Hyperpolarized C-13 Pyruvate as a Biomarker of PI3K/mTOR Pathway Inhibition in Patients With Advanced Solid Tumor Malignancies
Phase: PHASE1
Conditions: Prostate Cancer
Sponsor: Rahul Aggarwal

Hyperpolarized C-13 Pyruvate as a Biomarker of 
PI3K/mTOR Pathway Inhibition in Patients with Advanced 
Solid Tumor Malignancies
Protocol Number: 159517
Version Number:  Version 6.0
Version Date:  10-21-2019
IND Number: 109,956 
Funding: NIH R01CA183071
Principal Investigator (Sponsor Investigator)
Rahul Aggarwal, MD 
University of California San Francisco
Helen Diller Family Comprehensive Cancer Center
Co-Principal Investigators
Daniel Vigneron, PhD 
Pamela Munster, MD
Statistician
Jimmy Hwang, PhD
Revision History
Version 1.1
08/21/2015
Version 2.0
07/13/2017
Version 3.0
10/07/2017
Version 4.0
06/13/2018
Version 5.0
08/20/2018
Version 6.0
10/21/2019
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.
NCT# 02913131

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Protocol Signature Page
Protocol No.: 159517                                                        Version Date: 10/21/2019
1.
I agree to follow this protocol version as approved by the UCSF Protocol Review Committee 
(PRC), Institutional Review Board (IRB), and Data Safety Monitoring Committee (DSMC).
2.
I will conduct the study in accordance with applicable IRB requirements, Federal regulations, 
and state and local laws to maintain the protection of the rights and welfare of study 
participants.
3.
I certify that I, and the study staff, have received the requisite training to conduct this 
research protocol.
4.
I agree to maintain adequate and accurate records in accordance with IRB policies, Federal, 
state and local laws and regulations.
UCSF Principal Investigator / Study Chair
Printed Name
Signature
Date

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Abstract
Title
Hyperpolarized C-13 Pyruvate as a Biomarker of PI3K/mTOR Pathway Inhibition 
in Patients with Advanced Solid Tumor Malignancies
Patient 
population
Subjects will be enrolled in two sequential phases:

Part A: Feasibility Run-In (N =50 patients). Patients with advanced solid tumor 
malignancies with at least one liver or other intra-abdominal metastasis will be 
enrolled with iterative adjustment of coil design to optimize imaging parameters 
including spatial resolution and signal-to-noise ratio (SNR) of hyperpolarized 
pyruvate/lactate within the target metastatic lesion(s).

Part B: Biomarker Cohort (N = 30 patients). Patients with advanced solid tumor 
malignancies and the presence of at least one liver or other intra-abdominal 
metastasis amenable to hyperpolarized C-13 pyruvate metabolic MR imaging 
who are planning on being treated with agent targeting PI3K/mTOR pathway 
will be enrolled.
Exclusion criteria:

Patients unwilling or unable to undergo MR imaging, including patients with 
contraindications to MRI, such as cardiac pacemakers or non-compatible 
intracranial vascular clips.
Background 
and 
Rationale for 
Study
Dynamic nuclear polarization significantly enhances the signal-to-noise ratio of 
magnetic resonance (MR) spectroscopic imaging by 10,000-fold, enabling the 
visualizing of metabolic activity in cancer cells using hyperpolarized probes.
PI3K/mTOR-mediated expression of lactate dehydrogenase catalyzes a key reaction 
as part of the glycolytic process, namely the conversion from pyruvate to lactate. Thus, 
by injecting hyperpolarized 13C pyruvate, one can quantify the intra-tumoral conversion 
rate of pyruvate to lactate using metabolic MR imaging in real-time, thereby potentially
serving as a surrogate functional biomarker of PI3K/mTOR pathway activity. This 
hypothesis has been supported by pre-clinical models in which pyruvate-to-lactate 
conversion visualized on metabolic MR imaging was correlated with tissue–based 
assays of LDH enzymatic activity, and down-regulation of PI3K/mTOR activity (e.g. 
everolimus) led to significant down-regulation of pyruvate-to-lactate conversion, an 
effect that was not observed with non-specific cytotoxic agents (eg. temozolomide).
These data support the utility of hyperpolarized 13C pyruvate/metabolic MR imaging as 
a functional biomarker of PI3K/mTOR pathway activity.
A phase 1 study of hyperpolarized 13C pyruvate in patients with localized prostate 
cancer has demonstrated safety and feasibility of this approach. Since completion of 
this phase 1 study, there have been significant technological enhancements to enable 
broader applicability of hyperpolarized 13C metabolic MR imaging, including use of an
automated polarizer and construction of novel radiofrequency coils to enable imaging 
of other anatomic sites besides the prostate, including the liver and other intra- 
abdominal organs. We have recently completed a pilot study designed to optimize 
radiofrequency coil geometry enabling visualization of liver anatomy with high spatial 
resolution.
The current study is designed to clinically investigate the utility of hyperpolarized 13C 
pyruvate/metabolic MR imaging as a functional imaging biomarker of PI3K/mTOR 
pathway activity. In the feasibility run-in phase (Part A; N =50 pts), patients with 
advanced solid tumor malignancies of any tumor type with liver or other intra- 
abdominal metastases will be enrolled, with iterative adjustment of coil geometry and 
imaging sequences to optimize the signal-to-noise ratios of intra-tumoral 
hyperpolarized pyruvate and lactate signal within the liver or other intra-abdominal

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metastase(s).
Subsequently, during Part B of the study (N = 30 pts), patients with advanced solid 
tumor malignancies who possess at least one liver or intra-abdominal metastatic lesion 
amenable to metabolic MR imaging, who are also planning on undergoing systemic 
treatment with a PI3K/mTOR pathway inhibitor, will be enrolled. Patients will undergo 
baseline imaging and repeated after approximately 21 days of systemic therapy with 
PI3K/mTOR pathway inhibitor, to assess for change from baseline in intra-tumoral 
pyruvate-to-lactate metabolic flux. Patients will undergo optional paired core needle 
tumor biopsies to correlate imaging findings with tissue-based markers of pyruvate 
metabolism and the PI3K/mTOR pathway.
Promising results from the current study supporting the utility of hyperpolarized C-13 
pyruvate imaging as a potential biomarker of target inhibition would support its future 
integration in early phase clinical studies as a companion imaging biomarker to 
optimize dose selection and as a surrogate measure of on-target tumor response.
Primary 
Objectives
Part A: To optimize the signal-to-noise ratio in detecting intra-tumoral hyperpolarized 
C-13 lactate/pyruvate signal within liver or other intra-abdominal metastases using 
metabolic MR imaging in patients with advanced solid tumor malignancies.
Part B: To determine the mean percent change from baseline in peak intra-tumoral 
hyperpolarized lactate to pyruvate ratio after initiation of treatment with PI3K/mTOR 
pathway inhibitor.
Secondary 
Objectives

To investigate for an association between percent change from baseline in 
peak intra-tumoral hyperpolarized lactate to pyruvate ratio after initiation of 
treatment with PI3K/mTOR pathway inhibitor with subsequent clinical 
outcomes including objective response rate, clinical benefit rate, and 
progression-free survival. (Part B)

To characterize further the safety profile of hyperpolarized C-13 pyruvate 
injections

