Clinical trial NCT04565327
Conditions: Pancreatic Ductal Adenocarcinoma
Keywords: Hyperpolarized 13C Pyruvate Pancreatic Cancer
Sponsor: Zhen Wang, MD
Start date: 2020-08-14; Completion date: 2022-11-01
Enrollment: 7 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This phase II trial investigates whether magnetic resonance imaging (MRI) using hyperpolarized carbon-13 (13C) pyruvate can be useful for evaluating early treatment response in patients with pancreatic cancer that has spread to nearby tissue or lymph nodes (locally advanced) or spread to other places in the body (metastatic). Hyperpolarized 13C pyruvate is different from standard clinical MRI contrast (e.g. gadolinium) in that it provides information on how a tumor processes nutrients. MRI is used to see tumor uptake and breakdown of hyperpolarized carbon-13 pyruvate molecules, which can tell how the tumor processes nutrients. Hyperpolarized 13C pyruvate MRI may help in understanding how the tumor responds to the treatments patients may be receiving.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the signal-to-noise ratio of 13C pyruvate metabolism (peak 13C lactate/pyruvate ratio, 13C lactate/pyruvate area-under-the-curve (AUC) ratio, and apparent rate constant for pyruvate-to-lactate conversion, kPL) in the target tumor (primary tumor and/or abdominal metastases) in Cohort A.

II. To determine the percent changes in the target tumor (primary tumor and/or abdominal metastases) 13C pyruvate metabolism (peak 13C lactate/pyruvate ratio, 13C lactate/pyruvate AUC ratio, and kPL) between pre-treatment scan and scan obtained at 4-week (+/-2 weeks) following treatment initiation in Cohort B.

SECONDARY OBJECTIVES:

I. To determine the repeatability of 13C pyruvate metabolism measures in the target tumor (primary tumor and/or abdominal metastasis) in patients with same-day repeated dose in Cohort A and B.

II. To determine whether the baseline or the changes in the target tumor (primary tumor and/or abdominal metastases) 13C pyruvate metabolism at 4 weeks following treatment initiation are associated with the best objective response as defined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria on subsequent clinical computed tomography (CT) scans in Cohort B.

EXPLORATORY OBJECTIVE:

I. To explore 13C pyruvate metabolism between the primary tumor and abdominal metastases (when present) both at baseline and following treatment in both Cohort A and B.

OUTLINE: Patients are assigned to 1 of 2 cohorts.

COHORT A: Patients receive hyperpolarized carbon C 13 pyruvate intravenously (IV) over less than one minute then undergo MRI over 5 minutes at baseline in the absence of unacceptable toxicity.

COHORT B: Patients receive hyperpolarized carbon C 13 pyruvate IV over less than one minute then undergo MRI over 5 minutes at baseline and 4 weeks after beginning treatment in the absence of unacceptable toxicity.

In both cohorts, patients may receive an optional second hyperpolarized carbon C 13 pyruvate dose and undergo MRI within 15 to 60 minutes following the completion of the first scan.

After completion of study treatment, patients are followed up every 2-3 months

Arms: arm 1: Patients receive hyperpolarized carbon C 13 pyruvate intravenously (IV) over less than one minute then undergo MRI over 5 minutes at baseline arm 2: Patients receive hyperpolarized carbon C 13 pyruvate IV over less than one minute then undergo MRI over 5 minutes at baseline and 4 weeks after beginning treatment
Interventions: intervention 1: Hyperpolarized Carbon C 13 Pyruvate intervention 2: Magnetic Resonance Imaging (MRI)
Intervention descriptions: intervention 1: Given IV prior to imaging intervention 2: Undergo MRI

Protocol documents:
Prot_SAP_000.pdf: 
 
Proprietary and Confidential 
The information in this document is considered privileged and confidential, and may not be disclosed to others except 
to the extent necessary to obtain Institutional Review Board approval and informed consent, or as required by federal 
and state laws.  Persons to whom this information is disclosed should be informed that this information is privileged 
and confidential and that it should not be further disclosed. 
 
Hyperpolarized 13C pyruvate MRI for treatment response 
assessment in pancreatic ductal adenocarcinoma 
Protocol Number: CC# 20925 
Investigational Product:  Hyperpolarized 13C Pyruvate 
Version Number:  1.5 
Version Date: 07/29/2022 
IND Number: 148288 
NCT Number: NCT04565327 
 
Principal Investigator (Sponsor-Investigator) 
Zhen Jane Wang, MD 
University of California San Francisco 
  
 
Telephone:  
 
E-mail: 
  
 
Co-Principal Investigators 
Jeremy Gordon, PhD 
 
 
Daniel Vigneron, PhD 
 
Statistician 
Adam Olshen, PhD 
 
Revision History 
Version 1.0  
10/30/2019  
Version 1.1 
01/10/2020 
Version 1.2 
03/31/2020 
Version 1.3 
07/01/2020 
Version 1.4 
01/25/2022 
Version 1.5 
07/29/2022 
 
 
 


 
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Protocol Signature Page 
Protocol No.: CC# 20925 
 
 
I agree to follow this protocol version as approved by the UCSF Protocol Review Committee 
(PRC), Institutional Review Board (IRB), and Data and Safety Monitoring Committee 
(DSMC).  
I will conduct the study in accordance with Good Clinical Practices (ICH-GCP) and the 
applicable IRB, ethical, federal, state, and local regulatory requirements.  
I certify that I, and the study staff, have received the required training to conduct this 
research protocol.  
I agree to maintain adequate and accurate records in accordance with IRB policies, federal, 
state and local laws and regulations. 
 
UCSF Principal Investigator  
 
 
Printed Name 
 
 
Signature 
 
Date 
 


 
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Abstract 
Title 
Hyperpolarized 13C pyruvate metabolic MRI for treatment response assessment in 
pancreatic ductal adenocarcinoma 
Study 
Description 
This is a pilot prospective study to investigate the utility of HP 13C pyruvate MRI for 
assessing tumor metabolism and monitoring early treatment response in patients 
with locally advanced or metastatic PDA. 
Phase of Study 
Pilot 
Investigational 
Product 
HP 13C pyruvate injection 
Study 
Population 
Patients with locally advanced or metastatic pancreatic ductal adenocarcinoma 
(PDA) will be enrolled in parallel in one of two cohorts: 
Cohort A (N=20): Patients who are already on therapy will undergo hyperpolarized 
(HP) 13C pyruvate MRI at a single time-point.  
Cohort B (N=20): Patients will undergo HP 13C pyruvate MRI at baseline prior to 
the initiation of a new line of therapy (standard-of-care first- or second-line systemic 
therapies, radiotherapy, or therapies as part of a clinical trial), and again at 4 weeks 
(+/- 2 weeks) following treatment initiation. 
Primary 
Objective 
Cohort A: To determine the signal-to-noise ratio of 13C pyruvate metabolism 
measures (peak 13C lactate/pyruvate ratio, 13C lactate/pyruvate area-under-the-
curve (AUC) ratio, and apparent rate constant for pyruvate-to-lactate conversion, 
kPL) in the target tumor (primary tumor and/or abdominal metastases). 
 
Cohort B: To determine the percent changes in the target tumor (primary tumor 
and/or abdominal metastases) 13C pyruvate metabolism measures (peak 13C 
lactate/pyruvate ratio, 13C lactate/pyruvate AUC ratio, and kPL) between pre-
treatment scan and scan obtained at 4-week (+/- 2 weeks) following treatment 
initiation. 
Secondary 
Objectives 
Cohort A and B: To determine the repeatability of 13C pyruvate metabolism 
measures in the target tumor (primary tumor and/or abdominal metastasis) in 
patients with same-day repeated dose.  
 
Cohort B: To determine whether the baseline or the changes in the target tumor 
(primary tumor and/or abdominal metastases) 13C pyruvate metabolism measures 
at 4 weeks (+/-2 weeks) following treatment initiation are associated with the best 
objective response as defined by RECIST criteria on subsequent clinical CT scans. 
Exploratory 
Objective 
Cohort A and B: To explore 13C pyruvate metabolism between the primary tumor 
and abdominal metastases (when present) both at baseline and following 
treatment. 
Sample Size 
40 patients will be enrolled- 20 patients in Cohort A, and 20 patients in Cohort B. 
Duration of 
study 
The study is estimated to reach completion approximately 36 months from first 
patient is enrolled.  
 


 
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List of Abbreviations 
AE 
adverse event 
BUN 
blood urea nitrogen 
CBC 
complete blood cell (count) 
CNS 
central nervous system 
CR 
complete response 
CRF 
case report form 
CT 
computerized tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTMS 
Clinical Trial Management System 
DFS 
disease-free survival 
DLT 
dose limiting toxicity 
DSMC 
Data and Safety Monitoring Committee 
DSMP 
Data and Safety Monitoring Plan 
ECG/EKG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
FDA 
Food and Drug Administration 
FDG 
Fluorodeoxyglucose 
FLC 
free light chain 
GCP 
Good Clinical Practice 
GFR 
glomerular filtration rate 
HDFCCC 
Helen Diller Family Comprehensive Cancer Center 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IDS 
Investigational Drug Services (UCSF) 
IND 
investigational new drug application 
IP 
investigational product 
IRB 
Institutional Review Board 
IV 
intravenous 
LDH 
lactate dehydrogenase 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NCI 
National Cancer Institute 
ORR 
overall response rate 
PD 
disease progression 


 
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List of Abbreviations 
PK 
pharmacokinetics 
PO 
Per os (by mouth, orally) 
PR 
partial response 
PRC 
Protocol Review Committee (UCSF) 
SD 
stable disease 
 
 


 
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Table of Contents 
Protocol Signature Page ......................................................................................................... 2 
Abstract 3 
List of Abbreviations ................................................................................................................ 4 
Table of Contents .................................................................................................................... 6 
1 
Introduction ...................................................................................................................... 8 
1.1 Experience of 13C pyruvate injection in humans ............................................ 8 
1.1.1 UCSF Phase I experience of hyperpolarized 13C pyruvate in prostate 
cancer patients .............................................................................................. 9 
1.2 Safety of repeated HP 13C pyruvate injections ............................................. 10 
1.3 Rationale for use of HP 13C Pyruvate in patients with pancreatic cancer .... 10 
2 
Study Objectives ............................................................................................................ 13 
2.1 Hypothesis ................................................................................................... 13 
2.2 Primary Objective and Endpoints ................................................................ 13 
2.3 Secondary Objectives and Endpoints .......................................................... 14 
2.4 Exploratory Objective and Endpoints ........................................................... 14 
2.5 Imaging Endpoints ....................................................................................... 14 
3 
Study Design .................................................................................................................. 14 
3.1 Characteristics ............................................................................................. 14 
3.2 Sample Size ................................................................................................ 15 
3.3 Replacement Policy ..................................................................................... 15 
3.4 Eligibility Criteria .......................................................................................... 15 
3.4.1 Inclusion Criteria ............................................................................... 15 
3.4.2 Exclusion Criteria.............................................................................. 15 
3.5 Inclusion and Recruitment of Women and Minorities ................................... 16 
3.6 Study Timeline ............................................................................................. 16 
3.6.1 Primary Completion .......................................................................... 16 
3.7 Study Completion ........................................................................................ 16 
3.7.1 Study Termination ............................................................................ 16 
4 
Investigational Medicinal Product ................................................................................... 16 
4.1 Description, Supply and Storage of Investigational Medicinal Product ........ 16 
4.1.1 Hyperpolarized 13C Pyruvate ............................................................ 16 
4.2 Drug Accountability ...................................................................................... 19 
4.3 Drug Ordering .............................................................................................. 19 
5 
Treatment Plan ............................................................................................................... 19 
5.1 Early Stopping Rules for Safety ................................................................... 19 
6 
Study Procedures and Observations .............................................................................. 19 
6.1 Study Calendar ............................................................................................ 20 
6.2 Participant Registration ................................................................................ 21 
6.3 Schedule of Procedures and Assessments ................................................. 21 
6.3.1 Pretreatment Period ......................................................................... 21 
6.3.2 Treatment Period .............................................................................. 21 


