finding trials. Clin Trials. Dec;7(6):653-663. 


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Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 
1958;53:457-481. 
Moore MJ,Goldstein D, Hamm J, et al.: Erlotinib plus gemcitabine compared with gemcitabine 
alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer 
Institute of Canada Clinical Trials Group. J Clin Oncol. 2007;25:1960-1966. 
Narain N, Li J, Russell KJ, et al.Coenzyme Q10 inhibits the proliferation of oncogenic cells 
while stabilizing growth in primary cells in vitro. 2004a. Abstract presented to the Society for 
Investigative Dermatology, Providence, RI (April 28-May 1, 2004). 
Narain NR, Li J, Woan KV, et al. 2004b. Coenzyme Q10 induces apoptosis in human melanoma 
cells. Society for Investigative Dermatology poster (2004). 
Narain NR, Persaud I, Russell KJ, et al. 2006b. Coenzyme Q10: A novel bcl-2 drug target for the 
treatment of melanoma. Abstract presented to AACR, Washington, DC (March 30 to April 5, 
2006). 
Narain NR, Sloan AJ, Pinto L, et al. 2008. Normalization of Bcl-2 family members in breast 
cancer by Coenzyme Q10. Abstract presented to AACR, San Diego, CA (April 12 to 16, 2008). 
Persaud I, Narain NR, Woan KV, et al. 2005. Coenzyme Q10 induces apoptosis in human 
prostate and osteosarcoma cells. AACR poster (2005). 
Persaud I, Lindley L, et al. Induction of p53 by Coenzyme Q10 via modulation of mdm2 and 
p14. AACR poster (2008).  
Persaud I, McCook JP, et al. Apoptotic affect of ubiquinone precursors in melanoma. AACR 
poster (2009). 
Ristow M. (2006). Oxidative metabolism in cancer growth. Curr Opin Clin Nutr Metab Care. 
Jul;9(4):339-45. 
Rosner BA. Fundamentals of Biostatistics.2nd ed. Duxbury Press; 1986. 
Stoddard MJ. (2011) Methods Mol Biol. 740:1-6. 
Yount S, Cella D,  Webster K, Hefferman N, Chang C, Odom L, and van Gool R (2012), 
Assessment of Patient_reported Clinical Outcome in Pancreatic and Other Hepatobiliary 
Cancers: The FACT Hepatobiliary Index. J Pain and Symptom Management. July 1; 24 (1): 
32-44. 
Zhou W, Capello M, Fredolini C, Racanicchi L, Piemonti L, Liotta LA, et al. (2012). 
Proteomic analysis reveals Warburg effect and anomalous metabolism of glutamine in 
pancreatic cancer cells. J Proteome Res. Feb 3;11(2):554-63. Epub 2011 Nov 17. 
 


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16 
APPENDICES 
Appendix A: ECOG Performance Status Criteria 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity. Fully active, able to carry 
on all pre-disease performance without 
restriction. 
100 
Normal, no complaints, no evidence of disease. 
90 
Able to carry on normal activity; minor signs or 
symptoms of disease. 
1 
Symptoms, but ambulatory. 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). 
80 
Normal activity with effort; some signs or 
symptoms of disease. 
70 
Cares for self, unable to carry on normal activity 
or to do active work. 
2 
In bed < 50% of the time. Ambulatory and 
capable of all self-care, but unable to carry 
out any work activities. Up and about more 
than 50% of waking hours. 
60 
Requires occasional assistance, but is able to 
care for most of his/her needs. 
50 
Requires considerable assistance and frequent 
medical care. 
3 
In bed > 50% of the time. Capable of only 
limited self-care, confined to bed or chair 
more than 50% of waking hours. 
40 
Disabled, requires special care and assistance 
30 
Severely disabled, hospitalization indicated. 
Death no imminent. 
4 
100% bedridden. Completely disabled. 
Cannot carry on any self-care. Totally 
confined to bed or chair. 
20 
Very sick, hospitalization indicated. Death not 
imminent. 
10 
Moribund, fatal processes progressing rapidly. 
5 
Dead 
0 
Dead 
 
 


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Appendix B: New York Heart Association (NYHA) Classifications 
Class 
Functional Capacity 
Objective Assessment 
I 
Patients with cardiac disease but without resulting limitations of 
physical activity. Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnea, or anginal pain. 
No objective evidence of 
cardiovascular disease. 
II 
Patients with cardiac disease resulting in slight limitation of physical 
activity. They are comfortable at rest. Ordinary physical activity 
results in fatigue, palpitation, dyspnea, or anginal pain. 
Objective evidence of minimal 
cardiovascular disease. 
III 
Patients with cardiac disease resulting in marked limitation of 
physical activity. They are comfortable at rest. Less than ordinary 
activity causes fatigue, palpitation, dyspnea, or anginal pain. 
Objective evidence of 
moderately severe 
cardiovascular disease. 
IV 
Patients with cardiac disease resulting in inability to carry on any 
physical activity without discomfort. Symptoms of heart failure or 
the anginal syndrome may be present even at rest. If any physical 
activity is undertaken, discomfort is increased. 
Objective evidence of severe 
cardiovascular disease. 
Source: The Criteria Committee of New York Heart Association. Nomenclature and Criteria for Diagnosis of 
Diseases of the Heart and Great Vessels. 9th Ed. Boston, MA: Little, Brown & Co; 1994:253-256. 


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Appendix C: Guidelines Regarding Women of Childbearing Potential 
Women of Child-Bearing Potential are Defined as Follows: 
• 
Any female who has experienced menarche and until becoming post-menopausal 
unless permanently sterile and does not meet the criteria for “Women Not of 
Childbearing Potential”. 
Women Not of Childbearing Potential are Defined as Follows: 
• 
Women who are permanently sterilized (e.g., hysterectomy, bilateral salpingectomy, 
bilateral oophorectomy). 
• 
Women who are >45 years of age, not using hormone replacement therapy, and who 
have experienced total cessation of menses for at least 1 year OR who have a follicle 
stimulating hormone (FSH) value >40 mIU/mL and an estradiol value <40pg/mL (140 
pmol/L) without an alternative medical cause 
• 
Women who are >45 years of age, using hormone replacement therapy and who have 
experienced total cessation of menses for at least 1 year OR who have had documented 
evidence of menopause based on FSH >40 mIU/mL and estradiol <40 pg/mL prior to 
initiation of hormone replacement therapy. 
Acceptable Contraception Methods: 
Male patients with female partners of child-bearing potential and women patients of childbearing 
potential are required to use two forms of acceptable contraception, including one barrier 
method, during their participation in the trial and for 6 months (men and women) following 
discontinuation of BPM31510.  
Sexual abstinence, is defined as refraining from heterosexual intercourse during the entire period 
of risk associated with the study treatment. The choice by the study patient (and their partner) of 
sexual abstinence as their contraceptive method should be evaluated by the investigator in 
relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Ongoing assessment of patient compliance throughout the trial should be made to ensure that 
patients understand the need for contraception. 
Male patients must also refrain from donating sperm for 6 months following discontinuation of 
BPM31510. 
The following are acceptable forms of barrier contraception:  
• 
Latex condom, diaphragm or cervical/vault cap when used with spermicidal 
foam/gel/film/cream/suppository. 
The following are acceptable forms of secondary contraception, when used with a barrier method 
and spermicide:  
• 
True abstinence. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception. 
• 
Male sterilization (with the appropriate post-vasectomy documentation of the absence 
of sperm in the ejaculate).  
• 
Placement of an intrauterine device (IUD) or intrauterine system (IUS), with the 
exception of IUD progesterone T. 