To determine the reproducibility of intra-tumoral HP lac/pyr ratio with same-day 
repeated dose studies.
Exploratory 
Objective 
(Part B)

To investigate for an association between intra-tumoral hyperpolarized lactate 
to pyruvate ratio with histologic markers of PI3K/mTOR pathway and glycolytic 
metabolism including phosphorylated S6, pAKT, and LDH expression. (Part B; 
optional)

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Study Design
This is a single center prospective imaging study investigating the utility of 
hyperpolarized C-13 pyruvate/metabolic MR imaging. The current protocol will serve as 
a companion imaging biomarker study paired with therapeutic trials of PI3K/mTOR 
pathway inhibitors (e.g. CUDC-907, BYL719), as well as a stand-alone protocol for 
patients treated with standard-of-care therapies inhibiting the PI3K/mTOR signaling 
pathway (eg. everolimus).
In Part A (run-in feasibility phase), patients will undergo imaging at a single time point, 
without paired tumor biopsy. There will be no follow up imaging or requirement for 
treatment with PI3K/mTOR pathway inhibitor. Iterative adjustment of radiofrequency 
coil geometry and imaging sequences will be undertaken to optimize intra-tumoral 
hyperpolarized pyruvate/lactate signal-to-noise ratio.
In part B, patients will undergo paired baseline hyperpolarized C-13 pyruvate imaging + 
tumor biopsy, then initiate treatment with agent inhibiting the PI3K/mTOR pathway.
After 21 days (+/- 14 days), patients will undergo repeat hyperpolarized C-13 pyruvate 
MR imaging + tumor biopsy. Patients will subsequently be treated with PI3K/mTOR 
pathway inhibitor until disease progression, unacceptable toxicity, or patient/physician 
decision to discontinue therapy.
Part B Study Schema
Number of 
patients
 50 patients will be accrued during the feasibility run-in period (Part A). 30 patients 
will be accrued during the main biomarker investigational period (Part B).
Duration of 
Therapy
In Part A, patients will undergo imaging at a single time point without paired tumor 
biopsy.
In Part B, patients will undergo paired hyperpolarized pyruvate/metabolic MR imaging
+ tumor biopsy at baseline and after approximately 21 days of therapy.

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Duration of 
Follow up
In Part A, no follow up is planned.
In Part B, patients will be followed until discontinuation of treatment with PI3K/mTOR 
pathway inhibitor.
Duration of 
study
The anticipated accrual period is 24 months (~ 1.5 patients/month). Duration of follow 
up will vary by tumor type but is expected to average approximately 6 months, leading 
to an estimated total study duration of 30 months.
Imaging 
Agents
Hyperpolarized 13C pyruvate

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Table of Contents
Protocol Signature Page................................................................................................................2
Abstract…………………………………………………………………………………………………… 3
1
Background ..........................................................................................................................9
1.1
Study Rationale ......................................................................................................9
1.2
C-13 pyruvate serves as biomarker of PI3K/mTOR pathway in pre-clinical 
models
10
1.3
Previous Clinical Experience with Hyperpolarized C-13 Pyruvate .....................10
1.4
Expanding the anatomic coverage of metabolic MR imaging .............................13
1.5
Safety of Repeated HP C-13 Pyruvate Injections.................................................14
2
Study Objectives.................................................................................................................15
2.1
Primary Objectives...............................................................................................15
2.2
Secondary Objectives...........................................................................................15
2.3
Exploratory Objective (Part B).............................................................................15
3
Study Design ......................................................................................................................16
3.1
Characteristics ......................................................................................................16
3.2
Number of Subjects..............................................................................................16
3.3
Eligibility Criteria.................................................................................................17
3.4
Study Timeline .....................................................................................................18
3.5
Study Termination................................................................................................18
4
Investigational Medicinal Product.......................................................................................19
4.1
Description, Supply and Storage of Investigational Medicinal Product ..............19
4.1.1
Hyperpolarized C-13 Pyruvate.........................................................................19
4.2
Drug Accountability.............................................................................................21
4.3
Drug Ordering ......................................................................................................21
5
Study Procedures and Observations..................................................................................22
5.1
Screening Assessments.........................................................................................22
5.2
Metabolic MR Imaging ........................................................................................23
5.3
Tumor Biopsy (Part B only).................................................................................24
5.4
Initiation of PI3K/mTOR Pathway-Directed Therapy (Part B Only)...................24
5.5
Day 21 (+/- 14 day) Metabolic MR/HP C-13 Pyruvate study (Part B Only) .......24
5.6
Repeat Tumor Biopsy (Part B Only)....................................................................24
5.7
Every 6-12 weeks (Part B Only) ..........................................................................24
5.8
Supportive Care and Concomitant Medications...................................................25
6
Reporting and Documentation of Results...........................................................................27
6.1
Evaluation of Safety.............................................................................................27
6.2
Definitions of Adverse Events .............................................................................27
6.2.1
Adverse Event ..................................................................................................27
6.2.2
Adverse reaction...............................................................................................27
6.3
Recording of an Adverse Event............................................................................28
6.4
Follow-up of Adverse Events...............................................................................29
7
Statistical Considerations and Image Analysis...................................................................30
7.1
Image Processing and Analysis............................................................................30
7.2
Study Endpoints ...................................................................................................30

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7.3
Sample Size Determination..................................................................................30
7.4
Subject Characteristics .........................................................................................31
7.5
Replacement Policy..............................................................................................31
7.6
Accrual estimates .................................................................................................31
7.7
Interim Analysis ...................................................................................................31
7.8
Analytic Plan........................................................................................................32
7.8.1
Analysis Population..........................................................................................32
7.8.2
Primary Analysis ..............................................................................................32
7.8.3
Analysis of Secondary and Exploratory Endpoints..........................................32
8
Study Management ............................................................................................................33
8.1
Pre-study Documentation.....................................................................................33
8.2
Institutional Review Board Approval...................................................................33
8.3
Informed Consent.................................................................................................33
8.4
Changes in the Protocol........................................................................................33
8.5
Handling and Documentation of Clinical Supplies..............................................33
8.6
Case Report Forms (CRFs) ..................................................................................34
8.7
Oversight and Monitoring Plan ............................................................................34
8.8
Record Keeping and Record Retention................................................................34
References
          36
Appendix 1
Performance Status Criteria ...............................................................................37
Appendix 2
Data and Safety Monitoring Plan for a Phase 2 or 3 Institutional Study .............38
Appendix 3
UCSF Policy/Procedure for Required Regulatory Documents for UCSF 
Investigator-Initiated Oncology Clinical Trials with an Investigator held 
Investigational New Drug (IND) ..........................................................................40

