Clinical trial NCT03565367
Conditions: Malignant Central Nervous System Neoplasm Metastatic Malignant Neoplasm in the Central Nervous System
Sponsor: Daniel M. Spielman
Start date: 2018-11-06; Completion date: 2019-06-20
Enrollment: 9 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This early phase I trial studies how well hyperpolarized carbon C 13 pyruvate magnetic resonance imaging works in detecting lactate and bicarbonate in participants with central nervous system tumors. Hyperpolarized carbon C 13 pyruvate magnetic resonance imaging may be used to measure the metabolic state of malignant brain tumors.

Detailed description:
PRIMARY OBJECTIVES:

I. To assess the safety of intravenous (IV) injection of hyperpolarized carbon C 13 pyruvate (hyperpolarized \[1-13C\] pyruvate) for magnetic resonance imaging (MRI).

II. To assess the frequency and sensitivity with which lactate and bicarbonate signals can be detected in malignant brain tumors after IV injection of hyperpolarized \[1-13C\] pyruvate.

OUTLINE:

Participants undergo MRI over 45 minutes at baseline. Participants then receive hyperpolarized carbon C 13 pyruvate IV over 30-40 seconds. Within 1 minute, participants undergo magnetic resonance spectroscopic imaging (MRSI) over 3 minutes and MRI over 10 minutes (participants may receive gadolinium at the discretion of the protocol director).

After completion of study, participants are followed up periodically.

Arms: arm 1: Participants undergo MRI over 45 minutes at baseline. Participants then receive hyperpolarized carbon C 13 pyruvate IV over 30-40 seconds. Within 1 minute, participants undergo MRSI over 3 minutes and MRI over 10 minutes. arm 2: Participants undergo MRI over 45 minutes at baseline. Participants then receive hyperpolarized carbon C 13 pyruvate IV over 30-40 seconds. Within 1 minute, participants undergo MRSI over 3 minutes and MRI over 10 minutes (participants may receive gadolinium at the discretion of the protocol director).
Interventions: intervention 1: Gadolinium intervention 2: Hyperpolarized Carbon C 13 Pyruvate intervention 3: Magnetic Resonance Imaging intervention 4: Magnetic Resonance Spectroscopic Imaging
Intervention descriptions: intervention 1: gadolinium enhanced MRI intervention 2: Given IV intervention 3: Undergo MRI intervention 4: Undergo MRSI

Protocol documents:
ICF_002.pdf: 
A Pilot Study to Assess lactate and bicarbonate detection within Malignant Brain 
Tumors using [1-13C]-pyruvate DNP Magnetic Resonance Spectroscopy (MRS) 
Informed Consent Form 
NCT03565367 
October 19, 2021 


STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Lawrence Recht, M.D. 
Protocol Title: A Pilot Study to Assess lactate and bicarbonate detection within Malignant Brain Tumors using 
[1-13C]-pyruvate DNP Magnetic Resonance Spectroscopy (MRS)  
Page 1 of 13 
Pyruvate Imaging ICF dated 15 May 2019 
IRB Use Only 
Approval Date:   October 19, 2021 
Expiration Date: October 19, 2022 
Participant ID: 
Arm 2 CNS Malignancy Participants INFORMED CONSENT FORM 
Are you participating in any other research studies? _____ Yes _____No 
PURPOSE OF RESEARCH 
You are invited to participate in a research study to assess the safety of infusing 
13C-labeled hyperpolarized pyruvate (HP-pyruvate) prior to performing magnetic 
resonance spectroscopic imaging (MRSI).  HP-pyruvate is “investigational”, meaning that 
it is not approved by the US Food and Drug Administration (FDA) for use outside clinical 
research studies.  Pyruvate is a naturally produced sugar intermediate in your body that 
is essential for making energy.  Hyperpolarized MRSI is a new technology that enhances 
our ability to image the pyruvate by changing its magnetic properties, but otherwise the 
labeled pyruvate is identical to the sugar intermediate in your body.  The hyperpolarized 
pyruvate is non-toxic and non-radioactive, and will be metabolized by your body is the 
same rapid manner as all naturally produced pyruvate.   
In part because of their rapid growth rate, all cancer cells convert (metabolize) sugar into 
energy differently from normal cells.  Investigators hope to learn whether an IV infusion of 
hyperpolarized pyruvate can be used to measure the metabolic state of malignant brain 
tumors.  You were selected as a possible participant in this study because you have been 
diagnosed with Central Nervous System (CNS) malignancy. 
Investigators believe finding drugs that reverse the abnormal cancer metabolism would 
be effective in slowing cancer growth with minimal side effects on normal cells.  However, 
there is currently no good way to detect this abnormal cancer metabolism in patients.  
This research study hopes to test the use of hyperpolarized pyruvate as a way to detect 
abnormal cancer metabolism, which could help investigators study new ways to treat 
cancer. 
If you decide to terminate your participation in this study, you should notify Dr. Lawrence 
Recht at (650) 498-6000.   
This research study is looking for 5 healthy volunteers and 10 participants with a 
diagnosis of CNS malignancy, including metastases, who are eligible to undergo MRI.  
Stanford University expects to enroll 15 research study participants.   
VOLUNTARY PARTICIPATION 
Your participation in this study is entirely voluntary.  Your decision not to participate will 
not have any negative effect on you or your medical care.  You can decide to participate 
now, but withdraw your consent later and stop being in the study without any loss of 
benefits or medical care to which you are entitled. 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Lawrence Recht, M.D. 
Protocol Title: A Pilot Study to Assess lactate and bicarbonate detection within Malignant Brain Tumors using 
[1-13C]-pyruvate DNP Magnetic Resonance Spectroscopy (MRS)  
 
 
Page 2 of 13 
 
Pyruvate Imaging ICF dated 15 May 2019 
IRB Use Only 
Approval Date:   October 19, 2021 
Expiration Date: October 19, 2022 
Participant ID: 
DURATION OF STUDY INVOLVEMENT  
This research study is expected to take approximately 3 days.  Screening may take up 
to 14 days.  During the first day of treatment, you will undergo the experimental 
procedure and afterwards, an EKG will be obtained.  Once during the next 2-4 days, 
you will be contacted by the research study staff to collect information on any side 
effects of the procedure.   
 
PROCEDURES 
If you choose to participate, the Protocol Director Dr. Lawrence Recht and his research 
study staff will describe all procedures to be followed.   
 
Screening 
If you sign the informed consent form and agree to participate, the following screening 
procedures will be performed within 14 days prior to Day 1: 
• Collect demographics 
• Measure vital signs (heart rate, temperature, blood pressure), height and weight 
• Blood drawn for laboratory safety tests, totaling 1-2 teaspoons 
• Electrocardiogram (ECG): An ECG detects the heart's electrical activity through 
sticky pads attached to your body 
• If you are a female capable of bearing children, you will be required to have a 
blood (less than 1 teaspoon) pregnancy test. 
 
Treatment Period 
On Day 1, imaging will be performed in the Richard M. Lucas Center at Stanford 
University.  Production of HP-pyruvate will be coordinated with imaging schedule such 
that MRSI scan begins within 1 minute of HP-pyruvate administration.  
 
Following injection of HP-pyruvate, patients will be imaged on a standard 3T MRI 
scanner.  You will undergo the following procedures: 
• Measure vital signs 
• Magnetic Resonance Imaging (MRI) scan of brain, 45 min acquisition time using 
standard non-contrast clinical brain collection setup. MRI machines use a strong 
magnet and radiofrequency magnetic fields to make images of the body’s 
interior.  The scanning procedure is very much like an X-ray or CT scan.  You will 
be asked to lie on a long narrow couch for 1 hour while the machine gathers 
data.  During this time you will not be exposed to x-rays, but rather a strong 
magnetic field and radiofrequency magnetic fields, which you will not feel.  You 
will, however, hear repetitive tapping noises that arise from the MRI scanner.  We 
will provide earplugs or headphones that you will be required to wear.  The space 
within the large magnet in which you lie is somewhat confined, although we have 
taken many steps to relieve the "claustrophobic" feeling. 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Lawrence Recht, M.D. 
Protocol Title: A Pilot Study to Assess lactate and bicarbonate detection within Malignant Brain Tumors using 
[1-13C]-pyruvate DNP Magnetic Resonance Spectroscopy (MRS)  
 
 
Page 3 of 13 
 
Pyruvate Imaging ICF dated 15 May 2019 
IRB Use Only 
Approval Date:   October 19, 2021 
Expiration Date: October 19, 2022 
Participant ID: 
• Administration of HP-pyruvate through an intravenous (IV) tube placed in your 
arm 
• Magnetic Resonance Spectroscopy Imaging (MRSI) scan of brain, 3 min 
acquisition 
• MRI scan of brain, 10 min acquisition time using standard Gadolinium-enhanced 
contrast clinical brain collection. Gadolinium contrast agent may or may not be 
administered at the discretion of the Protocol Director. 
• Within 10 minutes after the conclusion of image collection 
o Measure vital signs 
o Collect any adverse events and monitor injection site 
• At least once more 20-45 min after the conclusion of image collection. 
o Measure vital signs 
o Collect any adverse events and monitor injection site 
• Within 1 to 5 hours after HP-pyruvate administration: 
o Measure vital signs 
o ECG 
o Collect any adverse events and monitor injection site 
  
Between Day 2 and Day 4, your study doctor or research staff will contact you by phone 
or in person at a clinic visit to see how you are feeling.   
 