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The following are unacceptable forms of contraception for women of childbearing potential:  
• 
IUD progesterone T  
• 
Female condom  
• 
Natural family planning (rhythm method) or breastfeeding  
• 
Fertility awareness  
• 
Withdrawal  
• 
Cervical shield 
 
 








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Appendix E: RECIST Response Criteria for Solid Tumors 
Evaluation of Target Lesions 
Complete Response (CR):  
Disappearance of all target lesions.  
Partial Response (PR):  
 
At least a 30% decrease in the sum of the longest diameter (LD) of target 
lesions, taking as reference the baseline sum LD. 
Stable Disease (SD):  
 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest (nadir) sum LD since the 
treatment started. 
Progressive Disease (PD):  
 
At least a 20% increase in the sum of the LD of target lesions, taking as 
reference the smallest (nadir) sum since the treatment started, or the 
appearance of one or more new lesions. Requires not only 20% increase, 
but absolute increase of a minimum of 5 mm over sum. 
Evaluation of Non-Target Lesions 
Complete Response (CR): 
Disappearance of all non-target lesions and normalization of tumor 
markers. All lymph nodes must be non-pathological in size (<10 mm short 
axis). 
 Non-CR/Non-PD:   
 
Persistence of one or more non-target lesions and/or persistence of tumor 
marker level above the normal limits. 
Progressive Disease (PD):  
 
Appearance of one or more new lesions and/or unequivocal progression of 
existing non-target lesions. When the patient also has measurable disease, 
to achieve “unequivocal progression” on the basis of the non-target 
disease, there must be an overall level of substantial worsening in non-
target disease such that, even in presence of SD or PR in the target disease, 
the overall tumor burden has increased sufficiently to merit discontinuation 
of therapy. 
Eisenhauer et al Eur J Cancer 45 (2009); 228-247  
 
 


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Appendix
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 


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Appendix G: Hy’s Law Criteria for Concomitant Elevations of Transaminases and 
Bilirubin 
According to the FDA Guidance “Drug-Induced Liver Injury: Premarketing Clinical Evaluation”, 
Hy’s law can be followed when assessing for drug-induced liver injury. Hy’s law is based on the 
work of Hy Zimmerman, a major scholar of drug-induced liver injury. 
Hy’s Law cases have the following 3 components: 
1. The drug causes hepatocellular injury, generally shown by a higher incidence of 3-fold or 
greater elevations above the ULN of ALT or AST than the (nonhepatotoxic) control drug 
or placebo. 
2. Among trial subjects showing such aminotransferase (AT) elevations, often with 
aminotransferases much greater than 3× ULN, one or more also show elevation of serum 
total bilirubin (TBL) to >2 ×ULN, without initial findings of cholestasis (elevated serum 
ALP). 
3. No other reason can be found to explain the combination of increased AT and TBL, such 
as viral hepatitis A, B, or C; preexisting or acute liver disease; or another drug capable of 
causing the observed injury. 
Finding one Hy’s Law case in the clinical trial database is worrisome; finding 2 is considered 
highly predictive that the drug has the potential to cause severe drug-induced liver injury when 
given to a larger population. 
 
 



SAP_001.pdf: 
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Statistical Analysis Plan 
 
 
Full Title of Study 
A Phase 2 Study of Gemcitabine plus BPM31510 
 Nanosuspension Injection Administered 
Intravenously with Gemcitabine as 2nd/3rd line therapy in 
Advanced Pancreatic Cancer Patients 
Protocol Number 
BPM31510IV-05  
Protocol Version 
Amendment 7 dated 25 August 2018 
IND Reference 
Number 
108,093 
Date of Plan 
23SEP2020 
Version  
Final 
Sponsor Name 
Berg LLC 
Sponsor Address 
500 Old Connecticut Path  
Building B 
Framingham, MA 01701 
 
 
 




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                                                                Table of Contents 
Statistical Analysis Plan ................................................................................................................1 
1.0 List of Abbreviations ............................................................................................................5 
2.0 Introduction ...........................................................................................................................6 
3.0 Study Objectives and Endpoints..........................................................................................6 
3.1 
Overview of Study 
6 
3.2 
Study Schedule and Assessments 
6 
4.0 Study Objectives and Endpoints..........................................................................................7 
4.1 
Study Objectives: Primary 
7 
4.2 
Study Objectives: Secondary 
7 
4.3 
Study Objectives: Exploratory 
7 
4.4 
Study Endpoints: Primary Endpoint 
8 
4.5 
Study Endpoints: Secondary Endpoint 
8 
4.6 
Study Endpoints: Exploratory Endpoint 
8 
4.7 
Response 
8 
4.7.1 
Evaluation of Target Lesions 
8 
4.7.2 
Evaluation of Non-Target Lesions 
9 
4.7.3 
Evaluation of Best Overall Response 
9 
5.0 Populations for Analysis .....................................................................................................10 
5.1        Safety Population 
11 
5.2 
Intent to Treat (ITT) 
11 
5.3      Adequately Treated Analysis Set (ATAS) 
11 
6.0      Statistical Methods and Determination of Sample Size.................................................11 
6.1       Determination of Sample Size 
11 
6.2        Statistical Considerations 
12 
6.2.1    Demographic and Baseline Data 
12 
6.2.2    Patient Disposition 
13 
6.2.3    Medical History 
13 
6.2.4    Concomitant and Prior Medications 
13 
6.2.5    Efficacy Analyses 
13 
6.2.5.1 Primary Endpoint - Tumor Response 
13 
6.2.5.2 Time to Event Endpoints 
14 
6.2.6    Safety Analyses 
14 
6.2.6.1 Adverse Events 
15 


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6.2.6.2. Clinical Laboratory Data 
17 
6.2.6.3  Vital Signs and Performance Status 
18 
6.2.7    Evaluation of Exploratory Parameters 
19 
6.2.8   Quality of Life Analyses 
20 
6.2.9   Sensitivity Analyses 
20 
6.2.10 Planned Interim Analyses 
20 
6.3       Drug Exposure 
20 
6.3.1.  Treatment Duration 
21 
6.3.2.   Compliance 
21 
6.3.3.   Dose Modification 
22 
6.3.4.   Dosing Delays during Cycles 2-12 
23 
6.3.5    Dose Interruptions 
23 
6.4 
Data Handling Rules 
23 
6.5 
Changes from protocol-specified analysis 
24 
6.6 
Other Issues and Further Details 
24 
 