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1
Background
1.1
Study Rationale
Dynamic nuclear polarization significantly enhances by 10,000-fold the signal-to-noise ratio of 
magnetic resonance (MR) spectroscopic imaging, enabling the visualizing of metabolic activity 
in cancer tissue using hyperpolarized metabolic probes including pyruvate (Figure 1).1 
Phosphatidylinositol 3-kinase (PI3K)/mammalian target of Rapamycin (mTOR)-mediated 
expression of lactate dehydrogenase (LDH) catalyzes the conversion from pyruvate to lactate. 
This is a key step in aerobic glycolysis, a hallmark of cancer cells. By injecting hyperpolarized 
13C pyruvate, one can quantify in real-time using metabolic MR imaging the intra-tumoral 
conversion rate of pyruvate to lactate, thereby potentially serving as a surrogate functional 
biomarker of PI3K/mTOR pathway activity (Figure 2). This hypothesis has been supported by 
pre-clinical models in which pyruvate-to-lactate conversion visualized on metabolic MR imaging 
was correlated with tissue –based assays of LDH enzymatic activity, and down-regulation of 
PI3K/mTOR activity (eg. everolimus) led to significant down-regulation of pyruvate-to-lactate 
conversion, an effect that was not observed with non-specific cytotoxic agents (eg. 
temozolomide). These data support the utility of hyperpolarized C-13 pyruvate/metabolic MR 
imaging as a functional biomarker of PI3K/mTOR pathway activity.
Figure 1. 13C-pyruvate uptake within 15-20s with high 
conversion in regions including biopsy-proven cancer. 
These studies demonstrated high signal-to-noise ratio 
compared with standard proton spectroscopy.
Figure 2. Link between PI3K/mTOR pathway and 
Pyruvate Metabolism via HIF-1 alpha and LDH.
A phase 1 study of hyperpolarized 13C pyruvate in patients with localized prostate cancer has 
demonstrated safety and feasibility of this approach.2 Since completion of this phase 1 study, 
there have been significant technological enhancements to enable broader applicability of 
hyperpolarized 13C metabolic MR imaging, including use of an automated polarizer and 
construction of novel radiofrequency coils to enable imaging of other anatomic sites besides the 
prostate, including the liver and other intra-abdominal organs.
The current study is designed to clinically investigate the utility of hyperpolarized C-13 
pyruvate/metabolic MR imaging as a functional imaging biomarker of PI3K/mTOR pathway 
activity. In the feasibility run-in phase (Part A; N = 50 pts), patients with advanced solid tumor 
malignancies of any tumor type will be enrolled, with iterative adjustment of coil geometry and 
imaging sequences to optimize the signal-to-noise ratio of intra-tumoral hyperpolarized pyruvate 
and lactate signal. Subsequently, during Part B of the study (N = 30 pts), patients with advanced 
solid tumor malignancies who possess at least lesion amenable to metabolic MR imaging, who 
are also planning on undergoing systemic treatment with a PI3K/mTOR pathway inhibitor, will

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be enrolled. Patients will undergo baseline imaging and repeated after approximately 21 days of 
systemic therapy with PI3K/mTOR pathway inhibitor, to assess for change from baseline in 
intra-tumoral pyruvate-to-lactate metabolic flux. Patients will undergo optional paired tumor 
biopsies to correlate imaging findings with tissue-based markers of pyruvate metabolism and 
the PI3K/mTOR pathway.
Promising results from the current study supporting the utility of hyperpolarized C-13 pyruvate 
imaging as a potential biomarker of target inhibition would support its future integration in early 
phase clinical studies as a companion imaging biomarker to optimize dose selection and as a 
surrogate measure of on-target tumor response.
1.2
C-13 pyruvate serves as biomarker of PI3K/mTOR pathway in pre-clinical 
models
Pre-clinical studies of breast and brain tumor 
xenografts treated with the established mTOR 
(TORC1) inhibitor everolimus demonstrated 
significant down-regulation of hyperpolarized 
pyruvate-to-lactate conversion detected by 
HP 13C MRI as early as two days after 
treatment initiation (Figure 3).3,4 In the 
preclinical model, declines in HP 
lactate/pyruvate signal within the tumor were 
observed prior to changes in tumor size, were 
associated with subsequent tumor growth 
stabilization, correlated with intra-tumoral 
immunohistochemical evidence of reductions 
in PI3K/mTOR pathway activity including 
decreased LDH and HIF-1α expression, and 
were not seen with treatment with a non- 
specific DNA damaging agent 
(temozolomide). These pre-clinical 
observations demonstrate that HP 13C MRI 
can provide early and specific evidence of 
effective PI3K/mTOR pathway inhibition.
Figure 3. PI3K/mTOR signal inhibition with 
everolimus leads to early declines in HP 13C 
pyruvate to lactate conversion in subcutaneous 
glioblastoma tumors (GS2 cell line with PTEN 
loss) prior to changes in tumor size.
1.3
Previous Clinical Experience with Hyperpolarized C-13 Pyruvate
As a first step in evaluating the use of 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 [1-13C]pyruvate was used. This study was completed in December 2007. In the 
original protocol it was planned that doses up to 0.71 ml/kg body weight would be given,

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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 pyruvate injection and 2 received saline. Doses 
up to 0.43 ml/kg body weight were well tolerated and no IMP-related AEs were observed that 
warranted unblinding the study to reveal which subjects had received Pyruvate Injection versus 
placebo. However, in the 0.57 ml/kg body weight cohort, 2 of 6 subjects showed IMP-related 
non-serious AEs (“unresponsiveness" in subject 001-0026 and “flushing" accompanied by 
changes in blood pressure and heart rate in subject 001-0030) that the principal investigator 
considered to be concerning and related to the administration of IMP. The study was unblinded 
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 both subjects 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 Pyruvate Injection was 
conducted in elderly (60 years of age) volunteers. All doses up to 0.43 ml/kg body weight 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.
On the basis that doses of pyruvate injection up to 0.43 ml/kg body weight 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. In this study, three dose levels of pyruvate 
injection, 0.14 ml/kg body weight, 0.28 mg/kg body weight, and 0.43 ml/kg body weight 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.

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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:
Table 1: Possibly, probably, or definitely related toxicities: Phase I Study at UCSF
Dose level
n
Toxicity
Grade
Orange urine
1
Pharmaceutical smell
1
1 (0.14 mL/kg)
6
Pruritus
1
Cold sensation with injection
1
2 (0.28 mL/kg)
6
Dysgeusia
1
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
3 (0.43 mL/kg)
19
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 in a patient who took a dose of metoprolol without checking his blood 
pressure prior (when he generally checks it prior to taking antihypertensives). Therefore, it was 
thought unlikely to be related, but a relationship to pyruvate injection could not definitively be 
ruled out.
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

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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).
The concerns for toxicity based on the earlier phase I experience prompted intensive monitoring 
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.
1.4
Expanding the anatomic coverage of metabolic MR imaging
To enable broader applicability of 
hyperpolarized 13C metabolic MR 
imaging, we have recently 
completed a pilot study in healthy 
volunteers (CC# 149516) 
evaluating the use of newly 
constructed radiofrequency coils to 
enable imaging of the liver and 
other intra-abdominal organs. A 
representative image of the liver 
captured by the new 
radiofrequency coil is shown in 
Figure 4. A summary of the 
observed signal-to-noise ratio 
achieved with the various coil 
geometries using two MR pulse 
sequences (SSFSE and LAVA) is
shown in Figure 5. The medium 
size flex coil gave the best SNR for 
up to 7cm deep in the liver and will 
be the starting coil geometry for 
the planned study.
Figure 4. A representative image of the liver in a healthy volunteer using 
the newly fabricated radiofrequency coils with capability for metabolic 
MR imaging with HP probes including C-13 pyruvate.
Figure 5. Average signal-to-noise ratios in the liver using the various 
sizes of radiofrequency coils. The medium flex coil resulted in the best 
signal-to-noise ratio up to 7 cm deep from the skin surface in the liver.