 
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6.4 Supportive Care ........................................................................................... 24 
7 
Reporting and Documentation of Results ....................................................................... 24 
7.1 Evaluation of Efficacy (or Activity) ............................................................... 24 
7.2 Evaluation of Safety ..................................................................................... 24 
7.3 Definitions of Adverse Events ...................................................................... 25 
7.3.1 Adverse Event .................................................................................. 25 
7.3.2 Adverse reaction............................................................................... 25 
7.4 Recording of an Adverse Event ................................................................... 26 
7.5 Follow-up of Adverse Events ....................................................................... 26 
7.6 Adverse Events Monitoring .......................................................................... 26 
7.7 Expedited Reporting .................................................................................... 26 
8 
Statistical Considerations and Evaluation of Results ...................................................... 27 
8.1 Sample Size Considerations ........................................................................ 27 
8.1.1 Sample Size and Power Estimate .................................................... 27 
8.1.2 Accrual Estimates ............................................................................. 28 
8.2 Imaging Analysis ......................................................................................... 28 
8.3 Analysis Plans ............................................................................................. 28 
8.3.1 Analysis Population .......................................................................... 28 
8.3.2 Primary Analysis ............................................................................... 28 
8.3.3 Secondary Analysis .......................................................................... 29 
8.3.4 Exploratory Analysis ......................................................................... 29 
9 
Study Management ........................................................................................................ 29 
9.1 Pre-study Documentation ............................................................................ 29 
9.2 Institutional Review Board Approval ............................................................ 30 
9.3 Informed Consent ........................................................................................ 30 
9.4 Changes in the Protocol .............................................................................. 30 
9.5 Handling and Documentation of Clinical Supplies ....................................... 30 
9.6 Case Report Forms (CRFs) ......................................................................... 31 
9.7 Oversight and Monitoring Plan .................................................................... 31 
9.8 Record Keeping and Record Retention ....................................................... 31 
10 References ..................................................................................................................... 33 
Appendix 1 Performance Status Criteria ................................................................................ 36 
Appendix 2 
Dosing Table ................................................................................................ 37 
Appendix 3 
Safety Data Sheets ....................................................................................... 38 
Appendix 4 
Data and Safety Monitoring Plan for a Phase II Institutional Study ............... 41 
Appendix 5 
GE SPINLabTM Hyperpolarizer and Sterile Fluid Path ................................... 44 
 


 
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1 Introduction 
1.1 
Experience of 13C pyruvate injection in humans 
As a first step in evaluating the use of 13C pyruvate injection in humans, a phase 1, placebo- 
controlled study was conducted to evaluate the safety of ascending doses in healthy volunteers 
between 18 and 45 years of age.  As no imaging was performed in this study, pyruvate injection 
produced using [1-natC] pyruvate was used.  This study was completed in December 2007 
(Investigators’ Brochure).  In the original protocol, it was planned that doses up to 0.71 ml/kg 
body weight (bw) would be given, providing there was no evidence of significant investigational 
medicinal product (IMP)-related adverse events (AEs) at lower dose levels. 
In each cohort of 6 subjects, 4 subjects received 13C pyruvate injection and 2 received saline. 
Doses up to 0.43 ml/kg bw were well tolerated and no IMP-related AEs were observed that 
warranted un-blinding the study to reveal which subjects had received pyruvate Injection versus 
placebo.  However, in the 0.57 ml/kg bw cohort, 2 of 6 subjects showed IMP-related non-serious 
AEs (“unresponsiveness‟ 
 and “flushing‟ accompanied by changes in blood 
pressure and heart rate 
) that the principal investigator considered to be 
concerning and related to the administration of IMP.  The study was un-blinded for this cohort 
and it was ascertained that the events of concern occurred in subjects who had received 
pyruvate injection. 
The event described as “unresponsiveness” was NOT unresponsiveness as it is 
generally defined.  Instead, the patient remained conscious with stable vital signs but did 
not answer a question immediately when asked (it took seconds longer than expected).  
The “flushing” event, accompanied by changes in systolic and diastolic blood pressure and 
heart rate, was thought to be indicative of a “baroreflex/hemodynamic” response.  All events in 
 resolved spontaneously without any treatment or intervention.  The events were 
reviewed by medically qualified sponsor representatives and it was decided not to proceed with 
the next planned dose level of 0.71 ml/kg.  The protocol was amended to repeat the 0.43 ml/kg 
dose, to confirm that it was as well tolerated in a second cohort of 6 healthy volunteers as it was 
in the first cohort.  The introduction of additional safety monitoring was considered, but none 
was found to be relevant or necessary as comprehensive and intense safety monitoring was 
already being applied.  Data from the second 0.43 ml/kg dose group confirmed that this dose 
was well tolerated. 
No serious adverse events (SAEs) occurred in the study, and all other non-serious AEs that 
occurred in any subject throughout the study were mild in intensity, short-lasting, and resolved 
spontaneously without any treatment or intervention.  Throughout the study, data on serum 
biochemistry variables and post-dosing changes were unremarkable, and no notable changes in 
vital signs, hematology, urinalysis, electrocardiogram (EKG) variables or other safety variables 
were registered. 
A similar, phase 1, placebo-controlled study with doses up to 0.43 ml/kg 13C pyruvate Injection 
was conducted in elderly (60 years of age) volunteers.  All doses up to 0.43 ml/kg bw were very 
well tolerated and no significant or serious AEs were reported.  All the non-serious AEs that 
occurred were mild in intensity, short-lasting and resolved spontaneously without treatment or 
intervention. No true “unresponsiveness”, unresponsiveness as defined in the prior study, 
flushing, or other events of concern occurred.  Throughout the study, data on serum 
biochemistry variables and post-dosing changes were unremarkable, and no notable changes in 
vital signs, hematology, EKG variables or other safety variables were registered. 


 
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1.1.1 UCSF Phase I experience of hyperpolarized 13C pyruvate in prostate cancer 
patients 
On the basis that doses of pyruvate injection up to 0.43 ml/kg bw were shown to be safe and 
well tolerated in young healthy volunteers and elderly volunteers, a phase I dose escalation 
study was undertaken at UCSF in men with localized prostate cancer who were on active 
surveillance or were pre-local therapy (IND # 109956). In this study, three dose levels of HP 13C 
pyruvate injection, 0.14 ml/kg bw, 0.28 mg/kg bw, and 0.43 ml/kg bw were evaluated.  Thirty-
one patients (
) underwent successful injection and 
imaging. Dose limiting toxicity was defined as any grade 2 or higher toxicity (excluding 
asymptomatic lab abnormalities).  Dose limiting toxicity is usually defined as grade 3 toxicity.  
However, given this is an imaging agent rather than a therapeutic agent, the threshold was set 
lower in this study.  There were no dose-limiting toxicities or toxicities deemed to be clinically 
significant.  All possibly, probably, or definitely related toxicities are listed in the table below: 
Possibly, probably, or definitely related toxicities: Phase I Study at UCSF 
Dose level  
n 
Toxicity 
Grade 
1 (0.14 mL/kg)  
6 
Orange urine 
1 
Pharmaceutical smell 
1 
Pruritus 
1 
2 (0.28 mL/kg) 
6 
Cold sensation with injection 
1 
Dysgeusia 
1 
3 (0.43 mL/kg) 
19 
Dizziness 
1 
Dysgeusia (4) 
1 
Fatigue 
1 
Hypocalcemia 
1 
Hypokalemia 
1 
Hypotension 
1 
Nausea 
1 
Pain - headache 
1 
Smell change (2)  
1 
Sore throat  
1 
Diarrhea 
2 
The one episode of grade 2 diarrhea was thought to be more likely related to the enema 
required prior to the endorectal coil placement for the MR, but its relationship to the pyruvate 
injection could not be ruled out.  The hypotension and dizziness occurred one day after the 
pyruvate injection 
 
, it was 
thought unlikely to be related, but a relationship to pyruvate injection could not definitively be 
ruled out.  


 
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The maximum administered dosage 0.43 mL/kg was established as the phase 2 dosage.  
Higher doses were not evaluated for three reasons: 1) the volume required to administer a 
higher dose would lengthen the time from the start of injection until when the imaging could be 
initiated, affecting the polarization, 2) the imaging at a dosage of 0.43 mL/kg was of sufficient 
quality to indicate that a higher dosage is not needed, 3) the aforementioned study raised 
concern for toxicity at higher doses (although this is questionable based on the original data).  
Intensive monitoring was performed during the UCSF phase I study, including continuous lead II 
EKG during and for ten minutes following the injection, serial EKGs for two hours following the 
injection, laboratory and clinical monitoring for two hours following the injection, and follow-up 
both one and seven days following the injection.  This monitoring did not yield any safety 
concerns. 
Since the initial UCSF Phase I study, multiple other human studies with hyperpolarized 13C 
pyruvate MRI in patients with various diseases as well as in normal healthy volunteers have 
been conducted(1-5), none have reported any safety concerns. 
1.2 
Safety of repeated HP 13C pyruvate injections 
There is ample evidence from pre-clinical studies and from the known short half-life of pyruvate 
metabolism to support the safety and feasibility of this approach. Specifically, hundreds of 
IUCAC approved pre-clinical 13C MRI studies (mice, rats and canines) at UCSF have used 
multiple injections of hyperpolarized [1-13C]pyruvate within the same imaging study without 
evidence of adverse events. The SPINlab DNP polarizer, used in patient studies, allows for up 
to 4 samples to be polarized and dissolved in rapid succession. We have shown in a rat model 
that minimal perturbations occurred in pyruvate metabolism as a result of 4 injections of 
hyperpolarized [1-13C]pyruvate injected in 5 minute intervals (6). Moreover, two injections of 
hyperpolarized [1-13C]pyruvate have already been approved and performed in over 20 human 
studies at UCSF (CHR#13-12719, CHR 17-24246). These studies have demonstrated the 
safety of serial injections without any adverse effects noted. 
1.3 
Rationale for use of HP 13C Pyruvate in patients with pancreatic cancer 
Need for rapid response monitoring in PDA: Pancreatic ductal adenocarcinoma (PDA) is the 3rd 
leading cause of cancer related death in the US and is anticipated to become the 2nd by 
2030(7). The majority of PDA patients (> 75%) present with locally advanced or metastatic 
disease for which systemic chemotherapy is the only life-prolonging treatment (8). The length of 
time these patients spend on effective therapy is the most important factor in their survival. 
Therefore, there is an urgent need for biomarkers to accurately assess treatment response, and 
to do so early so that patients can be spared the significant toxicities of ongoing ineffective 
treatment and can instead be offered alternative treatment (i.e. combination chemotherapy of a 
differing backbone from that administered in the first line) with a better chance of efficacy. 
Additionally, we need alternative endpoints for clinical trials other than overall survival, which is 
often complex in PDA and is often a function of treatment efficacy coupled with performance 
status and other factors. Given the deadliness of this disease, we need to rapidly determine 
response in order to inform decision of whether to continue an effective treatment or discontinue 
an ineffective one (9).   
Limitations of current response assessment tools in PDA: Objective treatment response in PDA 
is commonly assessed by measuring changes in tumor size at anatomic imaging according to 
RECIST (Response Evaluation Criteria in Solid Tumors) criteria several months into treatment. 
However, a change in tumor size is a relatively late endpoint in PDA. In addition, monitoring 
response to therapy in the primary tumor is particularly challenging because of the extensive 