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1.0 
List of Abbreviations 
 
Abbreviation 
Full Term 
AE  
adverse event  
ALT (SGPT)  
alanine aminotransferase  
ALP  
alkaline phosphatase  
AST (SGOT)  
aspartate aminotransferase  
ATAS 
adequately treated analysis set 
BPM  
Berg Molecule  
BUN  
blood urea nitrogen  
CA 19-9 
cancer antigen 19-9 
CA 125 
cancer antigen 125 
CEA  
carcinoembryonic antigen  
CR  
complete response  
CRAB  
Cancer Research and Biostatistics  
CRP  
C-reactive protein  
CTCAE  
Common Terminology Criteria for Adverse Events  
ECOG PS  
Eastern Cooperative Oncology Group Performance Status  
FDA  
Food and Drug Administration  
FACT-Hep 
Functional Assessment of Cancer Therapy – HEP 
GGT 
gamma glutamyl transferase 
INR  
International Normalized Ratio  
LLN 
Lower Limit of Normal 
MedDRA  
Medical Dictionary for Regulatory Activities  
NE 
Not evaluated 
ORR 
overall response rate 
OS 
overall survival 
PD  
progressive disease  
PET  
Positron Emission Tomography 
PFS  
progression free survival  
PR  
partial response  
PT 
prothrombin time 
PTT 
partial thromboplastin time 
RECIST  
Response Evaluation Criteria in Solid Tumors (v1.1)  
SAE  
serious adverse event  
SD 
stable disease 
TTP  
time to progression  
ULN 
Upper Limit of Normal 
WBC  
white blood cell  
 
 
 


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2.0 
Introduction 
This Statistical Analysis Plan (SAP) describes the analyses for the study entitled: “A 
Phase 2 Study of Gemcitabine plus BPM31510 
 Nanosuspension 
Injection Administered Intravenously with Gemcitabine as 2nd/3rd line therapy in 
Advanced Pancreatic Cancer Patients.”  
 
The purpose of this document is to ensure that adequate and appropriate statistical 
approaches and data handling conventions for key analyses are performed to determine 
study outcomes.  This plan will focus on the analysis of the primary endpoint, which is 
the assessment of overall response rate in patients treated with BPM31510 or with the 
combination of BPM31510 and Gemcitabine.  Secondary endpoints will also be 
described, including best response, disease control rate, overall survival, progression-free 
survival, time to progression, duration of response, toxicity profiles, quality of life 
(QOL), and change in CA 19-9 levels. The analyses of the primary and secondary 
endpoints will be described, the populations for analysis defined, and all the rules 
specified for “data handling” relevant to undertaking the key analyses will be discussed. 
 
3.0 
Study Objectives and Endpoints 
3.1 
Overview of Study 
This is a Phase 2 multicenter, open-label, non-randomized study to examine the safety 
and effectiveness of the combination of BPM31510 plus Gemcitabine in advanced 
pancreatic cancer patients as 2nd or 3rd line therapy. The primary safety endpoint is to 
determine the safety of BPM31510 as a combination therapy in this patient population. 
The primary efficacy endpoint is overall response rate. This study will occur in two parts.  
Part 1 of the study will enroll ten (10) evaluable patients. If at least one of ten patients 
treated experiences a complete response (CR) or partial response (PR), based on RECIST 
1.1 criteria after 2 cycles of treatment, then Part 2 of the study will enroll an additional 
fifteen (15) for a total of 25 patients.  In the absence of at least one CR or PR, if at least 3 
patients experience stable disease the Sponsor can choose to enroll an additional 15 
patients into the expansion stage. 
 
3.2 
Study Schedule and Assessments 
Study drug will be administered over a maximum of twelve cycles.  
 
 
 
 
 


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  Assessments of the antitumor activity of BPM31510 will be 
performed following the end of Cycle 2 and every two cycles thereafter using standard 
techniques such as computerized tomography (CT) or magnetic resonance imaging (MRI) 
for patients with measurable disease.  An 18-fluorodeoxyglucose (18-FDG) PET scan 
will be performed within 14 days prior to starting treatment, at the end of Week 2 and 
then again at the end of Cycle 2, and then after every additional two cycles of completed 
treatment.  The complete schedule of events can be found in Appendix D of the study 
protocol. 
 
4.0 
Study Objectives and Endpoints 
4.1 
Study Objectives: Primary 
x To evaluate the Overall Response Rate in patients treated with the 
combination of BPM31510 with Gemcitabine. 
4.2 
Study Objectives: Secondary 
x To evaluate Overall Survival 
x To evaluate Progression-Free Survival
 
  
x To evaluate Time to Progression (TTP); 
x To evaluate Tumor Response using Adaptive Molecular Responses (epi-
genomic analysis (SNP or X-omen technology)) 
x To determine the toxicity profile of BPM31510 in combination with 
gemcitabine when administered as a 144-hour (two 72-hr) intravenous (IV) 
infusion in patients with advanced pancreatic cancer. 
x To evaluate change in CA 19-9 levels between baseline and subsequent 
treatment cycles 
x To evaluate changes in patient reported Quality of Life using the validated 
FACT-HEP patient-reported outcomes instrument specific for patients with 
hepatobiliary and pancreatic cancers at the end of Cycle 2 and at End of Study 
or Early Termination 
4.3 
Study Objectives: Exploratory 
x To evaluate the effects of BPM31510 on shifting tumors to aerobic respiration 
by PET imaging. 
x Plasma and urine samples will be assayed for levels of markers of BPM31510 
activity using (but not limited to): genomic (e.g. microarray, SAGE, northern 
blotting, gene expression), proteomic (e.g., LC/MS based analysis, 2DE-MS, 


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MALDI TOF, antibody array, ELISA, immunohistochemistry, tissue 
microarray, flow cytometry, western blotting),metabolomics (e.g., global 
analysis of metabolites in biological samples; identification of specific 
markers of energy metabolism e.g., pyruvate, lactate), lipidomic (e.g., global 
analysis of lipid classes; identification of specific lipids e.g., derivatives of 
palmitate, linoleic acid, arachidonic acid). 
The objective of this integrative approach is to stratify patient populations based 
on phenotypic or molecular profiles for therapeutic benefit. This includes 
assessing the patient’s biofluid as well as the tumor for markers of positive, stable 
or negative outcome allowing for guidance of selection of participants in future 
cohorts. 
4.4 
Study Endpoints: Primary Endpoint 
Overall Response Rate 
4.5 
Study Endpoints: Secondary Endpoint 
x Disease control rate (CR+PR+SD) 
x Duration of response 
x Overall survival 
x Progression-free survival 
x Time to progression 
x FACT-Hep overall score and subscales 
x CA 19-9 level change 
 
Safety: Laboratory results, adverse events, vital signs, concomitant medications,  
concomitant procedures and ECG. 
4.6 
Study Endpoints: Exploratory Endpoint 
Tumor response as measured by 18-FDG PET 
4.7 
Response 
Per RECIST criteria as described in Appendix E of the protocol, determination of 
response is based on evaluation of Target and non-Target lesions for patients with 
measurable disease at baseline.  
4.7.1 Evaluation of Target Lesions 
 
Complete Response (CR) 
Disappearance of all target lesions. Any 
pathological lymph nodes (whether target or 
non-target) must have reduction in short axis to 
<10 mm.  