Future Use of Private Information  
Research using private information is an important way to try to understand human 
disease.  You are being given this information because the investigators want to save 
imaging data with private information for future research.  All study files and images 
will be labeled with a subject identification (ID) number and possibly initials. 
Identifiers might be removed from identifiable private information and, after such 
removal, the information could be used for future research studies or distributed to 
another investigator for future research studies without additional informed consent 
from you.  
 
PARTICIPANT RESPONSIBILITIES           
As a participant, your responsibilities include:  
• Follow the instructions of the Protocol Director and study staff. 
• Keep your study appointments.  If it is necessary to miss an appointment, please 
contact the Protocol Director or research study staff to reschedule as soon as 
you know you will miss the appointment. 
• Tell the Protocol Director or research study staff about any side effects, doctor 
visits, or hospitalizations that you may have. 
• Tell the Protocol Director or research staff if you believe you might be pregnant 
or gotten your partner pregnant. 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Lawrence Recht, M.D. 
Protocol Title: A Pilot Study to Assess lactate and bicarbonate detection within Malignant Brain Tumors using 
[1-13C]-pyruvate DNP Magnetic Resonance Spectroscopy (MRS)  
 
 
Page 4 of 13 
 
Pyruvate Imaging ICF dated 15 May 2019 
IRB Use Only 
Approval Date:   October 19, 2021 
Expiration Date: October 19, 2022 
Participant ID: 
• Ask questions as you think of them. 
• Tell the Protocol Director or research staff if you change your mind about staying 
in the study. 
 
WITHDRAWAL FROM STUDY 
If you first agree to participate and then you change your mind, you are free to withdraw 
your consent and discontinue your participation at any time.  Your decision will not 
affect your ability to receive medical care for your disease and you will not lose any 
benefits to which you would otherwise be entitled.   
If you decide to withdraw your consent to participate in this study, you should notify Dr. 
Lawrence Recht at (650) 498-6000. 
 
The Protocol Director may also withdraw you from the study without your consent for 
one or more of the following reasons:   
o Failure to follow the instructions of the Protocol Director and study staff. 
o The Protocol Director decides that continuing your participation could be 
harmful to you. 
o Pregnancy  
o The study is cancelled.   
o Other administrative reasons. 
o Unanticipated circumstances. 
 
POSSIBLE RISKS, DISCOMFORTS, AND INCONVENIENCES  
There are risks, discomforts, and inconveniences associated with any research study.  
These deserve careful thought.  You should talk with the Protocol Director if you have 
any questions. 
 
MRI / MRSI Risks: 
Magnetic fields do not cause harmful effects at the levels used in the MRI machine.  
However, the MR scanner uses a very strong magnet that will attract some metals and 
affect some electronic devices.  If you have a cardiac pacemaker or any other biomedical 
device in or on your body, it is very important that you tell the operator/investigator 
immediately.  As metallic objects may experience a strong attraction to the magnet, it is 
also very important that you notify the operator of any metal objects (especially surgical 
clips), devices, or implants that are in or on your body before entering the magnet room.  
All such objects must be removed (if possible) before entering the magnet room.  In some 
cases, having those devices means you should not have an MRI scan performed.  In 
addition, watches and credit cards should also be removed as these could be damaged.  
You will be provided a way to secure these items.  If you have any history of head or eye 
injury involving metal fragments, if you have ever worked in a metal shop, or if you could 
be pregnant, you should notify the operator/investigator.  You should also notify the 
operator/investigator if you have any tattoos on your body, including eyeliner and other 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Lawrence Recht, M.D. 
Protocol Title: A Pilot Study to Assess lactate and bicarbonate detection within Malignant Brain Tumors using 
[1-13C]-pyruvate DNP Magnetic Resonance Spectroscopy (MRS)  
 
 
Page 5 of 13 
 
Pyruvate Imaging ICF dated 15 May 2019 
IRB Use Only 
Approval Date:   October 19, 2021 
Expiration Date: October 19, 2022 
Participant ID: 
permanent makeup.  Tattoos could become warm and irritated during the scan and 
remain so for several days.  If you would prefer not to participate in the MR scan due to 
the presence of tattoos on your body, please inform a research team member. 
 
There is a possibility that you will experience a localized twitching sensation due to the 
magnetic field changes during the scan. This is not unexpected and should not be 
painful.  However, you may have the scan stopped at any time if this occurs. There is 
also a possibility of tinnitus (ringing in the ears) after the MRI. 
If you have had a previous reaction to Gadolinium-based contrast agents or a history of 
severe allergies, please notify the operator/investigator.  If you have kidney problems, 
please tell the operator. 
 
It has been observed that deposits of Gadolinium-based contrast agent (GBCA) remain in 
the brains of some people who undergo four or more contrast enhanced MRI scans, long 
after the last administration.  It is not yet known whether these Gadolinium deposits are 
harmful or can lead to adverse health effects.  You should talk to the study doctor if you 
have any questions about the use of GBCAs with MRIs. 
 
IF YOU FEEL DISCOMFORT AT ANY TIME, NOTIFY THE OPERATOR AND YOU 
CAN DISCONTINUE THE EXAM AT ANY TIME. 
 
The scans performed in this study are for specific research purposes and are not 
optimized to find medical abnormalities.  The investigators for this project may not be 
trained to perform medical diagnosis.  The investigators and Stanford are not 
responsible for failure to find existing abnormalities with these MRI scans.  However, on 
occasion the investigator may notice a finding on an MRI scan that seems abnormal.  
When this occurs, a physician will be consulted as to whether the findings merit further 
investigation, in which case the investigator will contact you and your primary care 
physician and inform you of the finding.  The decision as to whether to proceed with 
further examination or treatment lies solely with you and your physician.  The 
investigators, the consulting physician, and Stanford are not responsible for any 
examination or treatment that you undertake based on these findings.  Because the 
images collected in this study may not comprise a proper clinical MRI scan, these 
images will not be made available for diagnostic purposes. 
 
HP-Pyruvate Risks:  
In all clinical studies of HP-pyruvate performed to date, no dose-limiting side effects or 
toxicities deemed to be clinically significant were noted.  However, it is possible some 
risks are currently unknown or unforeseeable.  We will not exceed the maximum 
dosages used in prior studies.  
 
In other clinical studies of HP-pyruvate, the following adverse events were noted: 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Lawrence Recht, M.D. 
Protocol Title: A Pilot Study to Assess lactate and bicarbonate detection within Malignant Brain Tumors using 
[1-13C]-pyruvate DNP Magnetic Resonance Spectroscopy (MRS)  
 
 
Page 6 of 13 
 
Pyruvate Imaging ICF dated 15 May 2019 
IRB Use Only 
Approval Date:   October 19, 2021 
Expiration Date: October 19, 2022 
Participant ID: 
• Bad or metallic taste in mouth 
• Dizziness 
• Diarrhea 
• Flushing 
• Headache 
• Feeling hot 
• Throat discomfort 
 
All side effects noted in HP-pyruvate studies were mild, short-lasting reactions. The 
reported side effects are similar to those reported after IV injection of other contrast 
agents, such as those used for X-ray and MRI evaluations. 
 
Study Procedure Risks: 
Blood Draw:  Blood sampling and needle punctures carry some risk.  Possible side 
effects include, but are not limited to fainting, bleeding, bruising, discomfort, dizziness, 
infection and/or pain at the puncture site.  Rare but permanent nerve damage can 
occur. 
 
ECG Risk:  An electrocardiogram (ECG) is a harmless and painless test with no serious 
risks.  The ECG detects the heart's electrical activity and don't give off electrical 
charges, such as shocks.  You may develop a mild rash where the electrodes (soft 
patches) were attached, which may go away without treatment. 
 
POTENTIAL BENEFITS                              
Taking part in this study may or may not make your health better.  This information 
could help future cancer patients. 
 
We cannot and do not guarantee or promise that you will receive any benefits from this 
study. 
 
ALTERNATIVES 
The alternative is not to participate in this Study.  Choosing to not participate in this 
Study will not affect the care you receive at Stanford Hospital. 
 
PARTICIPANT’S RIGHTS 
You should not feel obligated to agree to participate.  Your questions should be 
answered clearly and to your satisfaction.  If you decide not to participate, tell the 
Protocol Director.   
 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Lawrence Recht, M.D. 
Protocol Title: A Pilot Study to Assess lactate and bicarbonate detection within Malignant Brain Tumors using 
[1-13C]-pyruvate DNP Magnetic Resonance Spectroscopy (MRS)  
 
 
Page 7 of 13 
 
Pyruvate Imaging ICF dated 15 May 2019 
IRB Use Only 
Approval Date:   October 19, 2021 
Expiration Date: October 19, 2022 
Participant ID: 
You will be told of any important new information that is learned during the course of 
this research study, which might affect your condition or your willingness to continue 
participation in this study. 
 