 
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desmoplasia and inflammation associated with the tumor and the difficulty in defining tumor 
margin (10). As a result, many patients’ functional status declines while we wait to determine 
whether or not the treatment is working at imaging read-out points (typically 8-12 weeks apart 
following treatment initiation). Many of these patients progress after months of ineffective 
therapy and are no longer suitable for second line therapy nor eligible for second line trials, 
resulting in worse survival.  
CA19-9 is a widely used serum marker in PDA, but also has limitations. It requires the presence 
of the Lewis blood group antigen (a glycosyl transferase) to be expressed, and about 10%-25% 
of PDA patients have tumors that do not express CA19-9 (11, 12). Additionally, while CA19-9 
response over months correlates well with overall survival (13), due to its long half-life, it is not a 
useful early predictor of response to therapy. In fact, CA19-9 at times can initially INCREASE in 
patients who will ultimately respond (14). Therefore, while CA19-9 is a useful long-term read-out 
of response, it is worthless in patients who do not express it, and is not a reliable early predictor 
of response in those who do. 
HP 13C pyruvate MRI: Hyperpolarized (HP) 13C MRI is an emerging molecular imaging method 
that allows rapid, noninvasive, pathway-specific investigation of dynamic metabolic processes 
that were previously inaccessible by imaging. Hyperpolarization, achieved through the dynamic 
nuclear polarization (DNP) technique(15), provides unprecedented gains in sensitivity (> 
10,000-fold signal increase) for imaging 13C-labeled bio-molecules that are endogenous, 
nontoxic, and nonradioactive. HP 13C pyruvate is the most widely used and a highly biologically 
relevant probe, as pyruvate lies at a critical branch point of multiple metabolic pathways, 
including glycolysis, tricarboxylic acid (TCA) cycle, and amino acid biosynthesis. HP 13C 
pyruvate MRI has already shown considerable promise in tumor grading (32) and response 
assessment in numerous preclinical studies(16-27). For example, decreased HP 13C pyruvate to 
lactate conversion was observed by 24 hours after the initiation of cytotoxic chemotherapy in a 
lymphoma model(16). In a Myc oncogene driven liver cancer model, increased HP 13C pyruvate 
conversion to lactate and alanine was observed to precede tumor formation, and there was a 
dramatic reversal of pyruvate to lactate conversion during early tumor regression before any 
size change(26).  
Notably, while 18-fluoro-deoxyglucose (FDG) PET, which assesses tissue glucose uptake, has 
shown great value in oncological imaging, HP 13C pyruvate MRI has several unique advantages 
including its ability to directly interrogate downstream metabolism that is not accessible by FDG 
PET(21, 28-30). For example, while prostate cancer has similar FDG avidity to the normal 
prostate(31), a grade-dependent increase in HP 13C pyruvate to lactate conversion has been 
observed in a mouse prostate cancer model as well in patient-derived prostate cancer 
tissues(28, 32), and a marked drop in HP 13C pyruvate to lactate conversion occurs following 
successful treatment(4) (Fig 1). As such, HP 13C pyruvate MRI can provide distinct and 
complementary information in tumor metabolism and response to therapy. 


 
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Fig 1. Multi-parametric MRI in a 52-yr-
old prostate cancer patient with 
extensive high-grade (Gleason 4+5) 
prostate cancer (A) before therapy and 
(B) 6 week after initiation of androgen 
ablation and chemotherapy. Before 
treatment, the region of prostate 
cancer can be seen (arrows) as low 
signal on the T2-weighted and ADC 
images, and high kPL. At 6 weeks after 
initiation 
of 
androgen 
deprivation 
therapy, there was near complete 
abrogation of elevated HP lactate 
peaks as seen on the spectral array  
and marked reduction in tumor kPL (kPL max 0.025 s-1 at baseline and 0.007 s-1 on follow-up). Notably, there 
was negligible change in size of tumor on T2-weighted MRI and only a modest change on ADC images, 
supporting the utility of HP 13C pyruvate MRI to detect early metabolic responses prior to changes on 
conventional images. Concordant with these findings, the patient subsequently achieved a marked clinical 
response, with an undetectable serum prostate specific antigen (PSA) nadir at 6 months after treatment 
initiation. 
 
In the context of PDA, mutations in the KRAS gene (occurring in 90% of PDA) play an important 
role in metabolic reprogramming(33). In particular, oncogenic KRAS drives glycolytic activity in 
PDA, with increased expression of several glycolytic enzymes including LDH-A, and elevated 
levels of glycolysis-associated metabolites including lactate. In transgenic mouse models, HP 
13C pyruvate MRI has been shown to detect and monitor the progression from pancreatic 
intraepithelial neoplasia (PanIN) precursor lesions to PDA, with an increase in 13C 
lactate/alanine ratio with disease progression(34). Another study in patient-derived mouse 
xenograft of PDA has demonstrated the ability of HP 13C pyruvate MRI to noninvasively monitor 
response/resistance to metabolic therapy before tumor size changes (35). A new clinical report 
has shown the feasibility of acquiring HP 13C pyruvate MRI in PDA patients, with increased 13C 
lactate/alanine ratio in the primary PDA compared to adjacent pancreas (36). We have also 
shown the feasibility of HP 13C pyruvate MRI of liver metastases in patients with PDA (Fig. 2). 
The images were acquired using a novel dynamic, metabolite-specific imaging approach that 
allows for volumetric imaging, and showed a marked increase in the pyruvate to lactate 
conversion in the liver metastases.  Taken together, these findings provide strong rationales 
supporting the clinical evaluation of this metabolic imaging technology to assess early treatment 
response/resistance in patients with PDA.  
 
 
Fig 2. Quantitative maps of the 
pyruvate to lactate conversion rate, 
kPL, in liver metastases from PDA 
(overlaid on T2 weighted anatomic 
images). Dynamic images of pyruvate 
and lactate are fit to a kinetic model to 
extract the first order rate constant 
(kPL) that characterizes the conversion 
of pyruvate to lactate, which is elevated 
in the liver metastases (arrows) in a 
patient with PDA, reflecting high LDH 
activity. 


 
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2 
Study Objectives 
2.1 
Hypothesis 
Our over-arching hypothesis is that early metabolic changes in PDA visualized on 
HP 13C pyruvate MRI are predictive of treatment response/resistance. 
2.2 
Primary Objective and Endpoints 
Primary Objective 
Endpoint(s) 
Time Frame 
1. To determine the signal-to-noise ratio of 13C 
pyruvate metabolism (peak 13C lactate/pyruvate 
ratio, 13C lactate/pyruvate area-under-the-curve 
(AUC) ratio, and apparent rate constant for 
pyruvate-to-lactate conversion, kPL) in the target 
tumor (primary tumor and/or abdominal 
metastases) in Cohort A. 
• 
signal-to-
noise ratio 
of 13C 
pyruvate 
metabolism 
From study 
initiation to 
enrollment of last 
subject  
2. To determine the percent changes in the target 
tumor (primary tumor and/or abdominal 
metastases) 13C pyruvate metabolism (peak 13C 
lactate/pyruvate ratio, 13C lactate/pyruvate AUC 
ratio, and kPL) between pre-treatment scan and 
scan obtained at 4-week (+/-2 weeks) following 
treatment initiation in Cohort B. 
• 
percent 
changes in 
the target 
tumor 13C 
pyruvate 
metabolism 
 From study 
initiation to 
enrollment of last 
subject  


 
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2.3 
Secondary Objectives and Endpoints 
Secondary Objective 
Endpoint(s) 
Time Frame 
1. To determine the 
repeatability of 13C 
pyruvate metabolism 
measures in the target 
tumor (primary tumor 
and/or abdominal 
metastasis) in patients with 
same-day repeated dose 
in Cohort A and B. 
• 
repeatability of 13C pyruvate 
metabolism measures in the target 
tumor 
From study 
initiation to 
enrollment of 
last subject 
2. To determine whether the 
baseline or the changes in 
the target tumor (primary 
tumor and/or abdominal 
metastases) 13C pyruvate 
metabolism at 4 weeks 
following treatment 
initiation are associated 
with the best objective 
response as defined by 
RECIST criteria on 
subsequent clinical CT 
scans in Cohort B. 
• 
The association between the 
baseline target tumor pyruvate 
metabolism and tumor best 
objective response as defined 
according to RECIST criteria on 
subsequent standard-of-care CT. 
• 
The association between the 
changes in the target tumor 
pyruvate metabolism post 
treatment initiation and tumor best 
objective response as defined 
according to RECIST criteria on 
subsequent standard-of-care CT. 
From study 
initiation to up 
to 18 months 
following 
enrollment of 
last subject 
2.4 
Exploratory Objective and Endpoints 
To explore 13C pyruvate metabolism between the primary tumor and abdominal metastases 
(when present) both at baseline and following treatment in both Cohort A and B. 
2.5 
Imaging Endpoints 
Tumor HP 13C pyruvate metabolism (peak lactate/pyruvate ratio, lactate /pyruvate AUC ratio, 
kPL) will be measured for each patient.  
 
3 
Study Design 
3.1 
Characteristics 
This is a pilot prospective study to investigate the utility of HP 13C pyruvate MRI for assessing 
metabolism and monitoring early treatment response in patients with locally advanced or 
metastatic PDA. Patients will be enrolled in parallel in one of two cohorts: 
Cohort A (N=20): Patients with locally advanced or metastatic PDA who are already on therapy 
will undergo hyperpolarized (HP) 13C pyruvate MRI at a single time-point. 
Cohort B (N=20): Patients with locally advanced or metastatic PDA will undergo HP 13C 
pyruvate MRI at baseline prior to the initiation of a new line of therapy (standard-of-care first- or 


 
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second-line systemic therapies, radiotherapy, or therapies as part of a clinical trial), and again at 
4 weeks (+/- 2 weeks) following treatment initiation. 
In both Cohort A and B, patients may undergo an optional second dose of 13C pyruvate injection 
followed by MRI during the same imaging session.  
3.2 
Sample Size 
A total of 40 patients will be enrolled.   
3.3 
Replacement Policy 
Patients may be replaced for the following reasons: 
• 
Inability to tolerate/complete imaging scan (with no administration of HP 13C pyruvate) 
• 
Failure of the HP 13C pyruvate to pass testing, preventing its administration 
• 
Patients who do not subsequently undergo treatment following the baseline HP 13C 
pyruvate MRI 
3.4 
Eligibility Criteria 
Patients must have baseline evaluations performed within 4 weeks prior to the HP 13C pyruvate 
MRI and must meet all inclusion and exclusion criteria.  In addition, the patient must be 
thoroughly informed about all aspects of the study, including the study procedures, and required 
evaluations and all regulatory requirements for informed consent.  The written informed consent 
must be obtained from the patient prior to enrollment. Once it has been ascertained that 
subjects are eligible for the study, their authorization to use personal health information for this 
study and their informed consent will be obtained. Each subject will be assigned a unique study 
identification number at the time of study enrollment to ensure confidentiality of study data. 
3.4.1 Inclusion Criteria 
Subjects may be included in the study if they meet all of the following criteria:  
1. Subjects must be 18 years or older. 
2. Locally advanced or metastatic pancreatic ductal adenocarcinoma, with at least one 
target lesion in the abdomen measuring  1cm.   
The subject is able and willing to comply with study procedures and provide signed and 
dated informed consent. 
Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.  
3.4.2 Exclusion Criteria 
1. Patients who because of age, general medical or psychiatric condition, or physiologic 
status cannot give valid informed consent.  
2. Patients unwilling or unable to undergo MR imaging, including patients with contra-
indications to MRI, such as cardiac pacemakers or non-compatible intracranial vascular 
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3. Poorly controlled hypertension, defined as either systolic >170 or diastolic >110. The 
addition of anti-hypertensives to control blood pressure is allowed for eligibility 
determination 
4. Congestive Heart Failure ≥ Class III 
5. Myocardial infarction within the past year 
6. History of QT prolongation on EKG, defined as pretreatment QTs > 440 msec in males 
or > 460 msec in females 
7. Pregnant and lactating females 
3.5 
Inclusion and Recruitment of Women and Minorities 
Individuals of any sex/gender, race, or ethnicity may participate. 
The study recruitment strategy aims to achieve representation of minority groups that reflects 
the demographics of the affected population in the catchment area. 
3.6 
Study Timeline 
3.6.1 Primary Completion 
The total planned accrual for this study is 40 patients. It is estimated that 1-2 subjects will be 
enrolled per month. It is estimated that 36 months will be required to complete accrual and data 
acquisition.  
3.7 
Study Completion 
The expected study completion date is December 2023 after the study opens to accrual. 
3.7.1 Study Termination 
The principal investigator reserves the right to terminate the study at any time. 
Termination of the study will be considered in the event of any safety concerns arising at any 
time during the performance of the study. 
The IRB must be promptly notified that the study will no longer be taking place and provided 
with a detailed written explanation. 
 