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Partial Response (PR) 
At least a 30% decrease in the sum of diameters 
of target lesions, taking as reference the baseline 
sum diameters. 
Stable Disease (SD) 
Neither enough shrinkage to qualify for PR nor 
enough increase to qualify for PD, taking as 
reference the smallest sum diameters while on 
study. 
Progressive Disease 
At least a 20% increase in the sum of diameters 
of target lesions, taking as reference the smallest 
sum on study (this includes the baseline sum if 
that is the smallest on study). In addition to the 
relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 
mm. (Note: the appearance of one or more new 
lesions is also considered progression). 
4.7.2 Evaluation of Non-Target Lesions 
 
Complete Response (CR) 
Disappearance of all non-target lesions and 
normalization of tumor marker level. All lymph 
nodes must be non-pathological in size (<10 mm 
short axis).  
 
Non-CR/Non-PD 
Persistence of one or more non-target lesion(s) 
and/or maintenance of tumor marker level above 
the normal limits.  
 
Progressive Disease (PD) 
Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target 
lesions. When the patient also has measurable 
disease, to achieve “unequivocal progression” 
based on the non-target disease, there must be an 
overall level of substantial worsening in non-
target disease such that, even in presence of SD 
or PR in the target disease, the overall tumor 
burden has increased sufficiently to merit 
discontinuation of therapy.  
 
4.7.3 Evaluation of Best Overall Response 
 
 
The best overall response is the best response recorded from the start of the treatment 
until   
disease progression/recurrence (taking as reference for progressive disease the 


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smallest  
 
 
measurements recorded since the treatment started). In general, the 
patient’s best response  
 
assignment will depend on the achievement of both 
measurement and confirmation  
 
 
criteria.  
             
             Per RECIST, confirmation of response (by repeat scans after 4 weeks or as specified 
             in the protocol) is required for this study in which response rate is the primary endpoint. 
             
 
 
 
 
 
 
 
 
 
 
 
 
 
5.0 
Populations for Analysis 
Target Lesions  
Non-Target 
Lesions  
New 
Lesions  
Overall Response  
CR  
CR  
NO  
CR  
CR  
NON-CR/NON-PD  NO  
PR  
CR  
NE  
NO  
PR  
PR  
NON-PD OR NE  
NO  
PR  
SD  
NON-PD OR NE  
NO  
SD  
NOT ALL 
EVALUATED 
NON-PD 
NO 
NE 
PD  
ANY  
YES OR 
NO  
PD  
ANY  
PD  
YES OR 
NO  
PD  
ANY  
ANY  
YES  
PD  


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5.1        Safety Population 
The Safety Population is defined as all patients who are enrolled to treatment and receive 
at least one dose of BPM31510. 
5.2 
Intent to Treat (ITT)  
 
The Intent to Treat (ITT) population will consist of all patients who are enrolled to 
treatment and        may or may not meet inclusion/exclusion criteria. Those subjects not 
having met inclusion/exclusion criteria received a waiver by the study medical monitor. 
 
 
5.3      Adequately Treated Analysis Set (ATAS) 
 
             The Adequately Treated Analysis Set (ATAS) is defined as all patients who meet  
 
 
 inclusion/exclusion criteria, complete at least the first two cycles of therapy with 
a total of  
 
 at least 18 days of drug infusion during Cycle 1 and at least 12 days of 
drug infusion   
 
 during Cycle 2, and have an initial evaluation of response 
following the end of the second  
 
 cycle such that an overall response is considered 
evaluable based on RECIST 1.1 criteria. 
 
6.0      Statistical Methods and Determination of Sample Size 
6.1       Determination of Sample Size 
  
For each treatment arm, Part 1 of the study will enroll until at least ten (10) patients are 
accrued to the adequately treated analysis set (ATAS).  If at least one of the first ten 
patients experiences a Complete Response (CR) or Partial Response (PR) based on 
RECIST 1.1 criteria after 2 cycles of treatment, then Part 2 of the study will enroll an 
additional fifteen (15) patients in that treatment arm, for a total of 25 patients in that arm.  
In the absence of at least one CR or PR, if at least 3 patients experience stable disease in a 
given treatment arm, the Sponsor can choose to enroll the additional 15 patients into that 
arm in the expansion stage.  
 
For each treatment arm, this two-stage design enrolls 10 patients in the first phase and 15 
patients in the second phase, with continuation to the second phase of enrollment if at 
least one response (CR or PR) is observed in the first 10 patients.  
 
 
 
 
 
 
 
 


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6.2        Statistical Considerations  
 