ClinicalTrials.gov 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by US Law.  This web site will not include information that can identify you.  
At most, the web site will include a summary of the results.  You can search this 
web site at any time.  
 
CONFIDENTIALITY 
The results of this research study may be presented at scientific or medical meetings or 
published in scientific journals.  Your identity and/or your personal health information will 
not be disclosed except as authorized by you or as required by law.  However, there is 
always some risk that even de-identified information might be re-identified.   
 
Patient information may be provided to Federal and other regulatory agencies as 
required.  The Food and Drug Administration (FDA), for example, may inspect research 
records and learn your identity if this study falls within its jurisdiction. 
 
The purpose of this research study is to obtain data or information on the safety and 
effectiveness of hyperpolarized [1-13C]-pyruvate; the results will be provided to the 
sponsor, the Food and Drug Administration and other federal and regulatory agencies 
as required. 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Lawrence Recht, M.D. 
Protocol Title: A Pilot Study to Assess lactate and bicarbonate detection within Malignant Brain Tumors using 
[1-13C]-pyruvate DNP Magnetic Resonance Spectroscopy (MRS)  
 
 
Page 8 of 13 
 
Pyruvate Imaging ICF dated 15 May 2019 
IRB Use Only 
Approval Date:   October 19, 2021 
Expiration Date: October 19, 2022 
Participant ID: 
Authorization To Use Your Health Information 
For Research Purposes  
Because information about you and your health is personal and private, it 
generally cannot be used in this research study without your written 
authorization.  If you sign this form, it will provide that authorization.  The 
form is intended to inform you about how your health information will be 
used or disclosed in the study.  Your information will only be used in 
accordance with this authorization form and the informed consent form and 
as required or allowed by law.  Please read it carefully before signing it.   
 
What is the purpose of this research study and how will my health 
information be utilized in the study? 
This is a clinical research study to evaluate the safety and efficacy of 
hyperpolarized [1-13C]-pyruvate, an investigational agent.  Your health 
information will be used to verify the study conduct and data entry, assess 
the study drug effects, and prepare regulatory documents for submission to 
FDA.  Your coded information may also be used in research related to the 
study drug, your cancer and related diseases, and/or diagnostics to inform 
treatment; or in scientific publications. 
 
Do I have to sign this authorization form? 
You do not have to sign this authorization form.  But if you do not, you will 
not be able to participate in this research study, including receiving any 
research-related treatment.  Signing the form is not a condition for receiving 
any medical care outside the study. 
 
If I sign, can I revoke it or withdraw from the research later? 
If you decide to participate, you are free to withdraw your authorization 
regarding the use and disclosure of your health information (and to 
discontinue any other participation in the study) at any time.  After any 
revocation, your health information will no longer be used or disclosed in 
the study, except to the extent that the law allows us to continue using your 
information (e.g., necessary to maintain integrity of research).  If you wish 
to revoke your authorization for the research use or disclosure of your 
health information in this study, you must write to:  
Lawrence Recht, M.D. 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Lawrence Recht, M.D. 
Protocol Title: A Pilot Study to Assess lactate and bicarbonate detection within Malignant Brain Tumors using 
[1-13C]-pyruvate DNP Magnetic Resonance Spectroscopy (MRS)  
 
 
Page 9 of 13 
 
Pyruvate Imaging ICF dated 15 May 2019 
IRB Use Only 
Approval Date:   October 19, 2021 
Expiration Date: October 19, 2022 
Participant ID: 
875 Blake Wilbur Drive, Rm 
  
Stanford, California 94305-
 
 
What Personal Information Will Be Obtained, Used or Disclosed? 
Your health information related to this study, may be used or disclosed in 
connection with this research study, including, but not limited to,  
• the history and diagnosis of your disease;  
• specific information about the treatments you received, including 
previous treatment(s) you may have had;  
• information about other medical conditions that may affect your 
treatment;  
• medical data, including laboratory test results, tumor measurements, 
CT scans, MRIs, x-rays, and pathology results;  
• information on side effects (adverse events) you may experience, and 
how these were treated;  
• long-term information about your general health status and the status 
of your disease;  
• data that may be related to tissue and/or blood samples that may be 
collected from you; and  
• numbers or codes that will identify you, such as your social security 
number, medical record number, initials, and date of birth.   
 
Who May Use or Disclose the Information? 
The following parties are authorized to use and/or disclose your health 
information in connection with this research study: 
• The Protocol Director Dr.  Lawrence Recht 
• The IND Holder, Dr. Daniel Spielman 
• The Stanford University Administrative Panel on Human Subjects in 
Medical Research and any other unit of Stanford University as 
necessary 
• Research Staff 
  
 
 
 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Lawrence Recht, M.D. 
Protocol Title: A Pilot Study to Assess lactate and bicarbonate detection within Malignant Brain Tumors using 
[1-13C]-pyruvate DNP Magnetic Resonance Spectroscopy (MRS)  
 
 
Page 10 of 13 
 
Pyruvate Imaging ICF dated 15 May 2019 
IRB Use Only 
Approval Date:   October 19, 2021 
Expiration Date: October 19, 2022 
Participant ID: 
Who May Receive or Use the Information? 
The parties listed in the preceding paragraph may disclose your health 
information to the following persons and organizations for their use in 
connection with this research study:  
• The Office for Human Research Protections in the U.S.  Department 
of Health and Human Services 
• The Food and Drug Administration 
 
Your information may be re-disclosed by the recipients described above, if 
they are not required by law to protect the privacy of the information. 
 
When will my authorization expire? 
Your authorization for the use and/or disclosure of your health information 
will end on December 31, 2050 or when the research project ends, 
whichever is earlier.   
 
Will access to my medical record be limited during the study? 
To maintain the integrity of this research study, you may not have access to 
any health information developed as part of this study until it is completed.  
At that point, you would have access to such health information if it was 
used to make a medical or billing decision about you (e.g., if included in 
your official medical record).   
 
 
________________________________            ______________ 
Signature of Adult Participant                                        Date 
 
 
________________________________             
 
Print Name of Adult Participant                                         
 
 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Lawrence Recht, M.D. 
Protocol Title: A Pilot Study to Assess lactate and bicarbonate detection within Malignant Brain Tumors using 
[1-13C]-pyruvate DNP Magnetic Resonance Spectroscopy (MRS)  
 
 
Page 11 of 13 
 
Pyruvate Imaging ICF dated 15 May 2019 
IRB Use Only 
Approval Date:   October 19, 2021 
Expiration Date: October 19, 2022 
Participant ID: 
FINANCIAL CONSIDERATIONS 
Payment 
You will receive a payment of $
 to participate in this study. 
 
Payments may only be made to U.S. citizens, legal resident aliens, and those who have 
a work eligible visa. You may need to provide your social security number to receive 
payment. 
 
Costs 
There is no cost to you for participating in this study, other than basic expenses like 
transportation and the personal time it will take to come to all of the study visits. 
 
Funding 
Stanford University and NIH funding is providing financial support and/or material for 
this study. 
 
COMPENSATION for Research-Related Injury 
All forms of medical diagnosis and treatment – whether routine or experimental – 
involve some risk of injury.  In spite of all precautions, you might develop medical 
complications from participating in this study.  If such complications arise, the Protocol 
Director and the research study staff will assist you in obtaining appropriate medical 
treatment.  In the event that you have an injury or illness that is directly caused by your 
participation in this study, reimbursement for all related costs of care first will be sought 
from your insurer, managed care plan, or other benefits program.  You will be 
responsible for any associated co-payments or deductibles as required by your 
insurance. 
 
If costs of care related to such an injury are not covered by your insurer, managed care 
plan or other benefits program, you may be responsible for these costs.  If you are 
unable to pay for such costs, the Protocol Director will assist you in applying for 
supplemental benefits and explain how to apply for patient financial assistance from the 
hospital. 
 
You do not waive any liability rights for personal injury by signing this form. 
 
CONTACT INFORMATION  
Questions, Concerns, or Complaints:  If you have any questions, concerns or 
complaints about this research study, its procedures, risks and benefits, or alternative 
courses of treatment, you should ask the Protocol Director, Dr. Lawrence Recht at (650) 
725-8630.  You should also contact him at any time if you feel you have been hurt by 
being a part of this study. 
 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Lawrence Recht, M.D. 
Protocol Title: A Pilot Study to Assess lactate and bicarbonate detection within Malignant Brain Tumors using 
[1-13C]-pyruvate DNP Magnetic Resonance Spectroscopy (MRS)  
 
 
Page 12 of 13 
 
Pyruvate Imaging ICF dated 15 May 2019 
IRB Use Only 
Approval Date:   October 19, 2021 
Expiration Date: October 19, 2022 
Participant ID: 
Independent Contact:  If you are not satisfied with how this study is being conducted, 
or if you have any concerns, complaints, or general questions about the research or 
your rights as a participant, please contact the Stanford Institutional Review Board (IRB) 
to speak to someone independent of the research team at (650) 723-5244 or toll free at 
1-866-680-2906.  You can also write to the Stanford IRB, Stanford University, 1705 El 
Camino Real, Palo Alto, CA 94306. 
 