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Rationale for Use of Multiple injections of Hyperpolarized [1-13C]pyruvate and/or  
[2-13C] pyruvate
When [2-13C]pyruvate, is used instead of [1-13C]pyruvate, the 13C-label is incorporated into TCA 
(tricarboxylic acid) cycle intermediates rather than being released as 13CO2 (Figure 1). Combined 
with the fact that GMP [2-13C]pyruvate has been synthesized, has the same safety profile as [1-
13C]pyruvate, and has been shown to be useful in monitoring TCA metabolism in pre-clinical 
studies of the heart (1), brain (2) and prostate makes [2-13C]pyruvate an attractive substrate for 
clinical translation. In the perfused rat heart (1), the conversion of HP pyruvate to [2-13C]lactate, 
[1-13C]acetyl-carnitine, [1-13C]citrate and [5-13C]glutamate was observed, and following cardiac 
ischemia, the TCA cycle intermediates, [1-13C]citrate and [5-13C]glutamate, decreased and [2-
13C]lactate increased (1). In the rat brain, increasing the HP pyruvate injection concentration to 
125mM led to the observation of multiple TCA cycle intermediate metabolites including [5-
13C]glutamate and [1-13C]citrate (2) indicating that pyruvate was getting across the blood brain 
barrier in sufficient time for metabolism to occur. By increasing PDH activity through DCA 
(dichloroacetate) stimulation, detection of HP [1-13C]acetyl carnitine signal, along with a 40% 
increase in HP [5-13C]glutamate were observed (2).  For studying prostate cancer, we have 
shown in ex vivo patient derived prostate cancer tissue slice studies that 13C labeling of both the 
C-1 and C-2 positions of pyruvate provides a way to assess both up-regulated Warburg effect 
(HP 13C lactate) and TCA cycle (HP 13C glutamate) in prostate cancer. However, the utility of 
[1,2-13C]pyruvate is limited by lower SNR due to 13C-13C coupling and overlap of the coupled 
resonances. Therefore, initial clinical translation will involve the use of HP 13C MRI protocols and 
employ sequential injections of [1-13C]pyruvate and/or [2-13C]pyruvate, thereby alleviating the 
problems associated with doubly labeled [1,2-13C]pyruvate. In addition to improving the metabolic 
information provided by injecting [1-13C]pyruvate alone, the second pyruvate injection, using 
either [1-13C]pyruvate or [2-13C]pyruvate, could also provide an expanded region of coverage (i.e. 
the ability to assess cancer lesions that were outside of the FOV of the first HP C-13 pyruvate 
MRI scan), and/or reproducibility of pyruvate metabolism (key to understanding the significance 
of metabolic changes with cancer aggressiveness and response to therapy). To accomplish the 
acquisition of this important metabolic data, patients will have the option of undergoing repeated 
dose imaging studies of HP C-13 pyruvate, up to two injections per time point, separated by 15-
60 minutes.
1.5
Safety of Repeated HP C-13 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 events5,6. 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. Moreover, two injections of 
hyperpolarized [1-13C]pyruvate have already occurred in patient studies. These studies have 
demonstrated the safety of serial injections without any adverse effects noted.

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2
Study Objectives
2.1
Primary Objectives
Part A:
To optimize the signal-to-noise ratio in detecting intra-tumoral hyperpolarized C-13 
lactate/pyruvate signal within liver or other intra-abdominal metastases using metabolic MR 
imaging in patients with advanced solid tumor malignancies.
Part B:
To determine the mean percent change from baseline in peak intra-tumoral hyperpolarized 
lactate to pyruvate ratio after initiation of treatment with PI3K/mTOR pathway inhibitor.
2.2
Secondary Objectives

To investigate for an association between percent change from baseline in peak intra- 
tumoral hyperpolarized lactate to pyruvate ratio after initiation of treatment with 
PI3K/mTOR pathway inhibitor with subsequent clinical outcomes including objective 
response rate, clinical benefit rate, and progression-free survival. (Part B)

To characterize further the safety profile of hyperpolarized C-13 pyruvate injection

To determine the reproducibility of intra-tumoral HP lac/pyr ratio with same-day repeated 
dose studies.
2.3
Exploratory Objective (Part B)
To investigate for an association between intra-tumoral hyperpolarized lactate to pyruvate ratio 
with histologic markers of PI3K/mTOR pathway and glycolytic metabolism including 
phosphorylated S6, pAKT, and LDH expression. (Part B; optional)

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3
Study Design
3.1
Characteristics
This is a single center prospective imaging study investigating the utility of hyperpolarized C-13 
pyruvate/metabolic MR imaging. The current protocol will serve as a companion imaging 
biomarker study paired with therapeutic trials of PI3K/mTOR pathway inhibitors (e.g. CUDC- 
907, BYL719) as well as a stand-alone protocol for patients treated with standard-of-care PI3K 
pathway targeting therapies (eg. everolimus).
In Part A (run-in feasibility phase), patients will undergo imaging at single time point, without 
paired tumor biopsy. There will be follow up imaging or requirement for treatment with 
PI3K/mTOR pathway inhibitor. Iterative adjustment of radiofrequency coil geometry and imaging 
sequences will be undertaken to optimize intra-tumoral hyperpolarized pyruvate/lactate signal- 
to-noise ratio during Part A of the study.
In Part B, patients will undergo paired baseline hyperpolarized C-13 pyruvate imaging + 
optional tumor biopsy, then initiate treatment with agent inhibiting the PI3K/mTOR pathway. 
After 21 days (+/- 14 days), patients will undergo repeat hyperpolarized C-13 pyruvate MR 
imaging + optional paired tumor biopsy. Patients will subsequently be treated with PI3K/mTOR 
pathway inhibitor until disease progression, unacceptable toxicity, or patient/physician decision 
to discontinue therapy.
3.2
Number of Subjects
Part A: 50 patients with advanced solid tumor malignancies with at least one metastatic liver 
or intra-abdominal lesion amenable to hyperpolarized C-13 pyruvate/metabolic MR imaging 
will be enrolled.
Part B: 30 patients with advanced solid tumor malignancies with at least one at least metastatic 
lesion amenable to percutaneous biopsy and metabolic MR imaging who are planning on being 
treated with PI3K/mTOR pathway inhibitor will be enrolled.

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3.3
Eligibility Criteria
Inclusion Criteria:

Presence of at least one target liver or other intra-abdominal lesion detected by standard 
staging scans that, in the judgment of Study Investigators, would be amenable to 
hyperpolarized C-13 pyruvate/metabolic MR imaging:
o
Target lesion must measure 1.0 cm in long axis diameter on CT or MRI

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 (see 
Appendix 1).

Adequate organ function, including creatinine < 1.5 x ULN or estimated creatinine 
clearance 50 mL/min (by the Cockcroft Gault equation) and total bilirubin <3x ULN.
Part B only:

No prior local therapy to target lesion.

If patient agrees to optional biopsy:

Presence of at least one target lesion amenable to percutaneous 
tumor biopsy in the judgment of Interventional Radiology 
•
No history of bleeding diathesis.
•
Patients on anti-coagulation they must be able to safely stop 
treatment for purposes of tumor biopsy.

Planned treatment with agent targeting PI3K/mTOR pathway (either standard of care or 
investigational agent)
Exclusion Criteria

Patients who because of age, general medical or psychiatric condition, or physiologic 
status cannot give valid informed consent.

Patients unwilling or unable to undergo MR imaging, including patients with contra- 
indications to MRI, such as cardiac pacemakers or non-compatible intracranial vascular 
clips.

Metallic implant or device that distorts local magnetic field and compromises the quality 
of MR imaging.

Poorly controlled hypertension, defined as systolic blood pressure at study entry greater 
than 160 mm Hg or diastolic blood pressure greater than 100 mm Hg. The addition of 
anti-hypertensives to control blood pressure is allowed.

Congestive heart failure or New York Heart Association (NYHA) status ≥ 2.

A history of clinically significant EKG abnormalities, including QT prolongation (QTcF > 
500 ms), a family history of prolonged QT interval syndrome, or myocardial infarction 
(MI) within 6 months of study entry. Patients with rate-controlled atrial fibrillation/flutter 
will be allowed on study.

Any condition that, in the opinion of the Principal Investigator, would impair the patient’s 
ability to comply with study procedures.

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3.4
Study Timeline
In Part A, no follow up is planned.
In Part B, patients will be followed until discontinuation of treatment with PI3K/mTOR pathway 
inhibitor.
The anticipated accrual period is 24 months (~ 1-2 patients/month). Duration of follow up will 
vary by tumor type but is expected to average approximately 6 months, leading to an estimated 
total study duration of 30 months.
3.5
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.
If it becomes necessary to consider termination of the study after dosing has begun, dosing may 
be suspended pending discussion between the investigators and the DSMC.

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4
Investigational Medicinal Product
4.1
Description, Supply and Storage of Investigational Medicinal Product
4.1.1   Hyperpolarized C-13 Pyruvate
13C is a stable, non-radioactive isotope of carbon with approximately 1% natural abundance.C-
13 pyruvate has exactly the same chemical characteristics as pyruvate. In C-13 pyruvate, either 
the C-1 or C-2 atom 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 DNP. As C-13 pyruvate has the same chemical characteristics as pyruvate, it is 
metabolized the same way. However, the fact that it can be hyperpolarized means that MRSI 
can be used to rapidly detect the hyperpolarized 13C-label in C-13 pyruvate and its metabolites, 
alanine, lactate, bicarbonate, and other metabolites of the TCA cycle such as glutamate.
Formulation
The formulation of IMP in this study will be compounded using 250 mM C-13 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) placed in an adjacent 
room to the MR suite, will then be used to generate the final hyperpolarized C-13 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) 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. The pre-filled sterile fluid paths will be stored at < -20 degrees C, and thawed prior to 
clinical use.
Preparation Methods
IMP will be compounded under the supervision of a trained pharmacist, using a mixture of 13C-
pyruvic acid and AH111501 sodium salt. The mixture will be used to pre-fill a sterile fluid path 
using laser welding technique under aseptic conditions. The pre-filled sterile fluid path will

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be stored frozen at <-20 degrees Celsius until the time of clinical use in the Surbeck imaging lab 
 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.
The hyperpolarization process will utilize the automated GE SPINLabTM hyperpolarizer, which is 
situated in a room adjacent to the MR suite. The mixture of 13C-pyruvic acid 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, filtered to remove AH111501 to a level below 3 M, diluted and neutralized 
with TRIS/EDTA buffered hydroxide solution, 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 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 ~40 mL of 250 
mM 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 is then delivered via the infusion pump to the subject at 
a rate of 5 ml/second.  Note that for different shipments of 13C-pyruvate, the concentration may 
be slightly different than 250 mM. If a slightly different concentration of 13C-pyruvate is available, 
the appropriate injection volume will be different but the amount of 13C-pyruvate injected will be 
unchanged. If this course of action is taken, 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.
Safety Information
Earlier studies of nonhyperpolarized pyruvate outside of the United States were summarized in 
the background section.
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

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Neurologic: headache (migraine), parosmia
However, the quality of these prior studies was unclear. The toxicity of the phase I study, which 
included comprehensive safety monitoring, is 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 
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.

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5
Study Procedures and Observations
Schedule of Procedures and Observations
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 patients who are consented 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.
5.1
Screening Assessments

The Screening procedures and assessments must be completed within 28 days of 
baseline MR scan except for staging scans which need to be completed within 12 
weeks of baseline MR.

Physical examination - This will include assessment for the presence of abnormalities in 
general appearance, lungs, cardiovascular system, and abdomen.

Vital signs including heart rate and blood pressure

Complete medical history and demographic information

Baseline conditions assessment

Concomitant medications

Disease assessment

Performance status

Laboratory procedures
o
Complete blood count (CBC) with differential
o
Blood chemistry assessment including creatinine, AST, ALT, total bilirubin, and 
lactate dehydrogenase (LDH)

Electrocardiogram (ECG)

Staging scans cross-sectional imaging of the abdomen/pelvis (CT or MRI; with IV 
contrast if medically permissible) (within 3 months of baseline MR scan) (chest imaging 
is optional)

Selection of target lesion: Study investigators will review the results of standard scans 
to select the target lesion amenable to metabolic imaging with HP C-13 pyruvate and 
paired tumor biopsy (review for biopsy in Part B only).

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5.2
Metabolic MR Imaging
Pre-Scan Evaluation
Vital signs (systolic and diastolic blood pressure, heart rate) will be monitored at screening and 
baseline (immediately before the subject is transferred to the MR suite).
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 scanning
Patient is transferred to the MR suite. High spatial resolution MRI to visualize the target lesion 
using appropriate radiofrequency coil will be performed with axial and coronal T1 and T2 1H fast 
spin echo MRI. Gadolinium contrast will be administered intravenously and contrast-enhanced 
images will be obtained.
Hyperpolarized C-13 Injection and Dynamic 13C MR imaging
Next, hyperpolarized C-13 pyruvate will be injected intravenously at a rate of 5 mL/second 
followed by a 20 mL saline flush at 5 mL/second.
1-2 minutes post-injection

Dynamic 13C MRI
o
13C 3D MRSI sequence with Multiband spectral-spatial excitation pulse for 
minimal [1-13C]pyruvate saturation and echo-planar spectroscopic imaging 
(EPSI) readout for accelerated spectral-spatial sampling.
o
The pre-selected target lesion will be imaged on a GE 5T system with 
parameters typically being TE = 3ms, TR = 125ms, 10 Hz spectral resolution, 581 
Hz spectra bandwidth, 8 (PE) x 18 (EPSI) matrix, 5x5 mm resolution, 5mm slice 
thickness, and 5 s per image. The sequence will be started 5 sec after 
completing the injection (including catheter flushing) of 250mM HP pyruvate 
(dose = 0.43 mL/kg, 20 to 45 cc’s).
o
A “clamshell” volume 13C transmit and/or external RF coils will be used for signal 
excitation and reception.
o
A second hyperpolarized C-13 injection and dynamic 13-C MRI scan may be 
performed within 15 to 60 minutes following completion of first scan.. This 
repeat injection and scan is optional.
Post-injection safety monitoring:
Vital signs (blood pressure and heart rate), adverse event assessment, and injection site 
monitoring will be performed at 30 minutes post-injection.
Reporting of MR Findings:
The HP C-13 pyruvate/MR scan is considered a research test and as such, will not be used in 
the clinical management of patients enrolled on the study. A trained radiologist will review all 
images within 24 hours of scan completion. If there are any unexpected clinically relevant