Statistical analyses will be descriptive.  All analyses will be presented by treatment arm 
(BPM31510 or BPM31510 plus Gemcitabine) unless otherwise indicated. If there are 
subjects enrolled on BPM31510 monotherapy, then the data will be analyzed in the tables 
descriptively (ITT Population) but not inferentially. Total frequencies and percentages 
will be presented for categorical variables.  Mean, median, standard deviation, and range 
will be presented for continuous variables, both overall and by treatment arm unless 
otherwise specified.  All analyses will be based on the study populations as defined in 
Section 4.0 unless otherwise indicated.  Exact 95% confidence intervals will be computed 
for selected proportions using the Clopper-Pearson method. 
6.2.1    Demographic and Baseline Data 
Demographics 
Demographic characteristics will be summarized for all analysis populations as defined in 
section 4.0 (Safety population, ITT population, and ATAS).  The total counts and 
percentages of patients will be presented for the categorical variables. The mean, median, 
standard deviation, and range will be presented for continuous variables.  Demographics 
to be summarized include age, sex, race, and ethnicity.  Age in years (defined as the date 
of signed informed consent minus the date of birth divided by 365.25 days truncated to 
the lowest integer) will be summarized as both a continuous variable and categorical 
variable, with grouping done as < 60 years, 60-69 years, and ≥ 70 years. 
Baseline Patient Characteristics   
The Pre-Study visit will occur within 14 days prior to randomization and baseline values 
are collected within the time frame given in the protocol Schedule of Events. Baseline 
values for vital signs and physical examination findings are defined as the last reported 
values prior to first dose of study drug.  
Baseline characteristics will be summarized for all analysis populations as defined in 
section 4.0 (Safety population, ITT population, and ATAS).  Baseline characteristics to 
be summarized include height, weight, ECOG performance status, and the number of 
reported prior pancreatic cancer therapies.   
            Pregnancy test: Positive results will be listed only, along with method (urine or plasma)   
Physical Examination at Baseline: Frequency table of patients with at least one abnormal 
finding.  
The total counts and percentages of patients will be presented for the categorical 
variables. The mean, median, standard deviation, and range will be presented for 
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6.2.2    Patient Disposition 
The numbers and percentages of patients who were enrolled and who are included in the 
safety, ITT, and adequately treated analysis sets will be summarized. The number and 
percentages of patients who discontinued from the study and the reason for 
discontinuation will also be presented.  
The treatment group, date of enrollment, date of first dose, date of last dose, date of 
discontinuation, and reason for discontinuation will be listed for each patient. 
6.2.3    Medical History  
Medical history will be summarized by treatment group using data from the “Baseline 
Abnormalities /Medical History” eCRF page. Medical history is coded with MedDRA 
version 19.0. Medical history will be displayed in terms of frequency tables: ordered by 
primary system organ class (SOC) and preferred term (PT) in decreasing frequency order:  
Medical history will be listed by treatment group and patient number.   
In case of partial or missing end date, medical history will be assumed to be ongoing                           
6.2.4    Concomitant and Prior Medications 
Concomitant medications are defined as all non-study medications, including any herbal 
preparations, indicated as having been taken on or after the patient’s date of informed 
consent and prior to the patient’s date of discontinuation from the study.  Medications 
with partial onset dates that indicate usage starting on or after the date of informed 
consent, including such medications with completely missing stop dates, will be 
classified as concomitant.  Prior medications are defined as all medications classified as 
concomitant and indicated as prior therapies in the CRF. 
 
Prior medications preceding study drug administration will be presented and will be 
summarized for analysis in the ITT population by assigned treatment. Prior and 
concomitant medications will be coded using the World Health Organization (WHO) 
Drug Dictionary as of September 2017. Levels of summarization will include global, 
WHO Anatomic Therapeutic Chemical (ATC) Level II drug class, and WHO generic 
term. At each level of summarization, a patient will be counted only once for each 
concurrent medication he/she has within that level. The percentage of patients having had 
at least one medication at each level will be calculated. 
6.2.5    Efficacy Analyses 
All efficacy analyses will be performed on the adequately treated analysis set (ATAS) 
unless otherwise noted, separately for each treatment arm.  
           6.2.5.1 Primary Endpoint - Tumor Response 
  
Objective responses will be evaluated using RECIST 1.1 as described in Section 
3.6 above. To compute a response rate, the number of patients who achieved a 


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specific level of response will be divided by the number of patients in the 
adequately treated analysis set.  Assessments based on response will include 
objective response rate based on best response (ORR: CR+PR) and response 
frequencies including disease control rate (DCR: CR+PR+SD) at each 
assessment. When a CR or PR is documented, a confirmatory scan will be 
obtained per RECIST guidelines.   
           6.2.5.2 Time to Event Endpoints 
The distribution of time-to-event endpoints will be estimated using the method of 
Kaplan-Meier (Kaplan and Meier, 1957).  The Kaplan-Meier method will be used 
to obtain estimates at every six-month interval after enrollment for which at least 
one patient is still alive for the probabilities of patients surviving. Kaplan-Meier 
curves will be presented, with the median presented along with the associated 
95% confidence interval using the Brookmeyer-Crowley method 
Progression Free Survival 
Progression-free survival (PFS) is defined as the number of days from the first 
dose of study drug to the first documentation of progression or death due to any 
cause. Patients who remain alive without progression will be censored for PFS at 
the date of their last tumor assessment. 
 
Time to Progression  
Time to Progression (TTP) is defined as the number of days from the first dose of 
study drug to the first documentation of progression. Patients without progression 
will be censored at the date of their last tumor assessment. 
 
Overall Survival 
Overall survival is defined as the number of days from the first dose of study drug 
to the date of death due to any cause. Patients alive at the time of analysis will be 
censored at the date of last contact. 
 
Duration of Response 
Duration of response is defined as the number of days from the first observation 
of response to the first observation of progression, or death. For patients who have 
not progressed, duration of response is censored at the time of last follow-up. 
6.2.6    Safety Analyses 
All patients who have received at least one dose of study medication (BPM31510) will be 
considered evaluable for safety. 
Safety assessments will be based on adverse events (AEs) and serious adverse events 
(SAEs), measurement of protocol-specified hematology, measures of coagulation (PT, 


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PTT, and INR), clinical chemistry, and urinalysis variables, measurement of protocol-
specified vital signs, and other protocol-specified tests that are deemed critical to the 
safety evaluation of the trial drug. Selected laboratory measurements will be graded using 
CTCAE criteria.  Adverse Events will be coded using MedDRA 19.0 (or the most current 
version specified by the study safety management plan). Toxicity grading will be defined 
using CTCAE v4.02.  
Safety observations and measurements including study drug exposure, adverse events, 
laboratory data, ECG findings, vital signs, and ECOG performance status will be 
summarized using descriptive statistics. Adverse events and serious adverse events will 
be tabulated by Preferred Term and maximum grade for each type of toxicity within a 
patient.  Laboratory test results will be summarized using values observed at each visit 
and shift from baseline values.  
Selected event types (such as death data and SAE) will be reflected in listings. 
.  
6.2.6.1 Adverse Events  
All AEs and SAEs will be collected and reported in the patient’s eCRF throughout study 
duration (i.e. from the first trial related activity after the subject signs the informed consent 
and until 30 days after last administration of BPM31510). All AEs along with the coded 
terms will be listed. 
Adverse Event (AE): Any untoward medical occurrence or deterioration of a pre-existing 
medical condition in a patient or clinical investigation subject following or during exposure 
to an investigational product. 
Serious Adverse Events (SAE): An adverse event or suspected adverse reaction is 
considered “serious”, if it results in any of the outcomes: Death, a life-threatening adverse 
drug experience, requires at least a 24-hour inpatient hospitalization or prolongation of 
existing hospitalization., a persistent or significant incapacity or substantial disruption of 
the ability to conduct normal life functions, a congenital anomaly/birth defect.  
The following general rules apply to adverse events  
 
TEAEs are defined as those AEs that started on or after the first dose of study 
medication or that worsened after the first dose of study medication and with an onset date 
occurring during the treatment period.  
 