EXPERIMENTAL SUBJECT’S BILL OF RIGHTS 
As a research participant you have the following rights.  These rights include but are not 
limited to the participant's right to: 
• 
be informed of the nature and purpose of the experiment;  
• 
be given an explanation of the procedures to be followed in the medical 
experiment, and any drug or device to be utilized;  
• 
be given a description of any attendant discomforts and risks reasonably to be 
expected;  
• 
be given an explanation of any benefits to the subject reasonably to be expected, 
if applicable;  
• 
be given a disclosure of any appropriate alternatives, drugs or devices that might 
be advantageous to the subject, their relative risks and benefits; 
• 
be informed of the avenues of medical treatment, if any available to the subject 
after the experiment if complications should arise;  
• 
be given an opportunity to ask questions concerning the experiment or the 
procedures involved;  
• 
be instructed that consent to participate in the medical experiment may be 
withdrawn at any time and the subject may discontinue participation without 
prejudice;  
• 
be given a copy of the signed and dated consent form; and  
• 
be given the opportunity to decide to consent or not to consent to a medical 
experiment without the intervention of any element of force, fraud, deceit, duress, 
coercion or undue influence on the subject's decision. 
 
Signing your name means you agree to be in this study and that you will receive a 
copy of this signed and dated consent form.   
 
 
_____________________________________  
 
____________ 
Signature of Adult Participant 
 
 
 
 
Date 
 
 
_____________________________________ 
Print Name of Adult Participant 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Lawrence Recht, M.D. 
Protocol Title: A Pilot Study to Assess lactate and bicarbonate detection within Malignant Brain Tumors using 
[1-13C]-pyruvate DNP Magnetic Resonance Spectroscopy (MRS)  
 
 
Page 13 of 13 
 
Pyruvate Imaging ICF dated 15 May 2019 
IRB Use Only 
Approval Date:   October 19, 2021 
Expiration Date: October 19, 2022 
Participant ID: 
 
 
_____________________________________  
 
____________ 
Signature of Person Obtaining Consent  
 
 
Date 
 
 
_____________________________________ 
Print Name of Person Obtaining Consent 
 
The following witness line is to be signed only if the consent is provided as a summary 
form and accompanied by a short form foreign language consent. 
 
 
_____________________________________  
 
____________ 
Signature of Witness 
 
 
 
 
 
Date 
 
 
_____________________________________ 
Print Name of Witness   
(e.g., staff, translator/interpreter, family member) 
• Translated short form must be signed and dated by both the participant (or their LAR) AND the 
witness. 
• The English consent form (referred to as the "Summary Form" in the regulations): 
− Must be signed by the witness AND the Person Obtaining Consent (POC). 
− The non-English speaking participant/LAR does not sign the English consent. 
− The non-English speaking participant/LAR should not sign the HIPAA participant line 
− If the participant or the LAR is non-English speaking, the Person Obtaining Consent (POC) must 
ensure that 1) the LAR's Description of Authority is completed and 2) that any questions or 
options presented by the consent form are documented and initialed by the POC on the Summary 
Form, per the participant's wishes, as they are understood during the consent process. 

Prot_SAP_000.pdf: 
 
 
 
 
A Pilot Study to Assess lactate and bicarbonate detection within Malignant Brain 
Tumors using [1-13C]-pyruvate DNP Magnetic Resonance Spectroscopy (MRS) 
Study Protocol and Statistical Analysis Plan 
NCT03565367 
May 15, 2019 


Study IRB-39845 / BRN0036 
Version Date 15 May 2019 
Page 1 of 18 
CONFIDENTIAL 
A Pilot Study to Assess lactate and bicarbonate detection within Malignant Brain 
Tumors using [1-13C]-pyruvate DNP Magnetic Resonance Spectroscopy (MRS) 
 
Protocol Director 
Lawrence Recht MD 
Phone: 650 725-8630 
Fax: 650 498-4686 
LRecht@stanford.edu 
 
Dept of Neurology, 
875 Blake Wilbur Drive, 
 
Palo Alto 94305 
 
 
Co-Investigators 
Daniel Spielman PhD 
Phone: 650 723-8697 
Fax: 650 723-9222 
spielman@stanford.edu 
 
 
Frederick T. Chin, Ph.D. 
Phone: 650 725-4182 
Fax: 650 618-0415 
chinf@stanford.edu 
 
 
Bin Shen Ph.D. 
Phone: 650-736-2844 
Fax: 650 618-0415 
binshen@stanford.edu 
 
 
Lucas Center for Medical Imaging, 
1201 Welch Rd, 
 
Stanford, CA  94305 
 
 
 
Biostatistician 
None 
 
Study Coordinator 
  Phone:  
 
  Phone: 
 
                                   
 Phone: 
 
 
800 Welch Road, 
 
Palo Alto, CA  94305 
 
Study Coordinators’ Fax:  
 


Study IRB-39845 / BRN0036 
Version Date 15 May 2019 
Page 2 of 18 
CONFIDENTIAL 
TABLE OF CONTENTS 
TABLE OF CONTENTS ............................................................................................................... 2 
SCHEMA ...................................................................................................................................... 4 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ........................................................ 5 
1. 
OBJECTIVES ....................................................................................................................... 6 
1.1. 
Primary Objectives ........................................................................................................ 6 
2. 
BACKGROUND .................................................................................................................... 6 
2.1. 
Study Disease ............................................................................................................... 6 
2.2. 
Study Agent/Device/Imaging procedure ........................................................................ 6 
2.3. 
Clinicaltrials.gov ............................................................................................................ 7 
2.4. 
Rationale ....................................................................................................................... 8 
2.5. 
Preliminary results ......................................................................................................... 8 
2.6. 
Study Design ................................................................................................................. 8 
3. 
PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES ................................... 8 
3.1. 
Inclusion Criteria............................................................................................................ 8 
3.2. 
Exclusion Criteria .......................................................................................................... 8 
3.3. 
Informed Consent Process ............................................................................................ 9 
3.4. 
Study Timeline............................................................................................................... 9 
4. 
IMAGING AGENT/DEVICE/PROCEDURE INFORMATION ................................................ 9 
4.1. 
Hyperpolarized [1-13C]-Pyruvate ................................................................................... 9 
4.2. 
Dissolution DNP MRSI .................................................................................................. 9 
4.3. 
Dose Modification .......................................................................................................... 9 
5. 
STUDY PROCEDURES ...................................................................................................... 10 
6. 
STUDY CALENDAR ........................................................................................................... 11 
7. 
ADVERSE EVENTS AND REPORTING PROCEDURES .................................................. 12 
7.1. 
Potential Adverse Events ............................................................................................ 12 
7.2. 
Adverse Event Collection ............................................................................................ 12 
7.3. 
Adverse Event Reporting ............................................................................................ 12 
8. 
REGULATORY CONSIDERATIONS ................................................................................. 13 
8.1. 
Institutional Review of Protocol ................................................................................... 13 
8.2. 
Data Management Plan ............................................................................................... 13 
8.3. 
Data and Safety Monitoring Plan ................................................................................. 13 
9. 
MEASUREMENTS .............................................................................................................. 14 
9.1. 
Primary and Secondary Outcome measures .............................................................. 14 
9.2. 
Measurement Methods ................................................................................................ 14 
9.3. 
Measurement Time Points .......................................................................................... 14 
9.4. 
Response Review ....................................................................................................... 14 
10. 
STATISTICAL CONSIDERATIONS ............................................................................... 14 
10.1. Statistical Design ......................................................................................................... 14 
10.2. Randomization ............................................................................................................ 14 


Study IRB-39845 / BRN0036 
Version Date 15 May 2019 
Page 3 of 18 
CONFIDENTIAL 
10.3. Interim analyses .......................................................................................................... 14 
10.4. Descriptive Statistics and Exploratory Data Analysis .................................................. 14 
10.5. Primary Analysis .......................................................................................................... 15 
10.6. Sample Size ................................................................................................................ 15 
10.7. Accrual estimates ........................................................................................................ 15 
10.8. Criteria for future studies ............................................................................................. 15 
11. 
REFERENCES ................................................................................................................ 16 
Appendix A:  Inclusion/Exclusion Criteria Checklist............................................................. 18 
 
 
 


Study IRB-39845 / BRN0036 
Version Date 15 May 2019 
Page 4 of 18 
CONFIDENTIAL 
SCHEMA 
 
 
 
 
 
 
 
 
 
Safety Monitoring until Day 2 (+2) 