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abnormal findings, these results will be communicated to patient and treating health care 
provider with 24 hours of completion of MR scan.
5.3
Tumor Biopsy (Part B only; optional)
Patients enrolled in Part B will undergo an optional core needle tumor biopsy of the pre-
selected target lesion following completion of baseline metabolic MR scan but prior to initiation 
of PI3K/mTOR pathway inhibitor. The fresh biopsy sample will be delivered to the Munster lab 
and will be analyzed for markers of PI3K/mTOR pathway activation, including phosphorylated 
S6 and Akt, as well as markers of glycolytic activity including LDH expression. When sufficient 
tissue is available, expression level of MCT1 and MCT 4 (major lactate transporters) will be 
measured
5.4
Initiation of PI3K/mTOR Pathway-Directed Therapy (Part B Only)
Patients enrolled in Part B will subsequently begin treatment with systemic therapy directed 
towards the PI3K/mTOR pathway following completion of baseline/screening procedures. 
Treatment may be given as standard of care with commercial supply (e.g. everolimus) or via 
participation on therapeutic clinical trial. The study procedures for patients enrolled on a 
therapeutic trial take precedent over the procedures outlined in the current protocol.
5.5
Day 21 (+/- 14 day) Metabolic MR/HP C-13 Pyruvate study (Part B Only)
Patients will undergo repeat MR scan as per above procedures after 21 days (+/- 14 days) of 
treatment with androgen signaling inhibitor. Where applicable, patients should take the 
PI3K/mTOR pathway inhibitor on the day of the MR scan. The target lesion to be evaluated by 
metabolic MRI will be the same as the prior MR unless lesion has become inevaluable in the 
interim in the judgment of study investigators. In these cases, an alternate lesion (evaluable 
baseline MR whenever possible, and adjacent to original target lesion) will be selected for 
analysis.
5.6
Repeat Tumor Biopsy (Part B Only; Optional)
Patients will undergo optional repeat core needle tumor biopsy following completion of the 
second MR scan. When possible, patients should remain on PI3K/mTOR pathway inhibitor 
through the time of the follow up biopsy. The same target lesion will be selected as that 
biopsied at baseline prior to study initiation whenever possible. In the event that the original 
target lesion is no longer accessible for repeat tumor biopsy, an alternative metastatic lesion will 
be selected. Whenever possible, this alternate lesion should be evaluable by metabolic MR 
imaging.
5.7
Every 6-12 weeks (Part B Only)
Patients will undergo standard disease assessments including standard staging scan every 6-12 
weeks per standard of care or per protocol on therapeutic clinical trial. Patients will be followed 
discontinuation of PI3K/mTOR pathway inhibitor therapy, due to disease progression, 
unacceptable toxicity, or patient/physician decision to discontinue therapy.

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Table 2: Schedule of Study Procedures and Assessments
Period/ 
Procedure
Screening 
(28 Days)
Cycle 1
Day 1
Day 21
(+/- 14
days)
Day 28
(+/- 14
days)
Every 6-12 
Weeks
Disease 
Progression
Informed 
consent
X
Baseline 
conditions
X
AE assessment
X
X
Concomitant 
medications
X
X
Physical exam
X
Vital signs
X
X
Medical history/
Demographics
X
Tumor 
Assessment by 
Standard Scans 
(within 3 months 
of C1D1)
X
X
(Part B 
only)
Performance 
status
X
CBC w/ Diff
X
Blood chemistry
X
HP C-
13/metabolic 
MRI
X
X (Part B 
only)
ECG/EKG
X
Part B Only
PI3K/mTOR
Pathway Inhibitor
Tumor biopsy 
(Optional)
X
X
5.8
Supportive Care and Concomitant Medications
There are no prohibited medications with hyperpolarized C-13 pyruvate administration. 
Subjects should receive full supportive care as medically indicated.

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The Principal Investigator or designee will be present during the administration and monitoring 
period.
Any events occurring during or subsequent to the administration of hyperpolarized C-13 
pyruvate 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.

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6
Reporting and Documentation of Results
6.1
Evaluation of Safety
The study will use the CTCAE v4.0 for reporting of adverse events that occur within 3 days of 
each imaging procedure and any biopsy-related adverse events.
6.2
Definitions of Adverse Events
6.2.1
Adverse Event
An adverse event (also known as an adverse experience) is defined as any untoward medical 
occurrence associated with the procedure, whether or not considered 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 procedure, without any judgment 
about causality.  An adverse event can arise from any use of the procedure.
6.2.2
Adverse reaction
An adverse reaction is defined as any adverse event caused by the procedure. Adverse 
reactions are a subset of all suspected adverse reactions for which there is reason to conclude 
that the procedure caused the event.
6.2.2.1 Suspected
A suspected adverse reaction is defined as any adverse event for which there is a reasonable 
possibility that the procedure 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 procedure and the adverse event. A suspected adverse reaction 
implies a lesser degree of certainty about causality than an adverse reaction.
6.2.2.2 Unexpected
An adverse event or suspected adverse reaction is considered unexpected if it is not not 
consistent with the risk information described in the general investigational plan or elsewhere in 
the protocol. 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 
protocol as being related to the imaging procedure.
6.2.2.3 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

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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.
6.2.2.4 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.
6.3
Recording of an Adverse Event
All grade 3 and above adverse events will be recorded using the NCI CTCAE v4.0. The 
Investigator will assign attribution of the possible association of the event with the imaging 
procedure.
Relationship
Attribution
Description
Unrelated
The AE is clearly NOT related to the
Unrelated to investigational 
intervention
Related to investigational 
intervention
intervention
Unlikely
The AE is doubtfully related to the
intervention
Possible
The AE may be related to the intervention 
Probable
The AE is likely related to the intervention 
Definite
The AE is clearly related to the intervention
Signs or symptoms reported as adverse events will be graded and recorded by the Investigator 
according to the CTCAE. When specific adverse events are not listed in the CTCAE they will be 
graded by the Investigator as none, mild, moderate or severe according to the following grades 
and definitions:
Grade 0
No AE (or within normal limits)
Grade 1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated
Grade 2
Moderate; minimal, local, or noninvasive intervention (e.g., packing, cautery) 
indicated; limiting age-appropriate instrumental activities of daily living (ADL)
Grade 3:
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self- 
care ADL
Grade 4:
Life-threatening consequences; urgent intervention indicated
Grade 5:
Death related to AE

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6.4
Follow-up of Adverse Events
All adverse events will be followed with appropriate medical management until resolved. 
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 the imaging procedure 
was stopped, a second attempt at imaging may be conducted if considered both safe and 
ethical by the Investigator.
Reporting to the Data and Safety Monitoring Committee
If a death occurs during the treatment phase of the study or within 30 days after the imaging 
procedure and it is determined to be related either to the 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 Institutional Review Board (IRB)
The Principal Investigator must report events meeting the UCSF IRB definition of “Unanticipated 
Problem” (UP) within 5 business days of his/her awareness of the event.

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7
Statistical Considerations and Image Analysis
7.1
Image Processing and Analysis
For each patient, a target metastatic lesion will be selected on the basis of standard imaging 
(CT or MRI). A region-of-interest (ROI) will be manually drawn in the target lesion, and the same 
lesion will be evaluated on serial MR scans if the lesion continues to remain evaluable by MRI. If 
lesion is no longer evaluable on follow up scan, an alternative lesion will be selected on the 
basis of proximity to original lesion and accessibility by radiofrequency coil for purposes of 
metabolic MR evaluation.
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 serial 
multiparametric imaging data. Intra-tumoral ROI will be used to quantify peak HP 
lactate/pyruvate ratio values in the selected volumes of interest.
In an exploratory fashion, additional metastatic sites in addition to the target lesion will be 
analyzed and interpreted to determine intra-tumoral peak HP lactate/pyruvate ratio.
7.2
Study Endpoints
Primary endpoints:
Part A: Signal-to-noise ratio with respect to intra-tumoral hyperpolarized C-13 lac/pyr ratio 
detected within target liver or other intraabdominal metastasis in patients with advanced solid 
tumor malignancies.
Part B: Mean percent change from baseline in peak intra-tumoral hyperpolarized 
lactate/pyruvate ratio after initiation of treatment with PI3K/mTOR pathway inhibitor.
Secondary endpoints

Frequency of adverse events as graded by Common Toxicity Criteria version 4.0

Association between percent change from baseline in peak intra-tumoral HP 
lactate/pyruvate ratio on metabolic MR imaging with subsequent outcomes on 
PI3K/mTOR pathway inhibitor therapy including clinical benefit rate and progression-free 
survival (Part B)

Intra-patient reproducibility of HP lac/pyr ratio for patients who undergo repeated dose 
imaging studies, as descriptively reported using summary statistics (mean difference, 
standard deviation, range).
Exploratory endpoint
Association between HP peak lactate/pyruvate signal with immunohistochemical expression 
level of markers of PI3K/mTOR and glycolytic pathway, including LDH, phosphorylated S6, and 
phosphorylated Akt. (Part B)
7.3
Sample Size Determination
In Part A of the study, 50 subjects with advanced solid tumor malignancies and at least one 
metastatic liver or intra-abdominal lesion will undergo hyperpolarized C-13

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pyruvate/metabolic MR imaging. The coil arrays will undergo iterative adjustment in geometry 
and design to optimize the signal-to-noise ratio of intra-tumoral HP lactate/pyruvate.
In Part B of the study, the sample size of 30 evaluable patients is based upon the primary 
endpoint of this portion of the study, the mean percent change from baseline in peak intra- 
tumoral lactate/pyruvate ratio in the target metastatic lesion after initiation of treatment with 
PI3K/mTOR pathway inhibitor. Assuming the intra-tumoral lactate/pyruvate ratio is 0.80 at 
baseline and the expected ratio at day 14 is 0.45 (e.g. a 35% decline), based on prior pre- 
clinical studies, then a sample size 30 will have > 85% power to detect the significance of the 
change in signal under paired t-tests with type I error of 5%.
7.4
Subject Characteristics
Demographic information (e.g. age, race, height, weight, and body mass index) will be 
summarized using descriptive statistics.
Concurrent medications will be recorded and coded using a standard classification system.
Disease factors for subjects accrued to the study will be characterized using descriptive 
statistics.
7.5
Replacement Policy
Patients may be replaced in Part B for the following reasons:

Inability to tolerate/complete imaging scan (with no administration of HP C-13 pyruvate)

Failure of the HP C-13 pyruvate to pass quality control testing, preventing its 
administration

Patients who do not undergo subsequent PI3K/mTOR pathway therapy
7.6
Accrual estimates
The study is estimated to accrue approximately 1-2 patients per month leading to an 
approximate total accrual period of 24 months.
7.7
Interim Analysis
Interim analyses will be conducted for both safety and feasibility. Toxicity will be reviewed on a 
continuous basis.  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.
Interim analysis for feasibility in Part B will be performed after 33% of patients have been 
enrolled. Images will be qualitatively reviewed and preliminary data with respect to signal-to- 
noise ratio within metastatic lesions will be assessed. If it is determined that insufficient signal- 
to-noise ratio is present to permit analyses of the primary and secondary endpoints, then study 
accrual will be halted until proper technological adjustments (e.g. alteration of radiofrequency 
coils, timing from polarization to injection of tracer) have been implemented to ensure higher 
quality SNR.

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7.8
Analytic Plan
7.8.1
Analysis Population
All 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.
7.8.2
Primary Analysis
Descriptive statistics will be used to characterize the mean change from baseline in intra- 
tumoral HP pyruvate/lactate ratio for the study cohort, along with 95% confidence interval.
7.8.3
Analysis of Secondary and Exploratory Endpoints
For the purposes of analyzing the association between percent change from baseline in intra- 
tumoral peak lactate/pyruvate ratio on HP MRI with subsequent clinical outcomes, the cohort  
will be dichotomized by the median percent change. The objective response rate by RECIST 1.1 
criteria and clinical benefit rate (response or stable disease for > 24 weeks) will be compared 
between dichotomized groups using the chi-squared test. The log rank test will be used to 
compare the radiographic progression-free survival between the two groups.
Safety analyses will be performed for all patients having received a dose of HP C-13 pyruvate. 
The study will use the NCI CTCAE v4.0.
Analyses will be performed to compare the HP MR markers with immunohistochemical and 
enzyme expression and activity data from biopsy tissue to investigate the molecular and 
physiological underpinnings of the HP 13C MR data. When both the HP biomarker and molecular 
biomarker (LDHA activity) are continuous variables, Spearman’s rank correlation coefficient will 
be used to investigate a possible correlation between them. If the outcome is categorical (e.g. 
immunohistochemistry score 0-1+ vs 2-3+ for pS6, pAkt, LDHA, and MCT 1/4 expression), the 
HP biomarker distributions will be compared between the two categories using the Mann- 
Whitney test.
Intra-patient reproducibility of HP lac/pyr ratio for patients who undergo repeated dose imaging 
studies will be descriptively reported using summary statistics (mean difference, standard 
deviation, range).
No adjustment will be made for multiple comparisons for the analysis of the secondary and 
exploratory endpoints.

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8
Study Management
8.1
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 trial, the Investigator will have written and dated approval from the 
Institutional Review Board for the protocol, written informed consent form, subject recruitment 
materials, and any other written information to be provided to subjects before any protocol 
related procedures are performed on any subjects.
8.2
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 Institutional Review Board (IRB). Prior to obtaining IRB 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.
8.3
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.
8.4
Changes in the Protocol
Once the protocol has been approved by the UCSF IRB, 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 IRB 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 IRB approval. In this circumstance, however, the 
Investigator must then notify the IRB 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.
8.5
Handling and Documentation of Clinical Supplies
The UCSF Principal Investigator and each participating site 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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8.6
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. All study data will be entered into OnCore® via standardized 
CRFs in accordance with the CTMS study calendar, using single data entry with a secure 
access account. 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.
8.7
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.
8.8
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, IRB correspondence and approval, signed patient consent forms).
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research 
study.
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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References
1. Ardenkjaer-Larsen JH, Fridlund B, Gram A, et al. Increase in signal-to-noise ratio of > 10,000 
times in liquid-state NMR. Proc Natl Acad Sci U S A 2003;100:10158-63.
2. Nelson SJ, Kurhanewicz J, Vigneron DB, et al. Metabolic imaging of patients with prostate 
cancer using hyperpolarized [1-13C] pyruvate. Science Translational Medicine 2013;5(198):1-10.
3. Ward CS, Venkatesh HS, Chaumeil MM, et al. Noninvasive detection of target modulation 
following phosphatidylinositol 3-kinase inhibition using hyperpolarized 13C magnetic resonance 
spectroscopy. Cancer Res 2010; 70(4):1296-1305.
4. Chaumeil MM, Ozawa T, Park I, et al. Hyperpolarized 13C MR spectroscopic imaging can be 
used to monitor Everolimus treatment in vivo in an orthotopic rodent model of glioblastoma.
5. V.Z. Miloushev; K.L. Granlund; S. Lyashchenko; P.J.DeNoble; L. DeAngelis; C. Brennan; V. 
Tabar; R.E. Sosa; D. Nicholson; Y. Guo; A.P. Chen; J. Tropp; H. Hricak; K.R. Keshari. First-in- 
human hyperpolarized [1-13C] pyruvate in human brain tumors. 2016 World Molecular Imaging 
Congress, New York, NY, 2016, LBA 015.
6. K.L. Granlund; E. Morris; H. Vargas; S., Lyashchenko; P.J. DeNoble; V. Sacchini; G. Plitas;
R.E. Sosa; M. Kennedy; D. Nicholson; Y. Guo; A.P. Chen; J. Tropp; H. Hricak; K.R. Keshari. 
Metabolic dynamics of hyperpolarized [1-13C] pyruvate in human breast cancer. 2016 World 
Molecular Imaging Congress, New York, NY, 2016, SS 085.

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

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Appendix 2  Data and Safety Monitoring Plan for a Phase 2 or 3 Institutional Study
The UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC) Data and Safety 
Monitoring Committee (DSMC) is responsible for monitoring data quality and subject safety for 
all HDFCCC institutional clinical studies.  A summary of DSMC activities for this study include:

Review of subject data

Review of suspected adverse reactions considered “serious”

Monitoring every six months (depending on study accrual)

Minimum of a yearly regulatory audit
Monitoring and Reporting Guidelines
Investigators will conduct continuous review of data and subject safety and discuss each 
subject’s treatment at monthly Site Committee meetings. These discussions are documented in 
the Site Committee meeting minutes. The discussion will include the number of subjects, 
significant toxicities in accordance with the protocol, and observed responses.
All institutional Phase 2 or 3 studies are designated with a moderate risk assessment. The data 
is monitored twice per year with twenty percent of the subjects monitored (or at least three 
subjects if the calculated value is less than three).
Adverse Event Review and Monitoring
All grade(s) 3-5 adverse events, whether or not unexpected, and whether or not considered to 
be associated with the use of the study drug, will be entered into OnCore®, UCSF’s Clinical 
Trial Management System.
All grade(s) 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 the attribution of relationship of the adverse event to the administration of 
the study drug(s).
In addition, all suspected adverse reactions considered “serious” entered into OnCore®, will be 
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.
If a death occurs during the treatment phase of the study or within 30 days after the last 
administration of the study drug(s) and is determined to be related either to the investigational 
drug or any research related procedure, the Investigator or or the assigned designee must be 
notified within 1 business day from the participating site(s) and the Study Chair must then notify 
the DSMC Chair or qualified alternate within 1 business day of knowledge of this event. The 
contact may be by phone or e-mail.
Increase in 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, a report should be submitted to 
the DSMC 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.
If at any time the Study Chair stops enrollment or stops the study due to safety issues, the 
DSMC Chair and DSMC Manager must be notified within 1 business day via e-mail. The DSMC 
must receive a formal letter within 10 business days and the IRB must be notified.

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Data and Safety Monitoring Committee Contacts
DSMC Chair:
DSMC Monitors
Phone: 
Email: 
Address:
 
Box 1705
UCSF
San Francisco, CA 94158
Box 0128
UCSF Helen Diller Family 
Comprehensive Cancer Center 
San Francisco, CA 94143
* DSMP approved by NCI 09/February2012

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Appendix 3 UCSF Policy/Procedure for Required Regulatory Documents for 
UCSF Investigator-Initiated Oncology Clinical Trials with an Investigator held 
Investigational New Drug (IND)
Purpose
This policy defines the required Regulatory Documents for Single Site and Multicenter 
Investigator Initiated Oncology Clinical Trials at the Helen Diller Family Comprehensive Cancer 
Center (HDFCCC) where the Principal Investigator (PI) holds the IND.
Background
The International Conference on Harmonization (ICH) Good Clinical Practices (GCP) Guidelines 
define Essential Regulatory Documents as those documents which individually and collectively 
permit evaluation of the conduct of a trial and the quality of data produced. These documents 
serve to demonstrate compliance with standards of GCP and with all applicable regulatory 
requirements. Filing essential documents in a timely manner can greatly assist in the successful 
management of a clinical trial.
The Regulatory Documents will consist of electronic files in both iMedRIS and OnCore®, as well 
as paper files in the Regulatory Binders for both the Coordinating Site and the Participating 
Site(s) in the HDFCCC Investigator Initiated Oncology Clinical Trials.
Procedures
1.
HDFCCC Essential Regulatory Documents
Documents Filed in iMedRIS:

IRB approvals for initial submission of application, all modifications, and continuing 
annual renewals

Current and prior approved protocol versions with signed protocol signature page(s)

Committee for Human Research (IRB) approval letters and Informed Consent Form(s) 
(ICF)

Current and prior versions of the Investigator Brochure (IB).

Serious Adverse Event Reporting

Protocol Violations and Single Patient Exception (SPE) Reports to IRB with supporting 
fax documentation
Documents Filed in OnCore®:

Package Insert (if the study drug is commercial) or Investigator Brochure

Protocol Review Committee (PRC) approved protocols, protocol amendments and 
Summary of Changes (SOC)

Patient handouts

Screening/enrollment log

Data and Safety Monitoring Committee (DSMC) monitoring reports

OnCore® Case Report Form (CRF) completion manual

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Documents Filed in Regulatory Binder:

Completed Food and Drug Administration (FDA) 1572 document with Principal 
Investigator’s signature

For all Principal Investigators and Sub-Investigators listed on the FDA 1572, will need 
Financial Disclosure Forms, CVs, MD Licenses, Drug Enforcement Agency (DEA) 
Licenses, and Staff Training Documents (i.e. Collaborative Institute Training Initiative 
(CITI), etc.)

Site Initiation Visit (SIV) minutes and correspondence with participating site(s).

As applicable, approvals for Biosafety Committee, Radiation Committee, and Infusion 
Center

Serious Adverse Event (SAE) reports to IRB and sponsor.

MedWatch reporting to FDA and sponsor

Delegation of Authority Form

Drug Destruction Standard Operating Procedure (SOP)

For all laboratories listed on the FDA 1572, will need CLIA certifications, CAP 
certifications, lab licenses, CVs of Lab Directors, and laboratory reference ranges