The treatment period is defined from the first dosing day of study treatment 
(minimum of the first dosing day for BPM31510, gemcitabine) until the last dose of study  
treatment. (maximum of the last dosing day BPM31510, gemcitabine) plus 30 days. If an 
AE is reported for a given patient more than once during treatment, the worst severity and 
the worst relationship to study treatment will be tabulated.  
 
In table summaries, patients will be counted only once at the PT level if multiple 
incidences of the same event occur within a SOC.  Patients will be counted only once at 
the SOC level if multiple events occur within that SOC.  For example, a patient who 


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experiences an event of anemia and an event of neutropenia will be counted twice at the 
PT level (anemia, neutropenia) and once at the SOC level (vascular disorders)  
 
Investigator-assessed causality and relationship to study drugs will also be 
presented.  
 
In case a subject had AEs with missing and non-missing grades, the maximum of 
the nonmissing grades will be displayed.  
The start dates for AEs are important for the following:  
1- 
Derivation of TEAE algorithm.  A TEAE is an event that first occurred or worsened 
in severity after baseline.  
2- 
Designation of unique AE occurrences.  
3- 
Completely missing or partially missing AE onset dates will be imputed after due 
diligence to obtain accurate AE information has failed.  The imputation will consider the 
start and stop dates relative to the each other, and relative to the date of consent and date 
of first dose.  
AEs with start dates that are completely or partially missing will be analyzed as follows:  
 
If the event start date is completely missing, then the event is assumed to be 
treatment-emergent.  
 
If the start date has the month and year but day is missing, the event will be 
considered treatment-emergent if the month and year of the event start date are equal 
to, or greater than, the month and year of the date of first dose of study drug.  
 
If the start date has the year, but day and month are missing, the event will be 
considered treatment-emergent if the year of the event start date is to the same as, or 
later than, the year of the date of the first dose of study drug.  
Only TEAEs will be summarized. The incidence of TEAEs will be presented by the number 
and percent of patients who experienced the TEAE by SOC and PT.   
All deaths and deaths occurring during the study (i.e. deaths after start of treatment and 
within 30 days after last dose of study treatment) as recorded in the “End of Study” eCRF 
section will be tabulated by treatment group. In addition, dates will be provided in 
individual patient data listings together with related AE information (PT, verbatim term 
from eCRF, start date of AE, end date of AE, related to BPM31510 (Yes/No), and action 
taken).  
In an overall AE summary table, the Incidence of treatment-related TEAEs will be 
summarized by SOC and PT (in alphabetic order) for patients experiencing at least one:  
 
TEAE  
 
Grade 3 or 4 TEAE  
 
Grade 3 or 4 study-drug related TEAE  
 
Study drug-related TEAE  
 
TEAEs by maximum intensity based on CTCAE grade  
 
SAE  
 
Study drug-related SAE  


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 
TEAE resulting in study drug discontinuation  
 
TEAE with an outcome of death  
 
TEAE of special Interest- Increased PT/PTT/INR, Bleeding events and ≥ Grade 3 
increased LFTs considered related to BPM31510.  
Results will be presented by treatment arm and overall. Adverse events will also be 
summarized using subject incidence rates by treatment group, SOC, and MedDRA 
preferred term. Therefore, in any tabulation, a subject contributes only once to the count 
for a given adverse event (preferred term). Further summaries by preferred term will 
include summaries for treatment related TEAEs, TEAEs with CTC Grade 3 or 4, treatment 
Related TEAEs with CTC Grade 3 or 4, serious TEAEs, treatment Related SAEs, TEAEs 
Occurring in at least 5% of patients in either treatment group, and deaths.  
SAEs will be followed until the event resolves.  
All AEs reported in the eCRF will be listed with the SOC, PT and Investigator’s verbatim 
term. 
Assessing Severity of Adverse Events  
The NCI CTCAE v4.02 will be used to assign the following severity scale to AEs.   
• 
Grade 1 = Mild  
• 
Grade 2 = Moderate  
• 
Grade 3 = Severe  
• 
Grade 4 = Life Threatening  
• 
Grade 5 = Death  
AEs that are not defined in the NCI CTCAE should be evaluated for severity according to 
the following scale:  
• 
Grade 1 = Mild  
• 
Grade 2 = Moderate  
• 
Grade 3 = Severe  
In addition, all AEs reported using the NCI CTCAE classification and graded as 4 or 5 are 
to be considered serious.  
The criteria for assessing severity are different than those used for seriousness.  
Classification of Causality  
Causality is a determination of whether there is a reasonable possibility that the study drug 
may have caused or contributed to an adverse event. 
Not Related: A causal relationship between the study treatment and the AE is not a 
reasonable possibility.  
Related: A causal relationship between the study treatment and the AE is a reasonable 
possibility.  Further the degree of certainty of relatedness is classified as Unlikely, 
Possible, Probable, Definite, Unknown.  
6.2.6.2. Clinical Laboratory Data  
Local laboratories are being used for this clinical study for all the laboratory tests.  For 
each individual laboratory used, laboratory reference ranges and units are collected.  
Reference ranges will be entered into the local laboratory normal range. Vitamin K and 


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advanced coagulation testing (for Grade 2 increases in INR) may be performed through 
local laboratory or through the central laboratory. 
The laboratory collection CRFs (hematology and serum chemistry) include fields for 
additional, nonprotocol-required clinically significant laboratory tests, including 
laboratory test name, result, units, normal range low, and normal range high.    
NCI CTCAE version v4.02 will be used for grading applicable laboratory tests.  
Standard biological assessments will be performed at the local laboratory of the 
Investigator ‘s site at selection, before any BPM31510 administration and at the end of 
each course of chemotherapy as follows:  
• 
Hematology: complete blood count (CBC) with differential, platelets;  
• 
Coagulation: partial thromboplastin time (PTT), prothrombin time (PT), INR 
(Screening only: Vitamin K)  
• 
Serum chemistry: Albumin, alkaline phosphatase, ALT, AST, blood urea nitrogen 
(BUN), calcium, carbon dioxide, chloride, creatinine, gamma-glut amyl transferase (GGT), 
glucose, lactate dehydrogenase, phosphorus, potassium, sodium, total bilirubin, total 
protein, serum magnesium, cholesterol, triglycerides 
• 
Urinalysis: Appearance, color, pH, specific gravity, ketones, protein, glucose, 
bilirubin, nitrite, urobilinogen, and occult blood (microscopic examination of sediment will 
be performed only if the results of the urinalysis dipstick evaluation are positive) 
• 
Laboratory work-up for any ≥ grade 2 INR: LFTs, levels of Vitamin-K 
dependent coagulation factors (II, VII, IX, X), Protein C, and Protein S. If ≥ grade 2 INR 
is not corrected following administration of Vitamin K, cryoprecipitate or fresh frozen 
plasma, additional tests such as mixing studies, fibrinogen level, D-dimer and fibrin split 
products is performed.   
 