Study IRB-39845 / BRN0036 
Version Date 15 May 2019 
Page 5 of 18 
CONFIDENTIAL 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Asparagine aminotransferase 
BIC 
Bicarbonate 
CBV 
Cerebral blood volume 
CNS 
Central nervous system 
CRF 
Case report form 
DCA 
Dichloroacetate 
DLT 
Dose Limiting Toxicity 
DNP 
Dynamic nuclear polarization 
DSMC 
Data Safety Monitoring Committee 
ECG 
Electrocardiogram 
EPA 
Electron paramagnetic agent 
FDA 
Food and Drug Administration 
GBM 
Glioblastoma multiforme 
GCP 
Good clinical practices 
GFR 
Glomerular filtration rate 
GGT 
Gamma-glutamyltransferase 
GLY 
Glycolysis 
IRB 
Institutional Review Board 
IV 
Intravenous 
LAC 
Lactate 
MRI 
Magnetic resonance imaging 
MRSI 
Magnetic resonance spectroscopy imaging 
MRS 
Magnetic resonance spectroscopy 
OXPHOS 
Oxidative phosphorylation  
PD 
Protocol Director 
PYR 
pyruvate 
SAE 
Serious adverse event 
SNR 
Signal to noise ratio 
SRC 
Scientific Review Committee 
T1 
Time constant for magnetization decay 
ULN 
Upper limit of normal 
VS 
Vital signs 
 
 
 


Study IRB-39845 / BRN0036 
Version Date 15 May 2019 
Page 6 of 18 
CONFIDENTIAL 
1. OBJECTIVES 
 
1.1. Primary Objectives 
To assess the safety of IV injection of hyperpolarized [1-13C]-pyruvate for MRI. 
 
1.2. Exploratory Objectives 
To assess the frequency and sensitivity with which lactate and bicarbonate signals can be 
detected in malignant brain tumors after IV injection of hyperpolarized [1-13C]-pyruvate. 
 
2. BACKGROUND 
 
2.1. Study Disease 
Our ultimate goal is to develop a strategy to manage cancer as a chronic disease for which 
treatment can be calibrated according to the tumor’s metabolic state.  In particular, cancer cells, 
in addition to their high growth rate, universally demonstrate an abnormal metabolism 
characterized by an overproduction of lactate (via a process known as glycolysis [GLY]) relative 
to the more energy efficient conversion of glucose to carbon dioxide and water (oxidative 
phosphorylation [OXPHOS]).  Originally described over 80 years ago by Otto Warburg, this 
altered metabolism, more recently termed metabolic reprogramming [1], is now viewed as a 
hallmark of cancer and appears linked to the need for carbon skeletons to produce biomass and 
is thus intimately tied to the ability of cancer cells to proliferate [2].  The novel clinical implication 
of these observations suggest that a potential anti-tumor strategy lies in reversing the “Warburg 
Effect” by forcing cancer cell metabolism away from GLY towards OXPHOS.  Although this 
would not result in cell kill per se, it should result in stabilization of growth with minimal toxicity.  
Although a number of targets exist for which active drugs could be directed, a major obstacle 
towards taking this to the clinic has been the inability to measure cancer metabolism in vivo.   
 
Using a rat model, we have developed magnetic resonance spectroscopic imaging (MRSI) 
of hyperpolarized [1-13C]-pyruvate as a noninvasive measure of lactate (Lac) and bicarbonate 
(Bic) production reflecting GLY and OXPHOS respectively [3], [4].  We now wish to translate this 
imaging technology to the clinic and demonstrate that these critical aspects of glucose 
metabolism can be measured in patients with glioma.  A hyperpolarizer that can be used 
clinically has been purchased and is now ready to be utilized.  We have funds in which to test 
15 subjects and would like to perform a pilot test to confirm two necessary aspects of our 
hypothesis: (i) determining that our methods for polarizing [1-13C]-pyruvate are safe for patient 
use; and (ii) evaluating if and how frequently we can detect lactate and bicarbonate signaling 
within brain tumor tissue. 
 
2.2. Study Agent/Device/Imaging procedure 
Dynamic nuclear polarization (DNP) magnetic resonance spectroscopic imaging (MRSI) is 
based on the transfer of polarization from the electron spins of paramagnetic centers embedded 
in a glassy frozen solution to neighboring nuclear spins through dipolar interactions, thus driving 
nuclei temporarily into a significant redistribution of the ordinary populations of energy levels [5].  
These spin states are not stable in the sense that the induced massive spin polarization decays 
during a relatively short period but within this period allows one to follow a nucleus (usually 
carbon or nitrogen) as it is processed by a tissue.  The absence of ionizing radiation and 
convenient integration with standard MRI imaging of hyperpolarized nuclei therefore offers the 
prospect of monitoring tumor metabolism noninvasively, the potential value of which depends on 
three factors: (i) the T1 signal needs to be sufficiently long so that enough material is preserved 
after injection to measure; (ii) the metabolic pathway itself much be sufficiently rapid so that the 
fate of the tracer can be measured; and (iii) the process must be relevant to tumor biology [6].   


Study IRB-39845 / BRN0036 
Version Date 15 May 2019 
Page 7 of 18 
CONFIDENTIAL 
 
[1-13C]-pyruvate is currently the tracer for which the most preclinical and clinical experience 
exists.  Pyruvate (Pyr) is situated at a hub of the glucose utilization pathway where it can be 
reduced to lactate, amidated to alanine or catalyzed to acetyl CoA and CO2.  Although an issue 
existed early in its development as to whether it could cross the blood brain barrier fast enough 
to allow imaging in brain tumors without disruption, unequivocal imaging of brain tumor 
metabolism of hyperpolarized [1-13C]-pyruvate in brain has been demonstrated [4]. 
 
Signal to noise (SNR) ratios are particularly strong for visualizing lactate (Lac), on which 
most studies to date have focused.  Using this technology, it has been possible to show lactate 
dehydrogenase catalyzed interconversion of label between Pyr and Lac in several tumor types 
including GBM and that changes occur in the rate of labeling with treatment [4], [7]-[9].  
Furthermore, it has also been demonstrated that an increased conversion of Pyr conversion to 
alanine is an early feature of experimental myc-driven hepatic tumors [10].   
 
Based on numerous previous reports, tracing Pyr fate into the mitochondria has been more 
challenging and there have been numerous reports noting that imaging both lactate and 
bicarbonate (Bic) is difficult, especially in brain tumor [11], [12], creating barriers for using this 
imaging modality to explore the question of whether forcing OXPHOS slows cancer growth.   
 
We recently overcame this hurdle through optimization of the acquisition protocol for spiral 
chemical shift imaging so as to be able to measure both lactate and bicarbonate in transplanted 
C6 glioma.  Furthermore, we were able to demonstrate a consistent and marked decrease in the 
ratio of Lac/Bic acutely after the administration of DCA [8], substantiating at least that change in 
Pyr flux is occurring so that more substrate is directed into the mitochondria (since that is where 
Bic is generated). 
 
This technology has been recently applied to clinical populations.  The first-in-man Phase I 
trial examined a cohort of prostate cancer patients.  It demonstrated the safety of administering 
250 mM hyperpolarized [1-13C]-pyruvate up to doses of 0.43 mL/kg body weight and that 
images could be acquired that demonstrated conversion of hyperpolarized pyruvate to lactate in 
regions of biopsy-proven tumor [13].  Since these experiments were reported from UCSF, this 
technology has become available for clinical study at Memorial Sloan Kettering Cancer Center, 
University of Texas at Southwestern (UTSW), Cambridge University, Oxford University, 
University of Toronto, and several other centers (including ours) are gearing up for study. 
 
2.3. Clinicaltrials.gov  
This study is submitted to IND-
 for the IV injection of [1-13C]-pyruvate, and will 
include submission of this protocol.  
 
For clinicaltrials.gov compliance:  This is a phase 0 (early phase 1), but relies in part on NIH 
funding so is required to register on clinicaltrials.gov and report results.  For Clinicaltrials.gov 
results reporting, the following outcome measures will be used: 
Primary Outcome Measure  
• 
Title: Safety of hyperpolarized [1-13C]-pyruvate injection 
• 
Time Frame: Up to Day 4 
• 
Description: Results will be reported as the number of Grade 2 or higher adverse 
events judged by the investigator to be clinically significant AND related/possibly-
related to hyperpolarized [1-13C]-pyruvate injection across all subjects administered 
study agent. 
 


Study IRB-39845 / BRN0036 
Version Date 15 May 2019 
Page 8 of 18 
CONFIDENTIAL 
Exploratory Outcome Measure  
• 
Title: Feasibility of Lactate and Bicarbonate signal detection 
• 
Time Frame: Up to 4 days 
• 
Description: Results will be reported as the percentage of subjects with CNS 
malignancy administered study agent and imaged who show 13C MR signal detection 
above background noise level, reported separately for lactate and bicarbonate 
signals. 
 
2.4. Rationale 
See Section 2.1 
 
2.5. Preliminary results 
The proposed study will be the first time at Stanford where this technology will be used in 
humans.  Prior use in cancer imaging, conducted at UCSF, is described in the Investigator’s 
Brochure. 
 