4 Investigational Medicinal Product 
4.1 
Description, Supply and Storage of Investigational Medicinal Product 
4.1.1 Hyperpolarized 13C Pyruvate  
13C is a stable, non-radioactive isotope of carbon with approximately 1% natural abundance.  [1-
13C]pyruvate has exactly the same chemical characteristics as pyruvate.  In [1-13C]pyruvate, the 
C-1 carbonyl has been replaced by a 13C-nucleus, which has a magnetic moment and can be 
hyperpolarized in the presence of an EPA, i.e., AH111501 sodium salt (a stable trityl radical) by 
dynamic nuclear polarization (DNP) technique.  As [1-13C] pyruvate has the same chemical 
characteristics as pyruvate, it is metabolized the same way.  The polarization procedure allows 


 
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MR imaging to rapidly detect the hyperpolarized 13C-label in [1-13C]pyruvate and its metabolites, 
[1-13C]lactate, [1-13C]alanine, and [1-13C]bicarbonate. 
Formulation 
The formulation of IMP in this study will be compounded using 250 mM [1-13C]pyruvate and up 
to 3 M AH111501 sodium salt.  The osmolality of this formulation is ~500 mosmol/kg.  After 
compounding is completed, a sterile fluid path will be pre-filled with the IMP under aseptic 
conditions. The sterile fluid path itself will be manufactured and cleaned under aseptic 
conditions in accordance with GMP guidelines (ISO level 7). The pre-filled sterile fluid path and 
automated hyperpolarizer/quality control instrument (GE SPINLabTM) (see Appendix 5), placed 
in an adjacent room to the MR suite, will then be used to generate the final hyperpolarized [1-
13C] pyruvate contained within a syringe for rapid injection into the patient (see preparation 
methods below).    
The IMP will be intravenously injected at a rate of 5 ml/second followed by a 20-ml saline flush 
at 5 ml/second.  Prior to dosing, the injection line will be primed with saline solution and some of 
this will be flushed into the subject ahead of the IMP.  In the case of unforeseen events, such as 
difficulties with the power injector, etc., hand injection will be allowed. 
Supply and Packaging 
Shipments containing kit supplies for IMP compounding will be provided by the manufacturer 
and shipped from their clinical supply unit. Site personnel at the clean room will be responsible 
for receiving kit supplies, compounding the IMP, filling the sterile fluid path using aseptic 
technique, performing quality control using the GE SPINLabTM instrument, and performing drug 
accountability. See preparation methods (below) and Appendix 5 for more information. 
Storage 
The investigators are responsible for ensuring that deliveries of IMP and other study materials 
from the manufacturer are correctly received, recorded, handled, and stored safely and properly 
in accordance with all applicable regulatory guidelines, and used only in accordance with this 
protocol. Pre-filled sterile fluid paths will be stored at -20 degrees C, and thawed prior to clinical 
use.  
Refer to Appendix 3 (Handling and Storage Safety Data Sheet) for information. 
Preparation Methods 
IMP will be compounded under the supervision of a trained pharmacist, using a mixture of [1-
13C] pyruvate and AH111501 sodium salt. The mixture will be used to pre-fill a sterile fluid path 
using laser-welding technique under aseptic conditions in a clean room adjacent to the MR 
scanner. The pre-filled sterile fluid path will be stored frozen at -20 degrees Celsius until the 
time of clinical use at the treatment unit in the Surbeck lab (1700 4th Street, Byers Hall, Rm 
104-115, San Francisco, CA) on the Mission Bay campus. At the time of clinical use, the sterile 
fluid path will be thawed using a warming module housed within the SPINLabTM instrument 
(see Appendix 5).  
The hyperpolarization process will utilize the fully automated GE SPINLabTM hyperpolarizer, 
which will be situated in a room adjacent to the MR suite.  The mixture of [1-13C]pyruvate and 
AH111501 sodium salt will be hyperpolarized by DNP at low temperature (<1 degree K) using a 
5T magnet and zero-helium loss cryogenics system. Following hyperpolarization, the IMP will be 
dissolved in sterile fluid water, diluted with TRIS/EDTA buffer solution, and forced through a C18 


 
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reverse-phase chromatographic column, which removes AH111501 to a level below 3 M, all in 
an automated fashion using the pre-fabricated sterile fluid path and SPINLabTM system. An 
integrated quality control (QC) system will analyze the IMP for pH, temperature, concentration, 
and polarization level, before it is approved for use by the local pharmacist.  A sample of IMP 
will be collected for sterility testing. The final IMP is automatically collected within a syringe. The 
yield is expected to be ~50 mL of 250 mM [1-13C]pyruvate. Following approval for use from the 
pharmacist, the syringe containing IMP is delivered to the MRI scanning room and connected to 
the tubing connected to the infusion pump.  The appropriate injection volume (per Appendix 2) 
is then delivered via the infusion pump to the subject at a rate of 5 ml/second.  Note that for 
different preparations of [1-13C]pyruvate, the concentration may be slightly different than 250 
mM.  The current concentration and corresponding injection volumes are provided (Appendix 2).  
If a slightly different concentration of [1-13C]pyruvate is available, the appropriate injection 
volume will be different but the amount of [1-13C]pyruvate injected will be unchanged.  If this 
course of action is taken, the table corresponding to the updated injection volume will be placed 
in each patient’s chart so that it is clear exactly what concentration and volume the patient 
received. 
The IMP is a colorless to slightly colored, clear liquid. 
Warning:  Do not use the IMP if any particulates are visible in the solution. 
Disposal:  Unused substances can be disposed of by flushing down a normal sink using tap 
water. 
For associated hazards and how to handle them, refer to Appendix 3 (Handling and Storage 
Safety Data Sheet). 
Safety Information 
Earlier studies of nonhyperpolarized pyruvate outside of the United States were summarized in 
section 1.2.1 
Reported IMP-related AEs in previous studies in humans include: 
Cardiovascular: dizziness, catheter site hematoma, heart rate increased, hypertension 
Constitutional symptoms: hypoesthesia, unresponsive to stimuli, feeling hot/flushing, fatigue, 
feeling abnormal 
Gastrointestinal: dysgeusia, dry mouth  
Genitourinary: micturition urgency  
Pain: catheter site pain 
Pulmonary: pharyngolaryngeal pain 
Neurologic: headache (migraine), parosmia 
However, the quality of these prior studies was unclear.  The findings from the phase I study of 
prostate cancer patients at UCSF, which included comprehensive safety monitoring, are 
summarized in the Background Section.  
The dosage of IMP that will be used in this study, and the injection rate of 5 ml/second, have 
been shown to be safe and well tolerated in the phase I study completed at UCSF.  Safety 


 
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monitoring included continuous lead 2 EKG monitoring for 10 minutes after injection, monitoring 
of vital signs, injection site, EKG, and adverse events, and laboratories for two hours after 
injection.  Patients were also evaluated clinically 24 hours and 7 days after injection.  No safety 
concerns were observed. 
4.2 
Drug Accountability 
The Investigational Pharmacist will manage drug accountability records. 
4.3 
Drug Ordering 
UCSF will obtain supplies for IMP compounding directly from the manufacturer as study supply. 
 
5 Treatment Plan 
Dosage and Administration 
Each subject will receive HP 13C pyruvate injection at a dosage of 0.43 mL/kg body weight, the 
maximum administered dose in the phase I study. It will be injected intravenously at a rate of 5 
mL/second followed by a 20 mL saline flush at 5 mL/second. 
5.1 
Early Stopping Rules for Safety 
Toxicity will be reviewed on a continuous basis.  In the event of one serious drug-related 
adverse event, enrollment will be halted for study safety review. If at any time (after two or more 
patients have been accrued) ≥33% of patients experience ≥grade 2 toxicity (excluding 
asymptomatic laboratory abnormalities deemed to be clinically insignificant by the PI or 
designee), accrual will be halted for further evaluation. At the time that it can be determined that 
continued accrual does not pose significant safety risks to patients, accrual may be re-initiated.   
 
6 Study Procedures and Observations 
The study-specific procedures and assessments are detailed in this section and outlined in the 
Study Calendar – Section 6.1.   
The Screening procedures and assessments must be completed within 28 days of IMP 
administration, unless otherwise noted. Any results falling outside of the reference ranges may 
be repeated at the discretion of the investigator. 
All on-study visit procedures are allowed a window of ± 5 days unless otherwise noted.  Visit 
delays for public holidays or weather conditions do not constitute a protocol violation.


 
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6.1 
Study Calendar 
Period / Procedure 
Screening 
Baseline HP 13C pyruvate MRI 
Follow up HP 13C pyruvate MRI1  
4w ± 2w post tx initiation 
Follow-Up 
 
 
Pre-
scan 
HP 13C MR 
Imaging 
Post-scan 
Pre-
scan 
HP 13C MR 
Imaging 
Post-
scan 
2-3mo 
interval tx 
initiation 
Study Day / Visit Day 
-28d - 0d 
 
 
 
 
 
 
Study Tx / Drug Admin 
 
 
 
 
 
 
 
 
HP 13C pyruvate injection 
 
 
X 
 
 
X1 
 
 
Administrative Procedures 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
Clinical Assessments 
 
 
 
 
 
 
 
 
Baseline conditions  
X 
 
 
 
 
 
 
 
Concomitant medications 
X 
 
 
 
 
 
 
 
Medical history/Demographics 
X 
 
 
 
 
 
 
 
Performance status 
X 
 
 
 
 
 
 
 
Vital signs 
X 
X 
 
X2 
X1 
 
X1,2 
 
AE assessment 
 
 
 
X2 
 
 
X1,2 
 
Laboratory Assessment 
 
 
 
 
 
 
 
 
Serum creatinine 
X 
 
 
 
 
 
 
 
Imaging Procedures 
 
 
 
 
 
 
 
 
MR Scan 
 
 
X 
 
 
X1 
 
 
Disease Assessment on SOC CT 
 
 
 
 
 
 
 
X1 
 
 
 
1 Cohort B only: For patients in Cohort B, a follow up HP 13C pyruvate MRI will be obtained as per above procedures at 4 weeks (+/- 2 weeks) following the initiation of systemic 
therapy or radiotherapy as per clinical care. 
2 Vital signs will be collected at the end of the visit (once the final scan is completed). AEs will be assessed following each scan. 
 