For laboratory parameters (i.e., hematology, coagulation, serum chemistry and urinalysis), 
shift analyses will be performed on laboratory abnormalities of the highest NCI CTCAE 
grade or the worst severity if there is no NCI CTCAE grade. Shifts from baseline will be 
classified as improved from baseline, no change from baseline, or worsened from baseline. 
These summaries will be presented by treatment group and overall.   
All laboratory data will be provided in data listings. A subset listing will be presented for 
all clinically significant abnormal laboratory values. This listing will present all lab values 
for any parameter with at least one clinically significant abnormal value so that a time 
course for that lab parameter can be presented.  
6.2.6.3   Vital Signs and Performance Status  
Vital signs parameters, measured in supine position, will include body temperature (°C), 
height (cm, measured only at baseline), weight (kg), heart rate (beats/min), systolic and 
diastolic blood pressures (mmHg) and will be evaluated by treatment group and overall. 
For Vital signs, shift tables from baseline to post-baseline values will be presented by 
treatment groups and overall. And among the three assessments (pre-dose, post infusion 


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and before discharge), for post-baseline results consider before discharge assessment. If 
before discharge is absent then consider post-infusion assessment. 
For ECOG Performance Status, shift tables from baseline to worst post-baseline values 
(normal, abnormal not clinically significant, abnormal clinically significant, missing) will 
be presented by treatment group and overall.  
By-subject listings of all vital sign and ECOG measurements will also be presented in data 
listings.  
 
6.2.7    Evaluation of Exploratory Parameters 
CA 19-9  
Change in CA 19-9 levels will be summarized by shift table to compare levels between 
baseline and subsequent cycles in the adequately treated analysis set.  
 
Pharmacodynamics and Adaptive Molecular Responses 
Blood samples will be collected for PD during BPM31510 treatment. PET scans 
performed will be evaluated for the Warburg effect by BPM31510 in the tumors. Up to 
five (5) core biopsy tissue samples will be collected for pathology and exploratory studies 
in patients who choose to participate. Core biopsies are prohibited with patients who have 
tumors that are highly vascular, located near major blood vessels or are proximal to vital 
organs.  
 
Exploratory PD analyses will be performed on blood and urine samples and biopsy 
samples assayed for markers of BPM31510 activity using (but not limited to) genomic 
(e.g., microarray, SAGE, northern blotting, gene expression), proteomic (e.g., LC/MS 
based analysis, 2DEMS, MALDI TOF, antibody array, ELISA, immunohistochemistry, 
tissue microarray, flow cytometry, western blotting), metabolomics (e.g., global analysis 
of metabolites in biological samples; identification of specific markers of energy 
metabolism e.g., pyruvate, lactate), lipidomic (e.g., global analysis of lipid classes; 
identification of specific lipids e.g., derivatives of palmitate, linoleic acid, arachidonic 
acid).  
 
The exploratory endpoints and subsequent analyses will be defined by molecular 
characteristics of patient populations that demonstrate predictive power in associating a 
profile of response, stable disease, or lack of efficacy to guide clinical decision making 
 
Tumor Response by FDG-PET 
Comparisons between baseline and follow-up PET imaging will be evaluated for 
response as determined by the local investigator and/or changes in SUV in a target lesion 
from baseline.    This will likely be a binary endpoint, with the time point of primary 


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interest being 10 weeks after start of treatment (2 treatment cycles). The primary analysis 
of this exploratory endpoint will be carried out in the adequately treated analysis set. 
6.2.8   Quality of Life Analyses 
 
Quality of Life assessments will be based on the FACT-Hep instrument, which includes 
18 items that assess specific symptoms for hepatobiliary and pancreatic cancers, all rated 
on a 5-point scale ranging from 0 (not at all) to 4 (very much).   Change from baseline to 
10 weeks, and from baseline to end of treatment, will be summarized and analyzed 
descriptively for the overall score as defined by the instrument, and for each of the 
following sub-scores: 
 
PWB - Physical Well-Being subscale 
SWB - Social/Family Well-Being subscale 
EWB - Emotional Well-Being subscale 
FWB - Functional Well-Being subscale 
AC    - Additional Concerns 
 
FACT-Hep Total Score (i.e., PWB+SWB+EWB+FWB+AC) 
6.2.9   Sensitivity Analyses  
 
Sensitivity analyses will be performed for efficacy measures on the ITT population. 
Sensitivity analyses will be performed for safety on the adequately treated analysis set.  
Sensitivity analyses performed will include best response rate, disease control rate, 
overall survival, progression-free survival, time to progression, and summaries of adverse 
events. 
6.2.10 Planned Interim Analyses 
 
No formal interim analysis is planned except for the analysis of response in the first 10 
enrolled patients in each treatment arm as described above in Section 5.1. 
 
6.3       Drug Exposure  
 
Cycle 1 of therapy is 6 weeks in duration for patients with BPM31510 administered twice 
weekly on Tuesdays and Fridays for 6 weeks. Patients will be treated with gemcitabine 
administered on Mondays, Days 21, 28 and 35 during the first treatment cycle.  
Response will be assessed after Cycle 2 (10 weeks) and patients who continue onto 
Cycles 3-12 will be assessed every 2 cycles (8 weeks). Cycles 2-12 are 4 weeks in 
duration with BPM31510 administered twice weekly on Tuesdays and Fridays for 4 
weeks and gemcitabine administered on Mondays, Days 7, 14 and 21 of each treatment 
cycle.  


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For patients receiving an alternate dosing schedule, the gemcitabine chemotherapy 
treatment will be given after the completion of the sixth infusion (three weeks following 
initiation of BPM31510 treatment).  
If the gemcitabine component of combination therapy is discontinued due to 
chemotherapy-related toxicity, patients may continue to receive BPM31510 as 
monotherapy at the investigator’s discretion. 
Analysis of all exposure to study drug will be based on the safety population. Overall 
exposure to study drug, the number of patients completing each cycle, and the dose 
intensity will be summarized using descriptive statistics.  
The dose intensity (for a cycle and overall) will be computed as (total actual dose 
received)/ (total actual dose expected) x 100.  In addition to dose intensity, other 
measures will be presented, as appropriate.  
 
6.3.1.  Treatment Duration 
 
 
Patients who experience no unacceptable toxicity or disease progression while on   
 
 
BPM31510 for 2 cycles of therapy (10 weeks) may receive additional 28-day cycles    
 
 
 
of their current treatment for up to 1 year (12 cycles) or until any of the  
 
 
 
 
discontinuation criteria listed in Section 3.4 are met. 
            Patients who experience disease progression but are, in the opinion of the investigator, 
receiving         clinical benefit may continue BPM31510 as a monotherapy or in combination with 
gemcitabine   
with approval from the Sponsor.   
            Treatment duration in weeks will be defined as: (last injection date – first injection date) / 
7.   
 
6.3.2.   Compliance  
 
For each therapy, overall compliance (%) will be defined as: number of injections 
received/number of injections planned  
Based on the definitions above, the following summary tables will be provided for 
BPM31510 combination with gemcitabine as well as for each therapy separately 
(BPM31510/gemcitabine) unless otherwise noted:  
 Study duration (weeks): summary statistics,   
 Treatment duration (weeks): summary statistics,   
 Total number of cycles with therapy Intake (i.e., number of infusions): summary 
statistics  
(overall by treatment group and broken down by each individual therapy)  
 Compliance: summary statistics and frequency table for the categories <60%, 
60% to <80%, 80% to 100%, >100%.  
   




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6.3.4.   Dosing Delays during Cycles 2-12 
If the criteria for managing toxicity specified in Section 6.3.2 are not met, BPM31510 
treatment may be delayed for a maximum of 2 weeks during Cycles 2-12. The patient 
may resume treatment if treatment is held for less than 2 weeks. No more than 2 weeks 
may be skipped within a cycle. If treatment cannot be given after a 2-week delay, the 
patient will be removed from the study and followed for 30 days from the date of the last 
dose. 
 
6.3.5    Dose Interruptions 
 
Due to Hemodynamic Instability 
If there is hemodynamic instability at any time during the BPM31510 infusion (loading 
dose or ambulatory infusion), the infusion will be stopped. 
The infusion is restarted at ½ the rate.  
 
 
Due to Infusion Pump Malfunction Outside of the Clinic 
The dosing interruption are captured as pump malfunction and delay on the dose eCRF. 
Data regarding the exact amount infused, the duration of any stoppage, and the volume 
remaining in the cassette at the time the infusion was discontinued are recorded in eCRF. 
 
6.4 
Data Handling Rules 
x Conversions from Days to Years, Months or Weeks 
Years = # of days / 365.25 
Months = # of days / 30.4375 (i.e. 365.25/12)  
Weeks = # of days / 7 
Values based on the above computations will be rounded to tenths. 
x Computation of Duration 
Duration for time variables based on two dates, e.g., Start Date and End Date, will be 
calculated as (End Date – Start Date + 1) (in days) unless otherwise specified. 
x Missing normal ranges for laboratory parameters 
When either the lower limit of normal, the upper limit of normal or both are missing 
or are not machine readable, a standardized reference range will be used.  
x Non-Numeric Laboratory Results and Calculation of Normal Ranges 
Laboratory values including symbols (“<” or “>”, for example) will not be used in 
summary analyses.   These values will be reflected in listings of the data. When there 


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are potential conflicts between local lab normal ranges and ranges used in CTC 
grading, CTC normal ranges will be used. 
x Missing outcome data 
For partial dates affecting calculations of clinical outcomes, missing month will be 
imputed with January and missing day will be imputed with 1. Non-ignorable missing 
quality of life data are a common problem in advanced stage disease trials. The 
primary analysis of QOL data will focus on the shorter-term time point of 10 weeks. 
For explorations of later time points, analytic techniques such as pattern mixture 
models will be used in the event of informative missing data for the FACT hep. 
 
6.5 
Changes from protocol-specified analysis 
The definition of the adequately treated analysis set has been modified from the protocol. 
The protocol states that patients withdrawn from treatment for any reason prior to 
completion of 2 cycles will be replaced. The subset of patients to be replaced for the 
adequately treated analysis set has been augmented in this SAP to also include patients 
who fail to receive at least 18 days of BPM31510 infusion during cycle 1, and at least 12 
days of BPM31510 infusion during cycle 2.  Additionally, patients must have an initial 
response assessment at the end of cycle 2.  
6.6 
Other Issues and Further Details 
 
All analyses will be performed using SAS® Version 9.4 or higher.  CRAB will follow its 
SOPs in the creation and quality control of all analysis datasets, tables, figures and 
listings. 


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References 
SAS Institute Inc. (2010).  SAS/STAT® 9.2 User’s guide.  Cary, NC: SAS Institute Inc. 
Clopper, C.; Pearson, E. S. (1934). "The use of confidence or fiducial limits illustrated in the 
case of the binomial." Biometrical 26: 404–413.  
Kaplan, E.L., and Meier P. (1958).  “Nonparametric estimation from incomplete observations.”  
J Am Stat Assoc, 53:457-481. 
 
 


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Appendices 
 
Appendix 1:  Suggested List of Tables and Figures 
 
Section 1.1 
Demographic and Baseline Data 
 
Demographics 
Baseline Characteristics 
Baseline Laboratory Values 
 
Patient Status 
Patient Disposition 
 
Summary of Inclusion/Exclusion  
Reasons for Screen Failure  
 
Section 1.2 
Efficacy Data 
Summary of Primary Efficacy Binary Endpoint 
 
-Overall Response Rate 
-Response by Visit 
 
Summary of Secondary Efficacy Endpoints 
 
-OS (table and figure) 
 
-PFS (table and figure) 
 
-Response Duration (table and figure) 
 
-Time to Progression (table and figure) 
 
-Disease Control Rate 
 
-CA19-9 Summary 
 
 
  
Section 1.3 
Safety Data 
 
 
Overall Summary of Adverse Events 
All Adverse Events by System Organ Class and MedDRA Preferred Term 
Serious Adverse Events by System Organ Class and MedDRA Preferred Term 
Adverse Events that Led to Discontinuation or Delay of Study Drug  
Adverse Events Resulting in Death by System Organ Class and MedDRA Preferred Term 
Adverse Events by System Organ Class, MedDRA Preferred Term, and Relationship 
Adverse Events by System Organ Class, MedDRA Preferred Term, and Maximum Grade 
Summary of Prior Medications by WHO ATC Level 2 Text 
Summary of Prior Medications by WHO Generic Medication Name 
Summary of Concomitant Medications by WHO ATC Level 2 Text 
Summary of Concomitant Medications by WHO Generic Medication Name 
Summary of Medical History by System Organ Class and MedDRA Preferred Term 
 


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Summary of Vitamin K Treatments 
Total Exposure to Study Drug 
Summary of Deaths 
Primary Cause of Death and Relation to Study Drug 
 
Vital Signs and Measurements – Actual and Change from Baseline 
ECG Measurements – Actual and Change from Baseline 
Hematology – Actual and Change from Baseline 
Serum Chemistry – Actual and Change from Baseline 
Hematology Change in Grade Shift Table 
Serum Chemistry Change in Grade Shift Table 
PT, PTT, and INR – Actual and Change from Baseline 
PTT and INR Change in Grade Shift Tables 
Other – Actual and Change from Baseline (CA 19-9/CEA/CA 125, physical exams, urinalysis, etc.) 
Quality of Life – Actual and Change from Baseline Tables for FACT-hep scores 
Summary of Adaptive molecular responses as determined by results 
Listing of FDG-PET evaluation of tumor response: Change from baseline to 10 weeks by patient