2.6. Study Design 
This is an open-label, two-armed study of 5 healthy volunteers and 10 patients with known 
CNS malignancy. 
• 
Arm 1: n = 5 healthy volunteers 
• 
Arm 2: n = 10 patients with known CNS malignancy 
 
3. PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES 
 
3.1. Inclusion Criteria 
3.1.1. (Arm 2 patients with known CNS malignancy only) Patients with a known 
diagnosis of CNS malignancy, including metastases, with known enhancement on 
MR who are otherwise eligible to undergo MRI. 
3.1.2. At least 18 years old. 
3.1.3. eGFR > 30 ml/min. 
3.1.4. (Arm 2 patients with known CNS malignancy only) No allergy to gadolinium. 
3.1.5. Ability to understand and the willingness to sign a written informed consent 
document. 
 
3.2. Exclusion Criteria 
3.2.1. Refusal to have an IV placed for injection. 
3.2.2. Acute major illness (e.g., unstable angina, etc.) or other condition that makes 
participation unsafe, per the investigator’s judgement. 
3.2.3. Total Bilirubin > 1.5 x ULN; AST/ALT > 2.5 x ULN; GGT > 2.5 x ULN. 
3.2.4. Pregnant or breast-feeding.   
3.2.5. Cardiovascular risk, including: 
o 
Poorly controlled hypertension, defined as either systolic > 170 or 
diastolic > 110. 
o 
Congestive heart failure 
o 
Myocardial infarction within the past year 
o 
QT prolongation, defined as pretreatment QTc > 440 msec in males or 
> 460 msec in females 
3.2.6. (Arm 1 Healthy volunteers only) Undergoing active treatment for malignancy 
 
 


Study IRB-39845 / BRN0036 
Version Date 15 May 2019 
Page 9 of 18 
CONFIDENTIAL 
3.3. Informed Consent Process 
All participants must be provided a consent form describing the study with sufficient 
information for participants to make an informed decision regarding their participation.  
Participants must sign the IRB approved informed consent 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.   
 
 
3.4. Study Timeline 
3.4.1. Primary Completion 
The study will reach primary completion once the last subject undergoes Day 2 safety 
evaluations. 
 
3.4.2. Study Completion 
We estimate that this study will take one year from first subject enrollment to complete. 
 
4. IMAGING AGENT/DEVICE/PROCEDURE INFORMATION 
 
4.1. Hyperpolarized [1-13C]-Pyruvate 
13C is a stable non-radioactive isotope of carbon.  [1-13C]-pyruvate has exactly the same 
chemical characteristics as pyruvate.  In [1-13C]-pyruvate, the C-1 carbonyl has been enriched 
with 13C-nuclei, which has a magnetic moment and can be hyperpolarized by DNP in the 
presence of an electron paramagnetic agent (EPA), i.e., AH111501 sodium salt (a stable trityl 
radical).  Although [1-13C]-pyruvate has the same chemical characteristics as unlabeled 
pyruvate and is metabolized the same way, the fact that it can be hyperpolarized means that 
MRSI can be used to rapidly detect the hyperpolarized 13C-label in [1-13C]-pyruvate and its 
metabolic products. 
 
Hyperpolarized [1-13C]-pyruvate will be prepared by qualified staff at the Lucas Center under 
aseptic GMP/GLP conditions using a DNP polarizer (SpinLab, GE Healthcare).  The imaging 
agent will be administered by IV injection at a rate of 5 ml/sec followed by a 20 ml saline flush at 
5 ml/sec (on average 30-40 seconds).  The formulation procedures are detailed in the current 
Investigator’s Brochure (IB).   
 
4.2. Dissolution DNP MRSI 
Hyperpolarized [1-13C]-pyruvate will be injected at a dosage of 0.43 ± 0.05 mL/kg body 
weight (concentration of 250 mM), the maximum safely administered dose attained in the Phase 
I study [13].  After hyperpolarization in the SpinLab polarizer, a syringe is automatically filled.  
The quality control module of the SpinLab measures the pyruvate concentration, volume, 
temperature, pH, polarization, and removal of the EPA in the syringe.  A quality control 
assessment is then performed to ensure all parameters are reached, after which the syringe is 
released by the protocol director and immediately passed to a nurse or radiology technician for 
initiation of injection.   
 
The overall imaging protocol will consist of 1) standard non-contrast clinical collection setup 
for brain imaging (~45 min), 2) hyperpolarized [1-13C]-pyruvate MRSI (single- or multi-slice 
acquisition, ~3-min acquisition), and 3) standard clinical brain gadolinium-enhanced MRI 
(~10min). 
 
4.3. Dose Modification 


Study IRB-39845 / BRN0036 
Version Date 15 May 2019 
Page 10 of 18 
CONFIDENTIAL 
The starting dose of [1-13C]-pyruvate will be 0.43 ± 0.05 mL/kg body weight (250 mM 
[1-13C]-pyruvate).  If we encounter a DLT at this dose (which seems unlikely since it has been 
well tolerated in safety studies elsewhere), we will decrease dose to 0.28 mL/kg. 
 
The choice whether or not to use the [1-13C]-pyruvate and/or gadolinium MRI contrast agent 
is made at Protocol Director’s discretion.  If the investigator choses to forego gadolinium 
contrast (due to concerns of gadolinium accumulation or other concerns), the second MRI brain 
scan may be skipped. 
 
 
 
5. STUDY PROCEDURES  
Healthy volunteers (Arm 1 of the study) will be recruited via an IRB-approved e-mail that 
refers them to the clinical research coordinator or research team. Eligible patients for arm 2 will 
be invited to participate at any time during their course of CNS malignancy treatment.  
Generally, arm 2 patients will be recruited during a regular clinic visit. 
 
If the patient signs the informed consent form and agrees to participate, the following 
screening procedures will be performed within 14 days prior to Day 1: 
• 
Collect demographics 
• 
Measure vital signs (heart rate, temperature, blood pressure), height and weight 
• 
Serum chemistry blood test 
• 
Serum pregnancy test, if woman of childbearing potential 
• 
Electrocardiogram (ECG) 
 
On Day 1, MRI and MRSI will be performed in the Richard M. Lucas Center for Imaging at 
Stanford University.  Production of hyperpolarized [1-13C]-pyruvate will be coordinated with 
imaging schedule such that MRSI begins within 1 minute of hyperpolarized [1-13C]-pyruvate 
administration.  Each subject will undergo the following procedures: 
• 
Measure vital signs 
• 
MRI scan of brain, 45 min acquisition time using standard non-contrast clinical brain 
collection setup 
• 
Administration of hyperpolarized [1-13C]-pyruvate (250 mM, 0.43 ± 0.05 mL/kg body 
weight) IV injection at a rate of 5 mL/sec followed by a 20 mL saline flush at 5 
mL/sec (on average 30-40 seconds) 
• 
MRSI scan of brain, 3 min acquisition on a 3T MRI scanner equipped with both 1HF 
and 13C RF coils. 
• 
MRI scan of brain, 10 min acquisition time using standard Gadolinium-enhanced 
contrast clinical brain collection. Gadolinium contrast agent may or may not be 
administered at the discretion of the Protocol Director. Gadolinium will not be used 
for Arm 1 Healthy Volunteers.  
• 
Within 10 min after the conclusion of image collection: 
o Measure vital signs 
o Collect any adverse events and monitor injection site 
• 
At least once more  20-45 minutes after the conclusion of image collection: 
o Measure vital signs 
o Collect any adverse events and monitor injection site 
• 
1 to 5 hours post pyruvate administration: 
o Measure vital signs 
o ECG 
o Collect any adverse events and monitor injection site 


Study IRB-39845 / BRN0036 
Version Date 15 May 2019 
Page 11 of 18 
CONFIDENTIAL 
 
Between Day 2 and 4, subjects will be contacted by phone or at an in-person clinic visit to 
collect any adverse events. 
 
Once initial imaging is completed, patients will be followed as expected by standard of care.  
Patients are free to enroll in other studies.   
 