 
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6.2 
Participant Registration 
A written, signed, informed consent form (ICF) and a Health Insurance Portability and 
Accountability Act (HIPAA) authorization must be obtained before any study-specific 
assessments are initiated.  A copy of the signed ICF will be given to the subject and a copy will 
be filed in the medical record.  The original will be kept on file with the study records.   
All participants consented to the study will be registered in OnCore®, the UCSF Helen Diller 
Family Comprehensive Cancer Center Clinical Trial Management System (CTMS). The system 
is password protected and meets HIPAA requirements. 
A list of study subjects will be completed, and will include each subject's study number and 
initials. The investigator must also maintain a separate log of all the subjects screened for 
participation in the study but who will not participate, the reasons for their exclusion or non-
participation, their initials, and the date on which the subject was excluded. 
6.3 
Schedule of Procedures and Assessments 
6.3.1 Pretreatment Period 
6.3.1.1 Screening Assessments 
• 
Administrative Procedures  
o Informed consent 
• 
Clinical Assessments 
o Vital signs including blood pressure and heart rate 
o Medical history and demographic information 
o Baseline conditions assessment 
o Concomitant medications 
o Documentation of disease assessment  
o Performance status  
• 
Laboratory Assessments 
o Serum creatinine  
6.3.2 Treatment Period  
6.3.2.1 Study Procedures, Baseline HP 13C pyruvate MRI  
• 
Pre-Scan 
o Clinical Assessments 
▪ 
Vital signs including blood pressure and heart rate 
Before vital signs are measured, the subject should be resting for at least 
5 minutes (if possible). The same position will be used each time vital 
signs are measured for a given subject and blood pressure will be 
measured from the arm contra-lateral to the site of IMP administration 
whenever possible. 
• 
Standard MR Scan 


 
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Patient is transferred to the MRI suite. Standard 1H MRI exam will be obtained in 
the abdomen, including T2 weighted imaging, and T1 weighted imaging pre and 
dynamically following gadolinium contrast administration (gadobutrol at 0.1ml/Kg 
body weight). If the patient has estimated glomerular filtration rate (eGFR) < 30, 
gadobutrol will not be administered. 
• 
HP 13C MR Imaging  
o Study Tx / Drug Admin: Hyperpolarized 13C pyruvate injection 
Hyperpolarized 13C pyruvate will be injected intravenously at a dose of 0.43 
mL/kg and at a rate of 5 mL/second followed by a 20 mL saline flush at 5 
mL/second. The volume to be injected is based upon body weight and is outlined 
in Appendix 2. 
o Imaging Procedures: Dynamic 13C MR imaging 
▪ 
1-2 minutes post-injection 
▪ 
13C 3D MRI sequence with Multiband spectral-spatial excitation pulse for 
minimal [1-13C] pyruvate saturation and echo-planar imaging (EPI) 
readout for accelerated spectral-spatial sampling.  
▪ 
An optional second HP 13C pyruvate injection and MRI acquisition will 
be performed within 15 to 60 minutes following completion of the first 
scan. This repeat injection and scan is optional. This second injection will 
only occur if there is no adverse reaction to the first injection. The optional 
second injection and MRI scan are used to assess the repeatability of 
tumor HP 13C pyruvate metabolism. 
• 
Post-Scan  
o Clinical Assessments 
▪ 
Vital signs including blood pressure and heart rate at the end of the visit 
(when the last scan is complete). 
Before vital signs are measured, the subject should be resting for at least 
5 minutes (if possible). The same position will be used each time vital 
signs are measured for a given subject and blood pressure will be 
measured from the arm contra-lateral to the site of IMP administration 
whenever possible. 
If the subject experiences an adverse event such as increased heart rate 
or decreased blood pressure that are deemed clinically significant by the 
monitoring MD or nurse on site, the subject will be monitored closely until 
all vital signs are stable. 
Therefore, the period for adverse event monitoring will be up to 24 hours. 
Notably, no significant adverse events have been observed in any of the 
other ongoing hyperpolarized 13C pyruvate MRI studies. 
o AE assessment: For all subjects, a MD or nurse will follow up with the subject 
with a phone call within 24 hours to assess for any side effects. AEs will also be 
assessed at the visit, after each scan is completed. 
 
 


 
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6.3.2.2 Study Procedures, Follow-Up HP 13C pyruvate MRI (cohort B only) 
For patients in Cohort B, a follow up HP 13C pyruvate MRI will be obtained as per above 
procedures at 4 weeks (+/- 2 weeks) following the initiation of systemic therapy or radiotherapy 
as per clinical care. 
• 
Pre-Scan 
o Clinical Assessments 
▪ 
Vital signs including blood pressure and heart rate 
Before vital signs are measured, the subject should be resting for at least 
5 minutes (if possible). The same position will be used each time vital 
signs are measured for a given subject and blood pressure will be 
measured from the arm contra-lateral to the site of IMP administration 
whenever possible. 
• 
Standard MR Scan 
Patient is transferred to the MRI suite. Standard 1H MRI exam will be obtained in 
the abdomen, including T2 weighted imaging, and T1 weighted imaging pre and 
dynamically following gadolinium contrast administration (gadobutrol at 0.1ml/Kg 
body weight). If the patient has estimated glomerular filtration rate (eGFR) < 30, 
gadobutrol will not be administered. 
• 
HP 13C MR Imaging  
o Study Tx / Drug Admin: Hyperpolarized 13C pyruvate injection 
Hyperpolarized 13C pyruvate will be injected intravenously at a dose of 0.43 
mL/kg and at a rate of 5 mL/second followed by a 20 mL saline flush at 5 
mL/second. The volume to be injected is based upon body weight and is outlined 
in Appendix 2. 
o Imaging Procedures: Dynamic 13C MR imaging 
▪ 
1-2 minutes post-injection 
▪ 
13C 3D MRI sequence with Multiband spectral-spatial excitation pulse for 
minimal [1-13C] pyruvate saturation and echo-planar imaging (EPI) 
readout for accelerated spectral-spatial sampling.  
▪ 
An optional second HP 13C pyruvate injection and MRI acquisition will 
be performed within 15 to 60 minutes following completion of the first 
scan. This repeat injection and scan is optional. This second injection will 
only occur if there is no adverse reaction to the first injection. The optional 
second injection and MRI scan are used to assess the repeatability of 
tumor HP 13C pyruvate metabolism. 
• 
Post-Scan  
o Clinical Assessments 
▪ 
Vital signs including blood pressure and heart rate at the end of the visit 
(when the last scan is complete). 
Before vital signs are measured, the subject should be resting for at least 
5 minutes (if possible). The same position will be used each time vital 
signs are measured for a given subject and blood pressure will be 
measured from the arm contra-lateral to the site of IMP administration 
whenever possible. 


 
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If the subject experiences an adverse event such as increased heart rate 
or decreased blood pressure that are deemed clinically significant by the 
monitoring MD or nurse on site, the subject will be monitored closely until 
all vital signs are stable. 
Therefore, the period for adverse event monitoring will be up to 24 hours. 
Notably, no significant adverse events have been observed in any of the 
other ongoing hyperpolarized 13C pyruvate MRI studies. 
o AE assessment: For all subjects, a MD or nurse will follow up with the subject 
with a phone call within 24 hours to assess for any side effects. AEs will also be 
assessed at the visit, after each scan is completed. 
 
Reporting of MR Findings: 
The HP 13C pyruvate MRI is considered a research test and as such, will not be used in the 
clinical management of patients enrolled on the study. If there are any clinically relevant 
abnormal findings detected on standard anatomic MR imaging, these results will be 
communicated to patient and treating health care provider within 24 hours of completion of MR 
scan. 
6.4 
Supportive Care 
Subjects should receive full supportive care as medically indicated. 
The Principal Investigator or designee will be present during the administration and monitoring 
period. 
Any events occurring during or subsequent to the administration of IMP will be addressed as 
required by the monitoring nurse and/or physician as deemed appropriate.   
Additional toxicities that arise, including the determination that the injection administered was 
not sterile, will be treated at the discretion of the treating physician. 
A site-specific, radiology tackle-box will be present at the imaging site. This tackle-box contains 
at a minimum: epinephrine 1mg/1ml, diphenhydramine 50 mg/ml, glucose tablets, NaCl 0.9% 
500 ml bag, atropine 1mg/ml, methylprednisolone 125mg/2ml vial, phentolamine 5 mg vial, 
albuterol 5.5 gram inhaler, sterile water 10ml vial. Any patient who becomes unstable will be 
stabilized and transferred to the hospital by ambulance. 
 
7 Reporting and Documentation of Results 
7.1 
Evaluation of Efficacy (or Activity) 
This is a pilot study to investigate whether Hyperpolarized 13C-pyruvate MRI can provide 
metabolic information and tumor response assessment in patients with pancreatic ductal 
adenocarcinoma. 
7.2 
Evaluation of Safety 
Analyses will be performed for all patients having received at least one dose of IMP.  The study 
will use the CTCAE v5.0 for reporting of non-hematologic adverse events and modified criteria 
for hematologic adverse events. 


 
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7.3 
Definitions of Adverse Events 
7.3.1 Adverse Event 
An adverse event (also known as an adverse experience) is defined as any untoward medical 
occurrence associated with the use of a drug in humans, whether or not considered drug 
related.  More specifically, an adverse event can be any unfavorable and unintended sign (e.g., 
an abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
drug, without any judgment about causality.  An adverse event can arise from any use of the 
drug (e.g., off-label use, use in combination with another drug) and from any route of 
administration, formulation, or dose, including an overdose.  
Laboratory test value abnormalities will not be recorded as AEs unless they are designated as 
clinically significant, defined as any one of the following: symptomatic, requiring treatment, 
resulting in dose modification or delay or premature study withdrawal, or placing the subject at 
risk for other toxicity in the judgment of the treating investigator. 
7.3.2 Adverse reaction 
An adverse reaction is defined as any adverse event caused by the use of a drug.  Adverse 
reactions are a subset of all suspected adverse events for which there is reason to conclude 
that the drug caused the event. 
7.3.2.1 Suspected 
A suspected adverse reaction is defined as any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event. For the purposes of IND safety reporting, 
“reasonable possibility” indicates that there is evidence to suggest a causal relationship between 
the drug and the adverse event.  A suspected adverse reaction implies a lesser degree of certainty 
about causality than an adverse reaction. 
7.3.2.2 Unexpected  
An adverse event or suspected adverse reaction is considered unexpected if it is not listed in 
the investigator brochure or package insert(s), or is not listed at the specificity or severity that 
has been observed, or, if an investigator brochure is not required or available, is not consistent 
with the risk information described in the general investigational plan or elsewhere in the current 
application.  
“Unexpected,” as used in this definition, also refers to adverse events or suspected adverse 
reactions that are mentioned in the investigator brochure as occurring with a class of drugs or 
as anticipated from the pharmacological properties of the drug, but are not specifically 
mentioned as occurring with the particular drug under investigation. 
Adverse events that would be anticipated to occur as part of the disease process are 
considered unexpected for the purposes of reporting because they would not be listed in the 
investigator brochure.  For example, a certain number of non-acute deaths in a cancer trial 
would be anticipated as an outcome of the underlying disease, but such deaths would generally 
not be listed as a suspected adverse reaction in the investigator brochure. 
Some adverse events are listed in the Investigator Brochure as occurring with the same class of 
drugs, or as anticipated from the pharmacological properties of the drug, even though they have 
not been observed with the drug under investigation.  Such events would be considered 
unexpected until they have been observed with the drug under investigation. For example, 


 
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although angioedema is anticipated to occur in some patients exposed to drugs in the ACE 
inhibitor class and angioedema would be described in the investigator brochure as a class 
effect, the first case of angioedema observed with the drug under investigation should be 
considered unexpected for reporting purposes. 
7.3.2.3 Serious 
An adverse event or suspected adverse reaction is considered serious if, in the view of either 
the investigator or sponsor, it results in any of the following outcomes:  
• 
Death 
• 
Life-threatening adverse event 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life function 
• 
Congenital anomaly/birth defect 
Important medical events that may not result in death, are life threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the patient or subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition.  Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse. 
7.3.2.4 Life-threatening 
An adverse event or suspected adverse reaction is considered life threatening if, in the view of 
either the investigator or sponsor, its occurrence places the patient or subject at immediate risk 
of death. It does not include an adverse event or suspected adverse reaction that, had it 
occurred in a more severe form, might have caused death.  
7.4 
Recording of an Adverse Event 
Refer to the Data Safety Monitoring Plan, located in Appendix 4. 
7.5 
Follow-up of Adverse Events 
All participants who experience adverse events will be followed with appropriate medical 
management until resolved or stabilized, as determined by the investigator, or until the initiation 
of new anti-cancer therapy, whichever occurs first. Patients removed from study for 
unacceptable adverse events will be followed until resolution or stabilization of the adverse 
event.  For selected adverse events for which administration of the investigational drug was 
stopped, a re-challenge of the subject with the investigational drug may be conducted if 
considered both safe and ethical by the Investigator. 
7.6 
Adverse Events Monitoring  
Refer to the Data Safety Monitoring Plan, located in Appendix 4. 
7.7 
Expedited Reporting  
Reporting to the Data and Safety Monitoring Committee 


 
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If a death occurs during the treatment phase of the study or within 30 days after the last 
administration of the IMP(s) and it is determined to be related either to the IMP(s) or to a study 
procedure, the Investigator or his/her designee must notify the DSMC Chair (or qualified 
alternate) within 1 business day of knowledge of the event.  The contact may be by phone or e-
mail. 
Reporting to UCSF Committee on Human Research (Institutional Review Board) 
The UCSF PI must report events to the UCSF IRB according to institutional guidelines. 
UCSF IRB website for guidance in reporting adverse events: https://irb.ucsf.edu/adverse-event 
Expedited Reporting to the FDA 
If the study is being conducted under an IND, the Sponsor (or the Sponsor-Investigator) is 
responsible for determining whether or not the suspected adverse reaction meets the criteria for 
expedited reporting in accordance with federal regulations (21 CFR §312.32).  
The Sponsor (or Sponsor-Investigator) must report in an IND safety report any suspected 
adverse reaction that is both serious and unexpected. The Sponsor needs to ensure that the 
event meets all three definitions:  
• 
Suspected adverse reaction  
• 
Unexpected  
• 
Serious  
If the adverse event does not meet all three of the definitions, it should not be submitted as an 
expedited IND safety report. 
The timeline for submitting an IND safety report to FDA is no later than 15 calendar days after 
the Investigator determines that the suspected adverse reaction qualifies for reporting (21 CFR 
312.32(c)(1)).  
Any unexpected fatal or life-threatening suspected adverse reaction will be reported to FDA no 
later than 7 calendar days after the Investigator’s initial receipt of the information (21 CFR 
312.32(c)(2)).  
Any relevant additional information that pertains to a previously submitted IND safety report will 
be submitted to FDA as a Follow-up IND Safety Report without delay, as soon as the 
information is available (21 CFR 312.32(d)(2)).  
 
8 Statistical Considerations and Evaluation of Results 
8.1 
Sample Size Considerations 
8.1.1 Sample Size and Power Estimate 
For Cohort A: Assuming signal-to-noise ratio of target tumor 13C pyruvate metabolism of 30 and 
standard deviation of 5, a sample size of 20 evaluable patients will provide an expected width of 
95% confidence intervals of +/-2.2, with a standard error of 1.1.  


 
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For Cohort B: A sample size of 20 evaluable patients will allow the detection of a standardized 
difference of 0.38 with 80% power at a 2-sided significance level of 0.05 using a paired t-test.  
8.1.2 Accrual Estimates 
It is estimated that 1-2 subject will be enrolled per month, and approximately 36 months will be 
required to complete accrual and data acquisition to the study. In the case of subjects being 
unevaluable for analysis of primary endpoint, additional subjects may be enrolled to reach the 
required total number of evaluable subjects. 
8.2 
Imaging Analysis 
For the analysis and interpretation of the HP 13C MR imaging data, we will utilize the open-
source DICOM software package (SIVIC) to align, display and quantitatively interrogate 
multiparametric imaging data. Tumor regions of interest (ROIs) will be drawn to quantify MR 
biomarker (peak lactate/pyruvate ratio, lactate /pyruvate AUC, kPL) values across the selected 
volumes of interest. The peak lactate/pyruvate ratio, lactate /pyruvate AUC, kPL represent 
different methods of analyzing the pyruvate to lactate metabolic conversion. 
8.3 
Analysis Plans 
Data from all subjects dosed in the study will be included in all listings, plots, summary tables, 
and statistical analyses when appropriate. Missing values will not be substituted by estimated 
values, but treated as missing in the statistical evaluation.   
In this pilot study, we will focus on the primary PDA HP 13C pyruvate metabolism (if present) 
because accurate assessment of treatment response in the primary PDA is particularly 
challenging on conventional imaging given its infiltrative nature(10). If the primary tumor has 
been resected, we will then focus our analysis on the largest abdominal metastasis that is 
amenable to HP MRI.  
We will not explicitly adjust for multiple comparisons in analyzing the data in this pilot study. 
8.3.1 Analysis Population 
Demographic information (e.g. age, race, height, weight, and body mass index) will be 
summarized using descriptive statistics. 
8.3.2 Primary Analysis 
Cohort A: Signal-to-noise ratio of 13C pyruvate metabolism measures (peak 13C lactate/pyruvate 
ratio, 13C lactate/pyruvate AUC ratio, and apparent rate constant for pyruvate-to-lactate 
conversion, kPL) in the target tumor (primary tumor and/or abdominal metastases). 
Cohort B: Percent changes in the target tumor (primary tumor and/or abdominal metastases) 
13C pyruvate metabolism measures (peak 13C lactate/pyruvate ratio, 13C lactate/pyruvate AUC 
ratio, and kPL) between pre-treatment scan and scan obtained at 4-week (+/- 2 weeks) following 
treatment initiation. 
Primary endpoint analysis: For Cohort A, the signal-to-noise ratio of the target lesion 13C 
pyruvate metabolism measures will be determined for each patient. Descriptive statistics will be 
used to summarize the mean, standard deviation, and 95% confidence interval of the 
measurements.  


 
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For Cohort B, paired t-test or Wilcoxon signed rank test will be used to compare the target tumor 
HP 13C pyruvate metabolism pre- and 4-week (+/- 2 weeks) post treatment initiation. 
8.3.3 Secondary Analysis 
Cohort A and B: Repeatability of 13C pyruvate metabolism measures in the target tumor (primary 
tumor and/or abdominal metastasis) in patients with same-day repeated dose.  
Cohort B: The association between the baseline or changes in the target tumor pyruvate 
metabolism at 4 weeks post treatment initiation and tumor best objective response as defined 
according to RECIST criteria on subsequent standard-of-care CT.   
Secondary endpoint analysis: For Cohort A and B, intraclass correlation coefficient (ICC) will be 
used to estimate the intra-subject agreement to assess repeatability of tumor HP 13C pyruvate 
metabolism in patients with same-day repeated dose. 
ICC will be used to estimate agreement, and obtained from a one-way analysis of variance 
model based on 2 measurements per subject. The result will be presented with a 95% 
confidence interval. If 20 (out of 40) subjects had repeated dose of the hyperpolarized 13C 
pyruvate, we will have 90% power to show an ICC of at least 0.6. 
For Cohort B, tumor best objective response will be defined using RECIST 1.1 on subsequent 
clinical CT scans. For the purpose of response assessment in this pilot study, we will group 
patients either as having disease control when the best response is complete response (CR), 
partial response (PR), or stable disease (SD) on subsequent clinical CT scans, or having 
disease progression when the best response is progressive disease (PD) on subsequent CT 
scans. Based on prior published studies (37, 38) in PDA patients who receive first- or second-
line therapies (i.e. FOLFIRINOX, gemcitabine plus nab-paclitaxel, or gemcitabine monotherapy), 
we estimate an average 50% disease control rate for this group of patients. We will compare the 
baseline or changes in the target tumor 13C pyruvate metabolism at 4 week (+/-2 weeks) after 
treatment initiation between the disease control group and disease progression group (as 
defined by RECIST on subsequent clinical CT scans) using the Mann-Whitney tests.  
8.3.4 Exploratory Analysis 
The correlation in HP 13C pyruvate metabolism between the primary tumor and abdominal 
metastases (when present) at baseline and following treatment.  
Exploratory endpoint analysis: Pearson correlation tests will be used to compare the HP 13C 
pyruvate metabolism between the primary tumor and abdominal metastasis when present. 
 
9 Study Management 
9.1 
Pre-study Documentation 
This study will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki as stated in 21 CFR §312.120(c)(4); consistent with GCP and all 
applicable regulatory requirements. 
Before initiating this study, the Investigator will have written and dated approval from the 
Institutional Review Board for the protocol, written informed consent form, subject recruitment 


 
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materials, and any other written information to be provided to subjects before any protocol 
related procedures are performed on any subjects.   
The clinical investigation will not begin until either FDA has determined that the study under the 
Investigational Drug Application (IND) is allowed to proceed or the Investigator has received a 
letter from FDA stating that the study is exempt from IND requirements.  
The Investigator must comply with the applicable regulations in Title 21 of the Code of Federal 
Regulations (21 CFR §50, §54, and §312), GCP/ICH guidelines, and all applicable regulatory 
requirements.  The IRB must comply with the regulations in 21 CFR §56 and applicable 
regulatory requirements. 
9.2 
Institutional Review Board Approval 
The protocol, the proposed informed consent form, and all forms of participant information 
related to the study (e.g. advertisements used to recruit participants) will be reviewed and 
approved by the UCSF CHR (UCSF Institutional Review Board).  Prior to obtaining CHR 
approval, the protocol must be approved by the Helen Diller Family Comprehensive Cancer 
Center Site Committee and by the Protocol Review Committee (PRC).  The initial protocol and 
all protocol amendments must be approved by the IRB prior to implementation.   
9.3 
Informed Consent 
All participants must be provided a consent form describing the study with sufficient information 
for each participant to make an informed decision regarding their participation.  Participants 
must sign the CHR-approved informed consent form prior to participation in any study specific 
procedure.  The participant must receive a copy of the signed and dated consent document.  
The original signed copy of the consent document must be retained in the medical record or 
research file.  
9.4 
Changes in the Protocol 
Once the protocol has been approved by the UCSF CHR, any changes to the protocol must be 
documented in the form of an amendment.  The amendment must be signed by the Investigator 
and approved by PRC and the CHR prior to implementation.   
If it becomes necessary to alter the protocol to eliminate an immediate hazard to patients, an 
amendment may be implemented prior to CHR approval.  In this circumstance, however, the 
Investigator must then notify the CHR in writing within five (5) working days after 
implementation.  The Study Chair and the UCSF study team will be responsible for updating any 
participating sites. 
9.5 
Handling and Documentation of Clinical Supplies 
The Principal Investigator will maintain complete records showing the receipt, dispensation, 
return, or other disposition of all investigational drugs.  The date, quantity and batch or code 
number of the drug, and the identification of patients to whom IMP has been dispensed by 
patient number and initials will be included.  The sponsor-investigator will maintain written 
records of any disposition of the IMP. 
The Principal Investigator shall not make the investigational drug available to any individuals 
other than to qualified study patients.  Furthermore, the Principal Investigator will not allow the 
investigational drug to be used in any manner other than that specified in this protocol. 


 
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9.6 
Case Report Forms (CRFs) 
The Principal Investigator and/or his/her designee will prepare and maintain adequate and 
accurate participant case histories with observations and data pertinent to the study.  Study 
specific Case Report Forms (CRFs) will document safety and treatment outcomes for safety 
monitoring and data analysis.  The Clinical Research Coordinator (CRC) will complete the CRFs 
as soon as possible upon completion of the study visit; the Investigator will review and approve 
the completed CRFs.  
The information collected on CRFs shall be identical to that appearing in original source 
documents.  Source documents will be found in the patient’s medical records maintained by 
UCSF personnel.  All source documentation should be kept in separate research folders for 
each patient. 
In accordance with federal regulations, the Investigator is responsible for the accuracy and 
authenticity of all clinical and laboratory data entered onto CRFs.  The PI will approve all 
completed CRFs to attest that the information contained on the CRFs is true and accurate.  
All source documentation and CTMS data will be available for review/monitoring by the UCSF 
DSMC and regulatory agencies. 
The Principal Investigator will be responsible for ensuring the accurate capture of study data.  At 
study completion, when the CRFs have been declared to be complete and accurate, the 
database will be locked.  Any changes to the data entered into the CRFs after that time can only 
be made by joint written agreement among the Study Chair, the Trial Statistician, and the 
Protocol Project Manager. 
9.7 
Oversight and Monitoring Plan 
The UCSF Helen Diller Family Comprehensive Cancer Center DSMC will be the monitoring 
entity for this study.  The UCSF DSMC will monitor the study in accordance with the NCI-
approved Data and Safety Monitoring Plan (DSMP).  The DSMC will routinely review all adverse 
events and suspected adverse reactions considered “serious”.  The DSMC will audit study-
related activities to ensure that the study is conducted in accordance with the protocol, local 
standard operating procedures, FDA regulations, and Good Clinical Practice (GCP).  Significant 
results of the DSMC audit will be communicated to the IRB and the appropriate regulatory 
authorities at the time of continuing review, or in an expedited fashion, as applicable.  See 
Appendix 4, Data and Safety Monitoring Plan for additional information. 
9.8 
Record Keeping and Record Retention 
The Principal Investigator is required to maintain adequate records of the disposition of the 
drug, including dates, quantity, and use by subjects, as well as written records of the disposition 
of the drug when the study ends.   
The Principal Investigator is required to prepare and maintain adequate and accurate case 
histories that record all observations and other data pertinent to the investigation on each 
individual administered the investigational drug or employed as a control in the investigation. 
Case histories include the case report forms and supporting data including, for example, signed 
and dated consent forms and medical records including, for example, progress notes of the 
physician, the individual's hospital chart(s), and the nurses' notes. The case history for each 
individual shall document that informed consent was obtained prior to participation in the study. 


 
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Study documentation includes all CRFs, data correction forms or queries, source documents, 
Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory documents (e.g., 
protocol and amendments, CHR correspondence and approval, signed patient consent forms). 
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research 
study. 
In accordance with FDA regulations, the investigator shall retain records for a period of 2 years 
following the date a marketing application is approved for the drug for the indication for which it 
is being investigated; or, if no application is to be filed or if the application is not approved for 
such indication, until 2 years after the investigation is discontinued and FDA is notified. 


 
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10 References 
1. Nelson SJ, et al. (2013) Metabolic imaging of patients with prostate cancer using 
hyperpolarized [1-(1)(3)C]pyruvate. Sci Transl Med 5(198):198ra108. 
2. Cunningham CH, et al. (2016) Hyperpolarized 13C Metabolic MRI of the Human Heart: 
Initial Experience. Circ Res 119(11):1177-1182. 
3. Park I, et al. (2018) Development of methods and feasibility of using hyperpolarized 
carbon-13 imaging data for evaluating brain metabolism in patient studies. Magn Reson 
Med 80(3):864-873. 
4. Aggarwal R, Vigneron DB, & Kurhanewicz J (2017) Hyperpolarized 1-[(13)C]-Pyruvate 
Magnetic Resonance Imaging Detects an Early Metabolic Response to Androgen Ablation 
Therapy in Prostate Cancer. Eur Urol 72(6):1028-1029. 
5. Miloushev VZ, et al. (2018) Metabolic Imaging of the Human Brain with Hyperpolarized 
(13)C Pyruvate Demonstrates (13)C Lactate Production in Brain Tumor Patients. Cancer 
research 78(14):3755-3760. 
6. Hu S, et al. (2013) Rapid sequential injections of hyperpolarized [1-(1)(3)C]pyruvate in vivo 
using a sub-kelvin, multi-sample DNP polarizer. Magn Reson Imaging 31(4):490-496. 
7. Rahib L, et al. (2014) Projecting cancer incidence and deaths to 2030: the unexpected 
burden of thyroid, liver, and pancreas cancers in the United States. Cancer research 
74(11):2913-2921. 
8. Ryan DP, Hong TS, & Bardeesy N (2014) Pancreatic adenocarcinoma. The New England 
journal of medicine 371(22):2140-2141. 
9. Rahib L, Fleshman JM, Matrisian LM, & Berlin JD (2016) Evaluation of Pancreatic Cancer 
Clinical Trials and Benchmarks for Clinically Meaningful Future Trials: A Systematic 
Review. JAMA Oncol 2(9):1209-1216. 
10. Katz MH, et al. (2012) Response of borderline resectable pancreatic cancer to 
neoadjuvant therapy is not reflected by radiographic indicators. Cancer 118(23):5749-
5756. 
11. Ballehaninna UK & Chamberlain RS (2012) The clinical utility of serum CA 19-9 in the 
diagnosis, prognosis and management of pancreatic adenocarcinoma: An evidence based 
appraisal. J Gastrointest Oncol 3(2):105-119. 
12. Aldakkak M, et al. (2015) Pre-treatment carbohydrate antigen 19-9 does not predict the 
response to neoadjuvant therapy in patients with localized pancreatic cancer. HPB : the 
official journal of the International Hepato Pancreato Biliary Association 17(10):942-952. 
13. Ko AH, et al. (2005) Serum CA19-9 response as a surrogate for clinical outcome in 
patients receiving fixed-dose rate gemcitabine for advanced pancreatic cancer. British 
journal of cancer 93(2):195-199. 
14. Dabritz J, Preston R, Hanfler J, & Oettle H (2012) K-ras mutations in the plasma 
correspond to computed tomographic findings in patients with pancreatic cancer. 
Pancreas 41(2):323-325. 


 
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15. Ardenkjaer-Larsen JH, et al. (2003) Increase in signal-to-noise ratio of > 10,000 times in 
liquid-state NMR. Proc Natl Acad Sci U S A 100(18):10158-10163. 
16. Day SE, et al. (2007) Detecting tumor response to treatment using hyperpolarized 13C 
magnetic resonance imaging and spectroscopy. Nat Med 13(11):1382-1387. 
17. Venkatesh HS, et al. (2012) Reduced phosphocholine and hyperpolarized lactate provide 
magnetic resonance biomarkers of PI3K/Akt/mTOR inhibition in glioblastoma. Neuro Oncol 
14(3):315-325. 
18. Chaumeil MM, et al. (2012) Hyperpolarized 13C MR spectroscopic imaging can be used to 
monitor Everolimus treatment in vivo in an orthotopic rodent model of glioblastoma. 
Neuroimage 59(1):193-201. 
19. Park I, et al. (2011) Detection of early response to temozolomide treatment in brain tumors 
using hyperpolarized 13C MR metabolic imaging. J Magn Reson Imaging 33(6):1284-
1290. 
20. Park I, et al. (2014) Changes in pyruvate metabolism detected by magnetic resonance 
imaging are linked to DNA damage and serve as a sensor of temozolomide response in 
glioblastoma cells. Cancer research 74(23):7115-7124. 
21. Ravoori MK, Singh SP, Lee J, Bankson JA, & Kundra V (2017) In Vivo Assessment of 
Ovarian Tumor Response to Tyrosine Kinase Inhibitor Pazopanib by Using Hyperpolarized 
(13)C-Pyruvate MR Spectroscopy and (18)F-FDG PET/CT Imaging in a Mouse Model. 
Radiology 285(3):830-838. 
22. Saito K, et al. (2015) 13C-MR Spectroscopic Imaging with Hyperpolarized [1-13C]pyruvate 
Detects Early Response to Radiotherapy in SCC Tumors and HT-29 Tumors. Clin Cancer 
Res 21(22):5073-5081. 
23. Matsuo M, et al. (2018) Co-imaging of the tumor oxygenation and metabolism using 
electron paramagnetic resonance imaging and 13-C hyperpolarized magnetic resonance 
imaging before and after irradiation. Oncotarget 9(38):25089-25100. 
24. Park JM, et al. (2016) Hyperpolarized (13)C-lactate to (13)C-bicarbonate ratio as a 
biomarker for monitoring the acute response of anti-vascular endothelial growth factor 
(anti-VEGF) treatment. NMR Biomed 29(5):650-659. 
25. Scroggins BT, et al. (2018) Hyperpolarized [1-(13)C]-Pyruvate Magnetic Resonance 
Spectroscopic Imaging of Prostate Cancer In Vivo Predicts Efficacy of Targeting the 
Warburg Effect. Clin Cancer Res 24(13):3137-3148. 
26. Hu S, et al. (2011) 13C-pyruvate imaging reveals alterations in glycolysis that precede c-
Myc-induced tumor formation and regression. Cell Metab 14(1):131-142. 
27. Witney TH, et al. (2010) Detecting treatment response in a model of human breast 
adenocarcinoma using hyperpolarised [1-13C]pyruvate and [1,4-13C2]fumarate. Br J 
Cancer 103(9):1400-1406. 
28. Keshari KR, et al. (2013) Metabolic reprogramming and validation of hyperpolarized 13C 
lactate as a prostate cancer biomarker using a human prostate tissue slice culture 
bioreactor. Prostate 73(11):1171-1181. 


 
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29. Gutte H, et al. (2015) In Vivo Phenotyping of Tumor Metabolism in a Canine Cancer 
Patient with Simultaneous (18)F-FDG-PET and Hyperpolarized (13)C-Pyruvate Magnetic 
Resonance Spectroscopic Imaging (hyperPET): Mismatch Demonstrates that FDG may 
not Always Reflect the Warburg Effect. Diagnostics (Basel) 5(3):287-289. 
30. Wang ZJ, et al. (2019) Hyperpolarized (13)C MRI: State of the Art and Future Directions. 
Radiology 291(2):273-284. 
31. Salminen E, Hogg A, Binns D, Frydenberg M, & Hicks R (2002) Investigations with FDG-
PET scanning in prostate cancer show limited value for clinical practice. Acta Oncol 
41(5):425-429. 
32. Albers MJ, et al. (2008) Hyperpolarized 13C lactate, pyruvate, and alanine: noninvasive 
biomarkers for prostate cancer detection and grading. Cancer Res 68(20):8607-8615. 
33. Vaziri-Gohar A, Zarei M, Brody JR, & Winter JM (2018) Metabolic Dependencies in 
Pancreatic Cancer. Front Oncol 8:617. 
34. Serrao EM, et al. (2016) MRI with hyperpolarised [1-13C]pyruvate detects advanced 
pancreatic preneoplasia prior to invasive disease in a mouse model. Gut 65(3):465-475. 
35. Rajeshkumar NV, et al. (2015) Therapeutic Targeting of the Warburg Effect in Pancreatic 
Cancer Relies on an Absence of p53 Function. Cancer research 75(16):3355-3364. 
36. Sodkilde-Jorgensen H, et al. (2019) Pilot Study Experiences With Hyperpolarized [1-(13) 
C]pyruvate MRI in Pancreatic Cancer Patients. J Magn Reson Imaging. 
37. Conroy T, et al. (2011) FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. 
N Engl J Med 364(19):1817-1825. 
38. Von Hoff DD, et al. (2013) Increased survival in pancreatic cancer with nab-paclitaxel plus 
gemcitabine. N Engl J Med 369(18):1691-1703. 
 
 


 
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Appendix 1 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 not 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 2 Dosing Table 
Injection Volumes (250 mM [1-13C] pyruvate ) for Individual Body Weights (mL) 
Body Weight (kg) 0.43 ml/kg 
Body Weight (kg) 0.43 ml/kg 
Body Weight (kg) 0.43 ml/kg 
40 
17 
77 
33 
114 
49 
41 
18 
78 
34 
115 
49 
42 
18 
79 
34 
116 
50 
43 
18 
80 
34 
117 
50 
44 
19 
81 
35 
118 
51 
45 
19 
82 
35 
119 
51 
46 
20 
83 
36 
120 
52 
47 
20 
84 
36 
121 
52 
48 
21 
85 
37 
122 
52 
49 
21 
86 
37 
123 
53 
50 
22 
87 
37 
124 
53 
51 
22 
88 
38 
125 
54 
52 
22 
89 
38 
126 
54 
53 
23 
90 
39 
127 
55 
54 
23 
91 
39 
128 
55 
55 
24 
92 
40 
129 
55 
56 
24 
93 
40 
130 
56 
57 
25 
94 
40 
131 
56 
58 
25 
95 
41 
132 
57 
59 
25 
96 
41 
133 
57 
60 
26 
97 
42 
134 
58 
61 
26 
98 
42 
135 
58 
62 
27 
99 
43 
136 
58 
63 
27 
100 
43 
137 
59 
64 
28 
101 
43 
138 
59 
65 
28 
102 
44 
139 
60 
66 
28 
103 
44 
140 
60 
67 
29 
104 
45 
141 
61 
68 
29 
105 
45 
142 
61 
69 
30 
106 
46 
143 
61 
70 
30 
107 
46 
144 
62 
71 
31 
108 
46 
145 
62 
72 
31 
109 
47 
146 
63 
73 
31 
110 
47 
147 
63 
74 
32 
111 
48 
148 
64 
75 
32 
112 
48 
149 
64 
76 
33 
113 
49 
150 
65 


 
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Appendix 3 Safety Data Sheets 
Conforms to the EU Directive 91/155/, amended 93/112 
Chemical product and company identification 
Product name:  Hyperpolarized 13C Pyruvate Solution for Injection. 
Synonyms: Hyperpolarized Pyruvate (13C) Injection 
Application: Diagnostic imaging  
Pyruvic acid (AH110896 or AH111710) is the active component, AH111501 is a processing aid. 
Tris/EDTA buffer solution is added during compounding to neutralize the pyruvic acid. 
Supplier: GE Healthcare AS, Sigma Aldrich Corp. 
Emergency number: UCSF: 
 
 
Composition and information on ingredients 
Composition: 
Pyruvic acid (AH110896 and AH111710), C3H4O3 
AH110896 is the 13-C enriched pyruvic acid; [1-13C]pyruvic acid. AH111710 is pyruvic acid (no 
enrichment). 
AH111501 sodium salt (EPA), Na3C64H87O18S12 
Trometamol (C4H11NO3), Na2EDTA (C10H14N2Na2O8), NaOH 
Contents: 
AH111501 is a stabilized radical with the following functional groups: carboxyl, methoxy, ethyl, benzyl, 
methyl and thiol. 
Pyruvic acid is an organic acid with the following functional groups: carboxyl, carbonyl and methyl. 
Tromethamol is the buffer component, Na2EDTA is added as a metal complexing agent, NaOH will 
provide a pH of 6-8 when mixed with the pyruvic acid. 
Main ingredients: 
Tromethamol (C4H11NO3) CAS No. 77-86-1 
Na2EDTA (C10H14N2Na2O8) CAS No. 6381-92-6 
NaOH CAS No.1310-73-2 
Pyruvic acid (C3H4O3 ) CAS No.127-17-3 
 
Hazards identification 
Emergency overview: 
The two drug kit components (Mixture of pyruvic acid and AH111501 sodium salt, and Tris/EDTA 
solution) are classified as corrosive due to low/high pH and may cause burns. For the final product, the 
AH111501 is chromatographically removed prior to injection into patients. Water for injection is used in 
the production process and will decrease all concentrations, and the final pH is in the range 6 - 8. 
The injection can be considered as harmless when used as intended.  If administered intravenously in 
doses greater than 0.43 ml/kg body weight or at injection rates greater than 5 ml/s, the injection may 
cause increases in heart rate and blood pressure. 
Potential adverse health effects: Not known 
Skin: Avoid contact with skin 
Eyes: Avoid contact with eyes 
Inhalation: Avoid inhalation 


 
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Ingestion: Avoid ingestion 
Hazard classification, Hazard symbols: Not known 
 
First-aid measures 
Skin contact: Remove contaminated clothing and shoes and flush with plenty of water 
Inhalation: Move to fresh air 
Eyes: Flush with water 
Ingestion: Wash out the mouth with water 
 
Fire-fighting measures 
Flammability: Non-flammable 
Fire Extinguishing Media: H2O, CO2 , or dry powder 
Fire Fighting Procedures: Not known 
Decomposition and Explosion Hazards: Not known 
 
Accidental release measures 
Personal protection: Wear protective clothing, chemical-resistant gloves, and eye protection. 
Clean up procedures: Ventilate the area, wash with plenty of water after material pickup is complete. 
Environmental precaution: Not known 
 
Handling and storage 
Handling precautions: Handle with care. Avoid contact with eyes and skin, inhalation and ingestion. 
Storage conditions: The solution produced for injection is to be used within short time. For analytical 
purposes, storage cold or at room temperature (not frozen), protected against light in airtight container. 
 
Exposure controls, personal protection 
Ventilation: N.A. 
Protective gloves: Use chemical-resistant gloves 
Eye protection: Use safety glasses 
Protective clothing: Use protective clothing (lab coat or similar). 
 
Physical and chemical properties 
Appearance, color: colorless to slightly colored, clear liquid 
Odor: No characteristic odor 
Specific gravity: Not known 
Melting point,  C: Not known 
Boiling point,  C: Not known 
Decomposition products: N.A. 
Solubility: soluble in water 
pH: 6-8 
Concentration (weight- %): 2.2 % w/w pyruvate 


 
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Stability and reactivity 
Stability: For analytical purposes, storage cold or at room temperature (not frozen), protected against 
light in airtight container. 
Reactivity: Not known 
Conditions or materials to avoid: Light and air 
 
 


 
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Appendix 4 Data and Safety Monitoring Plan for a Phase II Institutional Study 
1. Oversight and Monitoring Plan 
The UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC) Data and Safety 
Monitoring Committee (DSMC) is responsible for auditing data quality and participant safety for 
all HDFCCC institutional clinical studies.  A summary of DSMC activities for this study includes:  
• 
Semiannual auditing (depending on study accrual) 
• 
Review of serious adverse events 
• 
Minimum of biennial regulatory auditing 
2. Monitoring and Reporting Guidelines 
Investigators will conduct a continuous review of data and participant safety at monthly site 
committee meetings where the results of each participant’s treatment are discussed and 
documented in the site committee minutes.   
All institutional Phase II and III studies are designated with a moderate risk assessment.  The 
data is audited semiannually with a random selection of twenty percent of the participants 
audited (or at least three participants if the calculated value is less than three).  The DSMC 
Monitor/Auditor will audit a maximum of 5 cycles of treatment in the participants selected for the 
review, or until the selected participants discontinue study participation or the trial is closed with 
the IRB.  Additionally, the assigned DSMC Monitor/Auditor will review no more than a total of 10 
participant charts during the course of auditing this trial. DSMC Monitor/Auditors will send a 
follow-up report to the study team within 20 business days after the auditing visit is complete for 
the PI and the study team to resolve all action items from this report within 20 business days.  
Additionally, a regulatory audit will occur on a biennial basis to review all regulatory documents 
for the trial. 
3. Review and Oversight Requirements 
 
3.1 
Adverse Event Monitoring  
All Grade 3-5 adverse events (AEs), whether or not considered to be expected or unexpected 
and whether or not considered to be associated with the use of the investigational agent(s) or 
study procedure, will be entered into OnCore®, UCSF’s Clinical Trial Management System.   
Adverse events are graded according to the Common Terminology Criteria for Adverse Events 
(CTCAE) as developed and revised by the Common Therapy Evaluation Program (CTEP) of the 
National Cancer Institute.  Adverse events are further given an assignment of attribution or 
relationship to investigational agent or study procedure.  Attribution categories are: 
• 
Definite – The adverse event is clearly related to the investigational agent(s) or study 
procedure. 
• 
Probable – The adverse event is likely related to the investigational agent(s) or study 
procedure. 
• 
Possible – The adverse event may be related to the investigational agent(s) or study 
procedure. 
• 
Unrelated – the adverse event is clearly not related to the investigational agent(s) or 
study procedure. 


 
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All Grade 3-5 adverse events entered into OnCore® will be reviewed on a monthly basis at the 
Site Committee meetings.  The Site Committee will review and discuss the selected toxicity, the 
toxicity grade, and attribution assignment. 
 
3.2 
Serious Adverse Event Reporting  
By definition, an adverse event is defined as a serious adverse event (SAE) according to the 
following criteria: 
• 
Death. 
• 
Life-threatening (i.e. results in an immediate risk of death). 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization, 
• 
Permanent or significant disability/incapacity 
• 
Gives rise to a congenital anomaly/birth defect, or cancer, or any experience that 
suggests a significant hazard, contraindication, side effect, or precaution that may 
require medical or surgical intervention to prevent one of the outcomes listed above.  
• 
Event occurring in a gene therapy study. 
• 
Event that changes the risk/benefit ratio of a study. 
• 
Any other event the Principal Investigator judges to be serious or which would suggest a 
significant hazard, contraindication, side effect, or precaution. 
Serious adverse event reporting will be in accordance with all IRB regulations. For trials 
conducted under an investigational new drug (IND) application, the SAE will be reported in 
accordance with Code of Federal Regulation Title 21 Part 312.32 and will be reported on a Med 
Watch form.   
UCSF IRB website for guidance in reporting serious adverse events: 
https://irb.ucsf.edu/adverse-event  
Med Watch forms and information: 
www.fda.gov/medwatch/getforms.htm 
All serious adverse events are entered into OnCore®, as well as submitted to the IRB (per IRB 
guidelines).  The SAEs are reviewed and monitored by the Data and Safety Monitoring 
Committee on an ongoing basis and discussed at DSMC meetings, which take place every six 
weeks.  The date the SAE is sent to all required reporting agencies will be documented in 
OnCore®.  
If the SAE involves a subject death, and is determined to be possibly, probably or definitely 
related to the investigational drug or any research related procedure, the event must be 
reported to the DSMC Chair (or Vice Chair) and DSMC Director within one business day.   
3.3 
Review of Adverse Event Rates 
If an increase in the frequency of Grade 3 or 4 adverse events (above the rate reported in the 
Investigator Brochure or package insert) is noted in the study, the Principal Investigator will 
notify the DSMC via report at the time the increased rate is identified.  The report will indicate if 
the incidence of adverse events observed in the study is above the range stated in the 
Investigator Brochure or package insert. 


 
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If at any time the Investigator voluntarily holds enrollment or stops the study due to safety 
issues, the DSMC Chair (or Vice Chair) and the DSMC Director must be notified within one 
business day and the IRB must be notified as per IRB reporting regulations. 
 
Data and Safety Monitoring Committee Contacts: 
 (DSMC Chair) 
 
 
 
UCSF HDFCCC 
San Francisco, CA 94158 
 (DSMC Director) 
 
 
 
UCSF HDFCCC 
San Francisco, CA 94143 
 
 


 
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Appendix 5 GE SPINLabTM Hyperpolarizer and Sterile Fluid Path 
 
 
 
TOP: SPINLabTM hyperpolarizer will produce 
hyperpolarized [1-13C] pyruvate in an automated 
fashion with an integrated QC system for validation of 
IMP prior to each patient injection.  
RIGHT: Sterile fluid path. The sample vial will be filled 
with [1-13C] pyruvic acid and AH111501 and laser 
welded to the pre-fabricated sterile fluid path under 
aseptic conditions. The pre-filled sterile fluid path will 
then be loaded into the SPINLab system for automated 
preparation of hyperpolarized [1-13C] pyruvate, which 
is collected in an administration syringe for rapid 
patient injection.