 
 
6. STUDY CALENDAR 
 
 
Pre-Study 
(Within 14 Days of 
Day 1) 
Day 1 
Day 2 
(+2 days) 
Informed consent 
 
X 
 
 
 
 
Demographics 
 
X 
 
 
 
 
Vital signs 
 
X 
Xf 
 
Height 
 
X 
 
 
 
 
Weight 
 
X 
 
 
Serum chemistry a 
 
X 
 
 
ECG 
 
X 
 
X e 
 
 
Pregnancy test 
 
X b 
 
 
 
 
Non-contrast enhanced MRI c 
 
 
 
X 
 
 
[1-13C]-pyruvate IV injection 
  
X  
 
 
MRSI 
 
 
 
X 
 
 
Contrast enhanced MRI d 
  
 
X 
 
AE evaluation 
 
 
 
X 
 
X 
 
a: GFR., Total bilirubin, SGOT[AST], SGPT[ALT], GGT. 
b: 
Women of childbearing potential only 
c: 
Before [1-13C]-pyruvate IV injection and MRSI 
d:    After [1-13C]-pyruvate IV injection and MRSI. Arm 1 Healthy Volunteers will not receive contrast 
e:  Within 1-5 hours post [1-13C]-pyruvate IV injection 
f:     Collect on Day 1: at baseline prior to non-contrast MRI;  within 10 min after the conclusion of the image 
collection, 20-45 min after the conclusion of image collection; and 1-5 hours post [1-13C]-pyruvate IV 
injection 


Study IRB-39845 / BRN0036 
Version Date 15 May 2019 
Page 12 of 18 
CONFIDENTIAL 
7. ADVERSE EVENTS AND REPORTING PROCEDURES 
 
7.1. Potential Adverse Events 
In the original Phase I studies with [1-13C]-pyruvate, no dose-limiting toxicities or toxicities 
deemed to be clinically significant were noted [13].  We will consider any Grade 2 or higher 
toxicity judged related or possibly-related to [1-13C]-pyruvate as significant (excluding 
asymptomatic lab abnormalities).   
7.1.1. Stopping Rules 
The study will be stopped if infection attributable to any component of the pyruvate infusion 
is observed.  The study may resume after the necessary chemistry, manufacturing and controls 
(CMC) changes are made and the IND amendment is submitted to FDA and approved by IRB. 
In addition, the study will pause enrollment pending a safety review if two dose-limiting toxicity 
events (any Grade 2 or higher toxicity judged related or possibly-related to [1-13C]-pyruvate, 
excluding asymptomatic lab abnormalities) are observed. 
 
7.2. Adverse Event Collection 
Adverse events will be graded according to CTCAE v5.0.  Both Serious and Non-Serious 
Adverse Events will be clearly noted in source documentation and listed on study specific Case 
Report Forms (CRFs).  The Protocol Director (PD) or designee will assess each Adverse Event 
(AE) to determine whether it is unexpected according to the Informed Consent, Protocol 
Document, or Investigator’s Brochures, and related to the investigation.   
 
All AEs, regardless of seriousness or relationship to investigational agent, will be collected 
from Day 1 through safety follow-up contact.  From signing of informed consent to prior to 
Day 1, only AEs deemed related to study procedures will be collected.  All Serious Adverse 
Events (SAEs) will be tracked until resolution or 4 days after the last dose of the study 
treatment.  After the safety follow-up contact, any SAEs spontaneously reported to investigator 
and deemed related to investigational agent should be reported to the IND Sponsor-Investigator 
(Daniel Spielman, PhD). 
 
7.3. Adverse Event Reporting 
Non serious adverse events will be reported annually to FDA via an Annual Report 
(
) and to IRB via Continuing Review. 
 
The PD (aka Principle Investigator) must immediately report within 24 hours of knowledge of 
event to the IND Sponsor-Investigator (Daniel Spielman, PhD), any serious adverse event, 
whether or not considered related to study drug.  SAEs of all grades will be reported to the 
Sponsor-Investigator using the Stanford Cancer Institute SAE CRF.   
 
Adverse events deemed serious, unexpected (i.e. not described in the protocol, 
Investigator’s Brochure or informed consent documents) and related to investigational agent 
must be reported to the IND Sponsor-Investigator by email or fax using the FDA MedWatch 
form 3500a within 24 hours of knowledge of event.  The IND Sponsor-Investigator is responsible 
for deciding whether the event meets IND Safety Reporting criteria. 
 
Events will be submitted to Sponsor-Investigator Dr. Daniel Spielman, at: 
Daniel Spielman, PhD  
Professor of Radiology and Electrical Engineering (by courtesy) 
1201 Welch Rd 
Lucas Center, 
 
Stanford, CA  94305-5488 


Study IRB-39845 / BRN0036 
Version Date 15 May 2019 
Page 13 of 18 
CONFIDENTIAL 
Phone: 650-723-8697 
Fax: 650-723-9222 
spielman@stanford.edu 
 
It will be the responsibility of the Sponsor-Investigator to provide to the FDA all information 
concerning significant hazards, contraindications, side effects or precautions felt significant to 
the safety of the investigational agent being studied.  The PD is responsible for accurate and 
timely communication to the Sponsor-Investigator of any events reportable to FDA.   
 
SAEs CTCAE Grade 2 and above, and all subsequent follow-up reports will be reported to 
the Stanford Cancer Institute Data and Safety Monitoring Committee (DSMC) using the study 
specific CRF regardless of the event’s relatedness to the investigation.  Following review by the 
DSMC, events meeting the IRB definition of ‘Unanticipated Problem’ will be reported to the IRB 
using eProtocol within 10 working days of DSMC review, or within 5 working days for deaths or 
life-threatening experiences. 
 
8. REGULATORY CONSIDERATIONS 
 
8.1. Institutional Review of Protocol 
The protocol, the proposed informed consent and all forms of participant information related 
to the study (e.g.  advertisements used to recruit participants) will be reviewed and approved by 
the Stanford IRB and Scientific Review Committee (SRC).  Any changes made to the protocol 
will be submitted as a modification and will be approved by the IRB, and SRC if applicable, prior 
to implementation.  The Protocol Director will disseminate the protocol amendment information 
to all participating investigators. 
 
Protocol amendments will be submitted to the FDA under IND 
in accordance to the 
regulations. 
 
8.2. Data Management Plan 
The Protocol Director, 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 treatment outcomes for data analysis.  Case report forms 
will be developed using the Oncore database system and will be maintained by CCTO.  CRFs 
will be kept in a locked office, only accessible to the research team.” 
 
8.3. Data and Safety Monitoring Plan 
During the clinical investigation, the Protocol Director will evaluate the progress of the trial, 
including periodic assessments of data quality and timeliness, participant recruitment, accrual 
and retention, participant risk versus benefit, performance of trial sites, and other factors that 
can affect study outcome.  Monitoring of the trial will occur every 8 weeks and a record of 
monitoring activities will be maintained by the study team.   
 
The Stanford Cancer Institute Data and Safety Monitoring Committee (DSMC) will audit 
study related activities at least annually in accordance with the DSMC SOP to determine 
whether the study has been conducted in accordance with the protocol, local standard operating 
procedures, FDA regulations, and Good Clinical Practice (GCP).  This may include review of 
regulatory binders, case report forms, eligibility checklists, and source documents.  In addition, 
the DSMC will regularly review serious adverse events and protocol deviations associated with 
the research to ensure the protection of human subjects.  Results of DSMC audits will be 


Study IRB-39845 / BRN0036 
Version Date 15 May 2019 
Page 14 of 18 
CONFIDENTIAL 
communicated to the IRB and the appropriate regulatory authorities at the time of continuing 
review, or in an expedited fashion, as needed. 
 
9. MEASUREMENTS 
 
9.1. Primary and Exploratory Outcome measures 
Primary Outcome Measure: This is a pilot study which will allow us to develop a novel MRS 
technique for clinical application.  Our primary measurement will be safety of [1-13C]-pyruvate IV 
injection defined as the absence of Grade 2 toxicity (except for asymptomatic lab increases).   
 
Exploratory Outcome Measure: Detection of lactate and bicarbonate production in tumor 
and normal brain tissue, defined as the frequency of 13C MR signal detection above background 
noise level of both lactate and bicarbonate in all tumors screened. 
 
9.2. Measurement Methods 
Images will be analyzed for several conventional MR parameters, including tumor volume 
and CBV.  Pyruvate, bicarbonate and lactate signals will be assessed by peak integration of the 
corresponding spectral peaks.   
 
9.3. Measurement Time Points 
Assessments will be made only at one time point.   
 
9.4. Response Review 
No response review is planned. 
 
10. STATISTICAL CONSIDERATIONS 
 
10.1. 
Statistical Design 
This pilot study seeks to demonstrate safety of the [1-13C]-pyruvate IV injection as well as 
the ability to detect lactate and bicarbonate spectra.  Safety will be defined as the absence of 
Grade 2 toxicity (except for asymptomatic laboratory abnormalities). 
 
Another goal is an assessment of whether lactate and bicarbonate spectra can be detected 
in tumor.  Three answers are anticipated.  Either there will be bicarbonate spectra detected in 
all, some or none.  Our experimental data suggests that we should be able to see it in all 
enhancing areas, although the technical differences between experimental and clinical 
machines does not guarantee this outcome. 
 
5 healthy volunteers and 10 patients with CNS malignancies will be assessed, which is the 
maximum that our budget will allow.  These results will then be used to properly formulate a 
more formal experiment that will subsequently be submitted. 
 
10.2. 
Randomization 
No randomization. 
 
10.3. 
Interim analyses 
No interim analysis is planned.   
 
10.4. 
Descriptive Statistics and Exploratory Data Analysis 
N/A 
 


Study IRB-39845 / BRN0036 
Version Date 15 May 2019 
Page 15 of 18 
CONFIDENTIAL 
10.5. 
Primary Analysis  
N/A 
 
10.6. 
Sample Size 
Our budget allows 5 healthy volunteers and 10 patients with CNS malignancies for a total of 
15 subjects.  This number will allow us to accrue enough data to better understand lactate and 
bicarbonate detectability and safety.   
 
10.7. 
Accrual estimates 
15 subjects will be assessed over one year. 
 
10.8. 
Criteria for future studies 
 
The data obtained from the current study will be instrumental in helping us craft the first in 
human study assessing [1-13C]-pyruvate DNP MRS in GBM patients receiving bevacizumab. 
 


Study IRB-39845 / BRN0036 
Version Date 15 May 2019 
Page 16 of 18 
CONFIDENTIAL 
11. REFERENCES 
 
[1] 
E.  M.  Palsson-McDermott and L.  A.  J.  O'Neill, “The Warburg effect then and now: 
From cancer to inflammatory diseases,” BioEssays, vol.  35, no.  11, pp.  965–973, Sep.  
2013. 
[2] 
M.  G.  Vander Heiden, L.  C.  Cantley, and C.  B.  Thompson, “Understanding the 
Warburg Effect: The Metabolic Requirements of Cell Proliferation,” Science, vol.  324, 
no.  5930, pp.  1029–1033, May 2009. 
[3] 
J.  M.  Park, S.  Josan, T.  Grafendorfer, Y.-F.  Yen, R.  E.  Hurd, D.  M.  Spielman, and 
D.  Mayer, “Measuring mitochondrial metabolism in rat brain in vivo using MR 
Spectroscopy of hyperpolarized [2-¹³C]pyruvate.,” NMR Biomed., vol.  26, no.  10, pp.  
1197–1203, Oct.  2013. 
[4] 
J.  M.  Park, S.  Josan, T.  Jang, M.  Merchant, R.  Hurd, D.  Mayer, L.  Recht, and D.  
Spielman, “Metabolic Changes in a Rat Glioma Model After Anti-Angiogenic Treatment 
Measured by MR Spectroscopic Imaging of Hyperpolarized [1-13C]Pyruvate,” 
presented at the Scientific Meeting of the ISMRM, Milan, Itraly. 
[5] 
J.  H.  Ardenkjær-Larsen, A.  M.  Leach, N.  Clarke, J.  Urbahn, D.  Anderson, and T.  
W.  Skloss, “Dynamic nuclear polarization polarizer for sterile use intent,” NMR 
Biomed., vol.  24, no.  8, pp.  927–932, Mar.  2011. 
[6] 
R.  E.  Hurd, Y.-F.  Yen, A.  Chen, and J.  H.  Ardenkjaer-Larsen, “Hyperpolarized 13C 
metabolic imaging using dissolution dynamic nuclear polarization,” J.  Magn.  Reson.  
Imaging, vol.  36, no.  6, pp.  1314–1328, Nov.  2012. 
[7] 
I.  Park, R.  Bok, T.  Ozawa, J.  J.  Phillips, C.  D.  James, D.  B.  Vigneron, S.  M.  
Ronen, and S.  J.  Nelson, “Detection of early response to temozolomide treatment in 
brain tumors using hyperpolarized 13C MR metabolic imaging,” J.  Magn.  Reson.  
Imaging, vol.  33, no.  6, pp.  1284–1290, May 2011. 
[8] 
J.  M.  Park, L.  D.  Recht, S.  Josan, M.  Merchant, T.  Jang, Y.  F.  Yen, R.  E.  Hurd, 
D.  M.  Spielman, and D.  Mayer, “Metabolic response of glioma to dichloroacetate 
measured in vivo by hyperpolarized 13C magnetic resonance spectroscopic imaging,” 
Neuro-Oncology, vol.  15, no.  4, pp.  433–441, Mar.  2013. 
[9] 
M.  J.  Albers, R.  Bok, A.  P.  Chen, C.  H.  Cunningham, M.  L.  Zierhut, V.  Y.  Zhang, 
S.  J.  Kohler, J.  Tropp, R.  E.  Hurd, Y.-F.  Yen, S.  J.  Nelson, D.  B.  Vigneron, and J.  
Kurhanewicz, “Hyperpolarized 13C lactate, pyruvate, and alanine: noninvasive 
biomarkers for prostate cancer detection and grading.,” Cancer Research, vol.  68, no.  
20, pp.  8607–8615, Oct.  2008. 
[10] 
M.  M.  Darpolor, Y.-F.  Yen, M.-S.  Chua, L.  Xing, R.  H.  Clarke-Katzenberg, W.  Shi, 
D.  Mayer, S.  Josan, R.  E.  Hurd, A.  Pfefferbaum, L.  Senadheera, S.  So, L.  V.  
Hofmann, G.  M.  Glazer, and D.  M.  Spielman, “In vivo MRSI of hyperpolarized 
[1-13C]pyruvate metabolism in rat hepatocellular carcinoma,” NMR Biomed., vol.  24, 
no.  5, pp.  506–513, Dec.  2010. 
[11] 
M.  M.  Chaumeil, T.  Ozawa, I.  Park, K.  Scott, C.  D.  James, S.  J.  Nelson, and S.  
M.  Ronen, “Hyperpolarized 13C MR spectroscopic imaging can be used to monitor 
Everolimus treatment in vivo in an orthotopic rodent model of glioblastoma,” 
NeuroImage, vol.  59, no.  1, pp.  193–201, Jan.  2012. 
[12] 
S.  E.  Day, M.  I.  Kettunen, M.  K.  Cherukuri, J.  B.  Mitchell, M.  J.  Lizak, H.  D.  
Morris, S.  Matsumoto, A.  P.  Koretsky, and K.  M.  Brindle, “Detecting response of rat 
C6 glioma tumors to radiotherapy using hyperpolarized [1-13C]pyruvate and 13C 
magnetic resonance spectroscopic imaging,” Magnetic Resonance in  Medicine, vol.  
65, no.  2, pp.  557–563, Nov.  2010. 
[13] 
S.  J.  Nelson, J.  Kurhanewicz, D.  B.  Vigneron, P.  E.  Z.  Larson, A.  L.  Harzstark, M.  
Ferrone, M.  van Criekinge, J.  W.  Chang, R.  Bok, I.  Park, G.  Reed, L.  Carvajal, E.  


Study IRB-39845 / BRN0036 
Version Date 15 May 2019 
Page 17 of 18 
CONFIDENTIAL 
J.  Small, P.  Munster, V.  K.  Weinberg, J.  H.  Ardenkjaer-Larsen, A.  P.  Chen, R.  E.  
Hurd, L.  I.  Odegardstuen, F.  J.  Robb, J.  Tropp, and J.  A.  Murray, “Metabolic 
Imaging of Patients with Prostate Cancer Using Hyperpolarized [1-13C]Pyruvate,” Sci 
Transl Med, vol.  5, no.  198, pp.  198ra108–198ra108, Aug.  2013. 
 
 


Study IRB-39845 / BRN0036 
Version Date 15 May 2019 
Page 18 of 18 
CONFIDENTIAL 
Appendix A:  Inclusion/Exclusion Criteria Checklist 
*All subject files must include supporting documentation to confirm subject eligibility.  The 
method of confirmation can include, but is not limited to, laboratory test results, radiology test 
results, subject self-report, and medical record review.   
 
Inclusion Criteria 
(From IRB approved protocol) 
Yes 
No 
Not 
Applicable 
Supporting Documentation* 
1. (Arm 2 patients with known CNS 
malignancy only) Patients with a known 
diagnosis of CNS malignancy, including 
metastases, with known enhancement on 
MR who are otherwise eligible to undergo 
MRI 
 
 
 
      
2. At least 18 years old 
 
 
 
      
3. eGFR > 30 ml/min 
 
 
 
      
4. (Arm 2 patients with known CNS 
malignancy only) No allergy to gadolinium 
 
 
 
      
5. Ability to understand and willingness to 
sign a written informed consent document 
 
 
 
      
Exclusion Criteria 
(From IRB approved protocol) 
 
1. Refusal to have an IV placed for injection 
 
 
 
      
2. Acute major illness (e.g., unstable angina, 
etc.) or other condition that makes 
participation unsafe, per the investigator’s 
judgement 
 
 
 
      
3. Total Bilirubin > 1.5 x ULN;  
AST/ALT > 2.5 x ULN;  
GGT > 2.5 x ULN 
 
 
 
      
4. Pregnant or breast-feeding 
 
 
 
      
5. Cardiovascular risk, including: 
o 
Poorly controlled hypertension, defined as 
either systolic > 170 or diastolic > 110. 
o 
Congestive heart failure 
o 
Myocardial infarction within the past year 
o 
QT prolongation, defined as pretreatment 
QTc > 440 msec in males or > 460 msec 
in females 
 
 
 
      
6. (Arm 1 Healthy volunteers only) 
Undergoing active treatment for 
malignancy 
 
 
 
      
 
IV.  Statement of Eligibility 
This subject is [ 
 eligible / 
 ineligible ] for participation in the study. 
Signature: 
Date: 
Printed Name: