A Phase II Study of Sodium Thiosulfate (STS) for Prevention of Ototoxicity in Patients With Locally Advanced Squamous Cell Carcinoma of Head and Neck (SCCHN) Undergoing Concurrent Chemoradiation With Cisplatin
Phase: PHASE2
Conditions: Clinical Stage III Human Papillomavirus (HPV)-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8, Clinical Stage IV HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8, Locally Advanced Head and Neck Squamous Cell Carcinoma, Locally Advanced Hypopharyngeal Squamous Cell Carcinoma, Locally Advanced Laryngeal Squamous Cell Carcinoma, Locally Advanced Oral Cavity Squamous Cell Carcinoma, Locally Advanced Oropharyngeal Squamous Cell Carcinoma, Pathologic Stage III HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8, Pathologic Stage IV HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8, Stage III Hypopharyngeal Carcinoma AJCC v8, Stage III Laryngeal Cancer AJCC v8, Stage III Lip and Oral Cavity Cancer AJCC v8, Stage III Oropharyngeal (p16-Negative) Carcinoma AJCC v8, Stage IV Hypopharyngeal Carcinoma AJCC v8, Stage IV Laryngeal Cancer AJCC v8, Stage IV Lip and Oral Cavity Cancer AJCC v8, Stage IV Oropharyngeal (p16-Negative) Carcinoma AJCC v8, Stage IVA Hypopharyngeal Carcinoma AJCC v8, Stage IVA Laryngeal Cancer AJCC v8, Stage IVA Lip and Oral Cavity Cancer AJCC v8, Stage IVA Oropharyngeal (p16-Negative) Carcinoma AJCC v8, Stage IVB Hypopharyngeal Carcinoma AJCC v8, Stage IVB Laryngeal Cancer AJCC v8, Stage IVB Lip and Oral Cavity Cancer AJCC v8, Stage IVB Oropharyngeal (p16-Negative) Carcinoma AJCC v8, Stage IVC Hypopharyngeal Carcinoma AJCC v8, Stage IVC Laryngeal Cancer AJCC v8, Stage IVC Lip and Oral Cavity Cancer AJCC v8, Stage IVC Oropharyngeal (p16-Negative) Carcinoma AJCC v8
Sponsor: Hyunseok Kang, MD

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.
A Phase II study of Sodium thiosulfate (STS) for prevention of ototoxicity in 
patients with locally advanced squamous cell carcinoma of head and neck 
(SCCHN) undergoing concurrent chemoradiation with cisplatin
Protocol Number:  CC #20208
Investigational Product:  Sodium Thiosulfate (STS)
Version Number:  1.9
Version Date:  09-09-2022
IND Number: 148063
NCT Number: 04541355
Principal Investigator (Sponsor-Investigator)
Hyunseok Kang, MD 
University of California San Francisco
 
San Francisco, CA 94158
 
Statistician
Mi-Ok Kim, PhD 
Revision History
Version 1.9
09-09-2022
Version 1.8
06-07-2022
Version 1.7
12-16-2021
Version 1.6
03-31-2021
Version 1.5
06-26-2020
Version 1.4
05-18-2020
Version 1.3
04-29-2020
Version 1.2 
02-25-2020
Version 1.1 
02-01-2020
Version 1.0
10-09-2019

 UCSF Helen Diller Family Comprehensive Cancer Center
Version date: 09-09-2022
Protocol CC#: 20208
Phase II study - Sodium Thiosulfate (STS) 
 Page 2 of 44
Protocol Signature Page
Protocol No.: 20208
Version Date: 09-09-2022
1.
I agree to follow this protocol version as approved by the UCSF Protocol Review Committee 
(PRC), Institutional Review Board (IRB), and Data and Safety Monitoring Committee 
(DSMC). 
2.
I will conduct the study in accordance with Good Clinical Practices (ICH-GCP) and the 
applicable IRB, ethical, federal, state, and local regulatory requirements. 
3.
I certify that I, and the study staff, have received the required 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 
Printed Name
Signature
Date

 UCSF Helen Diller Family Comprehensive Cancer Center
Version date: 09-09-2022
Protocol CC#: 20208
Phase II study - Sodium Thiosulfate (STS) 
 Page 3 of 44
Abstract
Title
A Phase II study of Sodium thiosulfate (STS) for prevention of ototoxicity in 
patients with locally advanced squamous cell carcinoma of head and neck 
(SCCHN) undergoing concurrent chemoradiation with cisplatin
Study Description
This is a phase II study to establish feasibility of using sodium thiosulfate after 
intravenous cisplatin in head and neck cancer patients undergoing definitive 
concurrent chemoradiation for prevention of ototoxicity. Hypothesis is that 
use of intravenous STS would be feasible and safe in patients with locally 
advanced SCCHN undergoing concurrent chemoradiation with cisplatin. This 
is a prospective clinical trial for patients getting eitherweekly cisplatin 
(40mg/m2) or every-3-week cisplatin (100mg/m2). A total of 16 patients will be 
enrolled  and each subject will have baseline and post-treatment (3 months 
after the completion of concurrent chemoradiation) audiogram to assess 
hearing loss as defined by NCI CTCAE version 5.0. STS (10 g/m2 for weekly 
cisplatin group and 20g/m2 for high dose cisplatin group) will be infused 4 
hours after each cisplatin infusion is completed. Feasibility will be assessed 
by successful completion of planned treatment, defined by completion of 5 
weekly cisplatin or 2 high dose cisplatin without any extended treatment 
related delays more than > 7 days.
Phase of Study
Phase II Study 
Investigational 
Products
Sodium thiosulfate (STS)
Study population
Patients with locally advanced SCCHN (oral cavity, oropharynx, hypopharynx, 
and larynx) eligible for definitive concurrent chemoradiation with cisplatin 
would be eligible for the study. Patients must be at least 18 years old at the 
time of enrollment. Women and persons from ethnic minority groups are 
encouraged to participate the study.
Primary Objective
Primary objective is to establish feasibility of intravenous STS after each dose 
of concurrent cisplatin in patients with locally advanced head and neck 
squamous cell carcinoma undergoing definitive radiotherapy.
Secondary 
Objectives
Secondary objectives are to 1) determine the rate of grade  2 change of 
hearing impairment from baseline based on NCI CTCAE version 5.0 with use 
of STS after concurrent chemoradiation with cisplatin 3 months post-
treatment, 2) determine the rate of tinnitus measured by PRO-CTCAE with 
use of STS 3 months post-treatment, 3) describe patient reported outcomes 
with STS measured with PRO-CTCAE for selected oral, GI, neurologic and 
perceptual symptoms 4) describe patient reported outcomes measured with 
Hearing Handicap Inventory for Adults – Screening (HHIA-S) compared to 
results from standard NRG Oncology head and neck trials (such as RTOG 
1016). 
Sample Size
A total of 16 patients are going to be enrolled. 

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Protocol CC#: 20208
Phase II study - Sodium Thiosulfate (STS) 
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Duration of Study 
Treatment
Participants may continue study treatment for up to 7 weekly doses or 3 
every 21-day doses from the time of initiating treatment. 
Duration of Follow 
up
Participants will be followed up to 3 months post-therapy from the completion 
of radiation. 
Unique Aspects of 
this Study
This is the first study to evaluate the feasibility of STS in patients with locally 
advanced head and neck cancer undergoing concurrent chemoradiation 
therapy with cisplatin.

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Phase II study - Sodium Thiosulfate (STS) 
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List of Abbreviations
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BUN
blood urea nitrogen
CBC
complete blood cell (count)
CNS
central nervous system
CR
complete response
CRF
case report form
CT
computerized tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTMS
Clinical Trial Management System
DFS
disease-free survival
DLT
dose limiting toxicity
DSMC
Data and Safety Monitoring Committee
DSMP
Data and Safety Monitoring Plan
ECG/EKG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
FDA
Food and Drug Administration
FDG
Fluorodeoxyglucose
FLC
free light chain
GCP
Good Clinical Practice
GFR
glomerular filtration rate
HBeAg
hepatitis B “e” antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HDFCCC
Helen Diller Family Comprehensive Cancer Center
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
ICF
informed consent form
ICH
International Conference on Harmonization
IDS
Investigational Drug Services (UCSF)
IND
investigational new drug application
IP
investigational product
IRB
Institutional Review Board

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Version date: 09-09-2022
Protocol CC#: 20208
Phase II study - Sodium Thiosulfate (STS) 
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List of Abbreviations
IV
intravenous
LDH
lactate dehydrogenase
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
NCI
National Cancer Institute
ORR
overall response rate
PD
disease progression
PK
pharmacokinetics
PO
Per os (by mouth, orally)
PR
partial response
PRC
Protocol Review Committee (UCSF)
SD
stable disease
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase

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Phase II study - Sodium Thiosulfate (STS) 
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Table of Contents
Protocol Signature Page ............................................................................................................2
Abstract
3
List of Abbreviations...................................................................................................................5
Table of Contents.......................................................................................................................7
1
Introduction.....................................................................................................................9
1.1
Background on Indication..........................................................................9
1.2
Background on the Investigational Product(s) and Associated Known 
Toxicities ...................................................................................................9
1.3
Rationale for the Proposed Study ............................................................10
1.4
Rationale for the Dose Selection/Regimen..............................................10
2
Study Objectives ..........................................................................................................11
2.1
Hypothesis ...............................................................................................11
2.2
Primary Objective and Endpoint..............................................................11
2.3
Secondary Objectives and Endpoints ......................................................12
3
Study Design................................................................................................................12
3.1
Characteristics..........................................................................................12
3.2
Sample Size..............................................................................................13
3.3
Eligibility Criteria....................................................................................13
3.3.1
Inclusion Criteria ..........................................................................................13
3.3.2
Exclusion Criteria .........................................................................................14
3.4
Inclusion and Recruitment of Women and Minorities.............................15
3.5
Duration of Treatment .............................................................................15
3.6
Duration of Follow Up.............................................................................15
3.7
Primary Completion.................................................................................15
3.8
Study Completion ....................................................................................15
4
Investigational Product.................................................................................................16
4.1
Description, Supply and Storage of Investigational Product...................16
4.1.1
Sodium Thiosulfate.......................................................................................16
4.1.2
Cisplatin ........................................................................................................17
4.2
Accountability Records for Investigational Product(s) ...........................19
4.3
Ordering Investigational Product(s).........................................................19
5
Treatment Plan.............................................................................................................19
5.1
Dosage and Administration .....................................................................19
5.1.1
Radiation Therapy.........................................................................................21
5.2
Dose Modifications for Cisplatin.............................................................21
5.2.1
Neutropenia:..................................................................................................21
5.2.2
Thrombocytopenia:.......................................................................................21
5.2.3
Renal Adverse Events: ................................................................................21
5.2.4
Mucositis:......................................................................................................22
5.3
Monitoring after Sodium Thiosulfate infusion........................................22
5.4
Stopping Rules.........................................................................................22
6
Study Procedures and Schedule of Events..................................................................23

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Phase II study - Sodium Thiosulfate (STS) 
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Table of Contents
6.1
Study Calendar.........................................................................................24
6.2
Participant Registration............................................................................28
6.3
Schedule of Procedures and Assessments ...............................................28
6.3.1
Pretreatment Period.......................................................................................28
6.3.2
Treatment Period...........................................................................................29
6.3.3
Post-treatment/Follow-Up.............................................................................29
6.3.4
Long Term/Survival Follow-up ....................................................................30
6.4
Use of Concurrent/Concomitant Medications .........................................30
7
Reporting and Documentation of Results ....................................................................30
7.1
Evaluation of Safety.................................................................................30
7.1.1
Definitions.....................................................................................................30
7.1.2
Evaluation of Safety......................................................................................30
7.2
Definitions of Adverse Events.................................................................31
7.2.1
Adverse Event...............................................................................................31
7.2.2
Adverse Reaction..........................................................................................31
7.2.3
Suspected Adverse Reaction.........................................................................31
7.2.4
Recording of Adverse Events .......................................................................32
7.2.5
Follow-up of Adverse Events .......................................................................32
7.2.6
Adverse Events Monitoring ..........................................................................32
7.2.7
Expedited Reporting .....................................................................................32
8
Statistical Considerations and Analysis Plan ...............................................................33
8.1
Accrual Estimates ....................................................................................33
8.2
Sample Size Considerations.....................................................................34
8.3
Interim Analyses and Stopping Rules......................................................34
8.4
Analyses Plans.........................................................................................34
9
Study Management ......................................................................................................34
9.1
Pre-study Documentation ........................................................................34
9.2
Institutional Review Board Approval......................................................34
9.3
Informed Consent ....................................................................................34
9.4
Changes in the Protocol...........................................................................35
9.5
Handling and Documentation of Clinical Supplies .................................35
9.6
Case Report Forms (CRFs)......................................................................35
9.7
Oversight and Monitoring Plan................................................................35
9.8
Record Keeping and Record Retention ...................................................36
10
References...................................................................................................................37
Appendix 1
Performance Status Criteria............................................................................38
Appendix 2
Data and Safety Monitoring Plan for Phase II or III Institutional Study ...........39

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Phase II study - Sodium Thiosulfate (STS) 
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1
Introduction
1.1
Background on Indication
Most patients with SCCHN present with locally advanced disease which requires multimodality treatment 
including surgery, radiotherapy and/or chemotherapy. The majority of patients are treated with concurrent 
chemoradiation with cisplatin and survive the intensive treatment [2]. Especially for HPV positive SCCHN 
which has excellent prognosis, treatment deintensification has been attempted to save these patients 
from long term toxicities. Disappointingly, a recent, large randomized clinical trial comparing concurrent 
cetuximab and cisplatin has suggested that cetuximab may lead to inferior clinical outcome compared to 
cisplatin [3] and cisplatin remains the standard of care for concurrent chemoradiation in these patients. 
Cisplatin is a widely used systemic anti-cancer agent, and its toxicities including nephrotoxicity, 
neuropathy and ototoxicity have been well described. Indeed, in a prospective cohort study, 63% of 
locally advanced SCCHN patients who were treated with concurrent chemoradiation with cisplatin 
developed moderate to severe (grade  2 change from baseline (common terminology criteria for adverse 
events, CTCAE v4.03) ototoxicity with average time to onset of 2.25 months [4]. Furthermore, cisplatin 
induced ototoxicity seems to be dose-dependent. In testicular cancer patients, every 100mg/m2 increase 
in cisplatin dose resulted in a 3.2 dB impairment in the age-adjusted overall hearing threshold[5]. 
1.2
Background on the Investigational Product(s) and Associated Known 
Toxicities
Sodium Thiosulfate (STS) is an inorganic compound which is used widely for gold mining, water 
treatment, analytic chemistry, development of silver based photographic films and prints, as well as 
medicine. In medicine, it has been used as an antidote for cyanide poisoning, a topical treatment for 
certain fungal infections, and a systemic treatment for calciphylaxis in end stage renal disease patients. 
STS is approved by FDA for use of cyanide poisoning in conjunction with sodium nitrite. Adverse events 
that have been reported in medical literature include hypotension, headache, disorientation, nausea and 
vomiting, prolonged bleeding time, salty taste in mouth and warm sensation over body. These adverse 
events were not reported in the context of controlled trials or with consistent monitoring and reporting 
methodologies for adverse events. 
In humans, rapid administration of concentrated solutions or solutions not freshly prepared, and 
administration of large doses of sodium thiosulfate have been associated with a higher incidence of 
nausea and vomiting. However, administration of 0.1 g sodium thiosulfate per pound up to a maximum of 
15 g in a 10-15% solution over 10-15 minutes was associated with nausea and vomiting in 7 of 26 
patients without concomitant cyanide intoxication. In a series of 11 human subjects, a single intravenous 
infusion of 50 mL of 50% sodium thiosulfate was associated with increases in clotting time 1-3 days after 
administration. However, no significant changes were observed in other hematological parameters[6]. 
It also has been extensively studied as a “cisplatin rescue” agent to maximize dose intensity. Cisplatin 
favors positively charged platinum species, which possess both antitumor and toxic activities in a low 
chloride environment such as the intracellular space. Following IV administration, sodium thiosulfate 
rapidly distributes to extracellular space and reacts with cisplatin to form a covalently bound compound 
[7]. In a phase 1 study, in which cisplatin 100mg/m2 was infused with concurrent STS followed by 
continuous STS infusion for 2-3 hours, the pharmacokinetic properties of cisplatin including elimination 
rate constant, volume of distribution, or total body clearance did not change significantly [8]. In this clinical 
trial, reported toxicities included elevated creatinine, myelosuppression, nausea, vomiting and 
hypomagnesemia, which are consistent with known effects of cisplatin. 

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Version date: 09-09-2022
Protocol CC#: 20208
Phase II study - Sodium Thiosulfate (STS) 
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1.3
Rationale for the Proposed Study
As patients with HPV positive head and neck cancers have excellent clinical outcome [9], long-term 
treatment related toxicities such as hearing impairment can significantly impact patients’ quality of life. 
In head and neck cancers, sodium thiosulfate delivered after intra-arterial cisplatin has shown to be 
associated with decreased risks of hearing loss in previous research [10, 11]. Furthermore, recent 
clinical trials demonstrated IV sodium thiosulfate after 6 hours of cisplatin infusion can protect pediatric 
cancer patients from cisplatin induced hearing impairment with an acceptable safety profile [1, 12]. One 
of the trials also demonstrated that there was no significant difference in oncologic outcome between 
the STS group and the control group in pediatric patients with hepatoblastoma when STS infusion was 
given 6 hours after cisplatin dose[1]. Although efficacy and safety of STS has been established in 
pediatric hepatoblastoma patients receiving 480mg/m2 (cumulative dose) of single agent cisplatin, no 
prospective studies exist for STS in locally advanced SCCHN patients undergoing definitive 
chemoradiation. Once the feasibility and safety of STS infusion are deemed promising in this population 
based on this phase IIt study, the concept could be easily expanded to a larger study for definitive 
testing which could be conducted in the head and neck cancer population or a broader population with 
various cancers which utilize cisplatin-based chemotherapy in NRG Oncology, either as a stand-alone 
supportive care focused trial or as an adjunctive study to existing or new therapeutic clinical trials.  
1.4
Rationale for the Dose Selection/Regimen 
Intravenous STS 10 g/m2 or 20 g/m2 will be administered over 1-2 hours, 4 hours after each cisplatin dose 
is completed, depending on weekly or high dose cisplatin regimen. In recent clinical trials in pediatric 
cancer patients, STS 20 g/m2 infused after 6 hours of cisplatin has been well tolerated with little 
compromise in oncologic outcome. STS can reduce toxicities from cisplatin by quenching reactive oxygen 
species, preserving the activity of antioxidant enzymes, and forming biologically inactive complexes with 
cisplatin to effectively reduce the systemic exposure to cisplatin. In pediatric hepatoblastoma study, STS 
20 g/m2 was given after cisplatin 80mg/m2. For lower dose, weekly cisplatin, 10g/m2 would be reasonable, 
as only half dose of cisplatin (40mg/m2) is given.  In animal studies, STS given 4 hours after cisplatin was 
able to protect rats from ototoxicity with minimal compromise in anti-tumor activity of cisplatin, whereas 
STS 8 and 12 hours after cisplatin had less and no protective effects at all [13].STS is a FDA approved 
agent for treatment of cyanide poisoning and it is approved to be given as a single dose of 12.5g after 
infusion of 300mg of sodium nitrite. In a phase 3 trial for calciphylaxis, STS is given 25 g per day for 3 
times a week[14]. 
Figure 1. (A) Hearing loss (Brock grade ≧ 1) occurred in 33% in cisplatin-
STS group and 63% in cisplatin-alone group (RR 0.52, 95% CI 0.33-0.81) 
(B) There was no significant difference event-free survival between 

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Phase II study - Sodium Thiosulfate (STS) 
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2
Study Objectives 
2.1
Hypothesis
We hypothesize that use of intravenous STS would be feasible in patients with locally advanced SCCHN 
undergoing concurrent chemoradiation with cisplatin. 
2.2
Primary Objective and Endpoint
Primary Objective
Endpoint
Time Frame
To establish feasibility of intravenous STS after each 
dose of concurrent cisplatin in patients with locally 
advanced head and neck squamous cell carcinoma 
undergoing definitive radiotherapy.
Feasibility measured 
by successful 
completion of planned 
treatment, defined by 
completion of at least 
5 weekly cisplatin or 2 
high dose cisplatin 
administrations 
without extended 
treatment related 
delays more than 7 
days.
Occurring up to 7 
days after the last 
dose of STS

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2.3
Secondary Objectives and Endpoints
Secondary Objectives
Endpoints
Time Frame
1.
To determine the rate of grade  2  hearing 
impairment based on CTCAE version 5 with use 
of STS after concurrent chemoradiation with 
cisplatin 3 months post-treatment
Incidence of ototoxicity 
defined by of grade  2 
hearing impairments 
based on NCI CTCAE 
version 5.0 (for patients 
on a monitoring 
program) with 
audiogram in each 
cohort
3 months after 
completion of 
chemoradiation
2.
To determine the rate of tinnitus measured by 
PRO-CTCAE with use of STS 3 months post-
treatment

Incidence of 
tinnitus using PRO-
CTCAE in each 
cohort
3 months after 
completion of 
chemoradiation
3.
To describe patient reported outcomes with STS 
measured with PRO-CTCAE for selected oral, 
GI, neurologic and perceptual symptoms

Description of 
incidence and trend 
of patient reported 
outcomes using 
PRO-CTCAE in 
each cohort
3 months after 
completion of 
chemoradiation
4.
To describe patient reported outcomes measured 
with Hearing Handicap Inventory for Adults – 
Screening (HHIA-S) compared to results from 
standard NRG Oncology head and neck trials 
(such as RTOG 1016)

Description of 
incidence and trend 
of patient reported 
outcomes using 
HHIA-S in each 
cohort
3 months after 
completion of 
chemoradiation
3
Study Design
3.1
Characteristics
This is a phase II study to determine feasibility of STS infused 4 hours after each dose of either weekly or 
every-3-week cisplatin in SCCHN patients undergoing definitive concurrent chemoradiation with cisplatin. 
Patients with locally advanced SCCHN (oral cavity, oropharynx, hypopharynx, and larynx) eligible for 
definitive concurrent chemoradiation with cisplatin would be eligible for the study.  

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3.2
Sample Size
Target accrual is a total of 16 patients, and to account for screen failures and withdrawals, we will consent 
up to 18 patients. Patients can be enrolled to the and can get  concurrent chemoradiation with weekly 
cisplatin (40 mg/m2) given once a week or concurrent chemoradiation with high dose cisplatin (80-100 
mg/m2) given every 3 weeks. Participants who do not receive any dose of STS will not be evaluable and 
will be replaced.  
3.3
Eligibility Criteria
3.3.1 Inclusion Criteria
1.
Participants must have histologically or cytologically confirmed locoregionally advanced 
squamous cell carcinomas of mucosal surfaces of head and neck who are being treated with 
concurrent chemoradiation with cisplatin.
2.
Participants must be eligible for cisplatin-based concurrent chemotherapy in conjunction with at 
least 6 weeks of daily fractionated radiation therapy.  
3.
Age ≥18 years
4.
ECOG performance status ≤ 2 (Karnofsky ≥ 50%, see Appendix 1)
5.
Demonstrates adequate organ function as defined below:
Adequate bone marrow function:

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absolute neutrophil count
≥1,000/mcL
platelets
≥100,000/mcL
Adequate hepatic function:
total bilirubin
within normal institutional limits, unless elevated due 
to Gilbert’s syndrome and direct bilirubin is within 
normal limits
AST(SGOT)
≤3 X institutional upper limit of normal
ALT(SGPT)
≤3 X institutional upper limit of normal
Adequate renal function:
creatinine
≤ 1.5 x within institutional upper limit of normal
OR
creatinine clearance
GFR ≥ 60 mL/min/1.73 m2,calculated using the 
Cockcroft-Gault equation, unless data exists 
supporting safe use at lower kidney function values, 
no lower than 30 mL/min/1.73 m2 
6.
Ability to understand a written informed consent document, and the willingness to sign it
7.
Individuals with a prior or concurrent malignancy whose natural history or treatment does not 
have the potential to interfere with the safety or efficacy assessment of the investigational 
regimen are eligible for this trial.
8.
The effects of sodium thiosulfate (STS) on the developing human fetus are unknown.  For this 
reason and because cisplatin used in this trial are known to be teratogenic, women of child-
bearing potential and men must agree to use adequate contraception such as hormonal and/or 
barrier method of birth control for the duration of study participation and for 3 months after last 
administration of study treatment.  Should a woman become pregnant or suspect she is pregnant 
while she or her partner is participating in this study, she should inform her treating physician 
immediately.  
Men treated or enrolled on this protocol must also agree to use adequate contraception prior to 
the study, for the duration of study participation, and 3 months after last administration of study 
treatment.
3.3.2 Exclusion Criteria
1.
Participants that are not eligible for cisplatin-based chemoradiation for reasons such as chronic 
kidney disease, severe hearing loss, and severe peripheral neuropathy. 
2.
Uncontrolled inter-current illness or psychiatric illness/social situation that would limit compliance 
with study requirements 
3.
Has known hypersensitivity to cisplatin, sodium thiosulfate or any of its excipients. 
4.
Has profound hearing impairment at baseline and cannot hear a sound below 90 dB
5.
Participants with uncompensated congestive heart failure NYHA class 3 or above.

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6.
Participants who cannot get secure venous access using either a Mediport or a PICC line for safe 
administration of intravenous sodium thiosulfate.
7.
Pregnant women are excluded from this study because cisplatin is a cytotoxic agent with the 
potential for teratogenic or abortifacient effects.  Because there is an unknown but potential risk 
for adverse events in nursing infants secondary to treatment of the mother with cisplatin or 
sodium thiosulfate, breastfeeding should be discontinued if the mother is treated with either 
agent.
3.4
Inclusion and Recruitment of Women and Minorities
Individuals of any sex/gender, race, or ethnicity may participate.
3.5
Duration of Treatment
In the absence of treatment delays due to adverse events, treatment may continue for 7 weeks 
or until:

Disease progression which requires discontinuation of the study treatment;

Inter-current illness that prevents further administration of treatment;

Unacceptable adverse event(s);

Participant decides to withdraw from the study;

Significant participant non-compliance with protocol;

If the participant meets an exclusion criterion (either newly developed or not previously; or, 
recognized) that precludes further study participation

General or specific changes in the participant’s condition render the participant 
unacceptable for further treatment in the judgment of the investigator.
3.6
Duration of Follow Up
Participants will be followed for 36 months after last treatment or removal from study, or until 
death, whichever occurs first.  Participants removed from study for unacceptable treatment or 
study related adverse event(s) will be followed until resolution or stabilization (as determined by 
the investigator) or until initiation of new anti-cancer therapy, whichever occurs first.
3.7
Primary Completion 
The expected primary completion is 9 months after the study opens to accrual.
3.8
Study Completion
The expected study completion date is 12 months after the study opens to accrual.

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4
Investigational Product
4.1
Description, Supply and Storage of Investigational Product
4.1.1 Sodium Thiosulfate
Classification
Sodium thiosulfate has the chemical name thiosulfuric acid, disodium salt, pentahydrate. The chemical 
formula is Na2S2O3· 5H2O and the molecular weight is 248.17. The structural formula is: 
Structure of Sodium Thiosulfate Pentahydrate
Sodium thiosulfate injection is a sterile aqueous solution and is intended for intravenous injection. Each 
vial contains 12.5 grams of sodium thiosulfate in 50 mL solution (250 mg/mL). Each mL also contains 2.8 
mg boric acid and 4.4 mg of potassium chloride. The pH of the solution is adjusted with boric acid and/or 
sodium hydroxide. Sodium thiosulfate injection is a clear solution with a pH between 7.5 and 9.5. 
Mechanism of Action
Sodium thiosulfate can reduce cisplatin-induced toxicity by scavenging reactive oxygen species, 
preserving the activity of antioxidant enzymes (e.g., SOD), and forming biologically inactive complexes 
with cisplatin to effectively reduce the systemic exposure to cisplatin. Of the thiol-containing compounds 
that have been shown to protect against cisplatin-induced ototoxicity, sodium thiosulfate is by far the most 
nucleophilic and forms complexes with cisplatin faster than any other sulfur-containing otoprotectant. The 
structural basis for the formation of the Pt–STS complexes has been recently described and a Pt–STS 
complex has been characterized as a four-coordinate Pt(II) species, [Pt(S2O3)4]6–, by the use of X-ray 
absorption spectroscopy[Metallomics 2016, 8, 1170–117610.1039/C6MT00183A]. In vitro, STS decreases 
the amount of free cisplatin in human plasma, with 31% of free cisplatin remaining in plasma within 10 
min of STS incubation, as compared with 87% with no STS. Furthermore, the free cisplatin remains in 
human plasma for less than 50 min in the presence of excess STS, as compared with more than 3 h in 
the absence of STS. 
Metabolism
Thiosulfate taken orally is not systemically absorbed. Most of the thiosulfate is oxidized to sulfate or is 
incorporated into endogenous sulphur compounds; a small proportion is excreted through the kidneys. 
Approximately 20-50% of exogenously administered thiosulfate is eliminated unchanged via the kidneys. 
After an intravenous injection of 1 g sodium thiosulfate in patients, the reported serum thiosulfate half-life 
was approximately 20 minutes. However, after an intravenous injection of a substantially higher dose of 

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sodium thiosulfate (150 mg/kg, that is, 9 g for 60 kg body weight) in normal healthy men, the reported 
elimination half-life was 182 minutes. 
Contraindications
None (as per the drug label)
Formulation, Appearance, Packaging, and Labeling
Sodium thiosulfate is supplied as one 50 mL glass vial of 250 mg/mL (containing 12.5 grams of sodium 
thiosulfate) for intravenous administration. 
Availability
Sodium thiosulfate is being obtained as commercial supply. 
Storage and handling
Sodium thiosulfate is stored at the UCSF investigational pharmacy at controlled room temperature 
between 20°C and 25°C (68°F to 77°F); excursions permitted from 15 to 30°C (59 to 86°F). It needs to be 
protect from direct light. It should not be frozen. 
Side Effects
Complete and updated adverse event information is available in product package insert. 
4.1.2 Cisplatin 
Classification
Cisplatin injection infusion concentrate is a clear, colorless, sterile aqueous solution available in amber 
vials. The active ingredient, cisplatin, is an anti-neoplastic agent, which is yellow to orange crystalline 
powder with the molecular formula PtCl2H6N2, and a molecular weight of 300.1. Cisplatin is a heavy 
metal complex containing a central atom of platinum surrounded by two chloride atoms and two ammonia 
molecules in the cis position. It is soluble in water or saline at 1 mg/mL and in dimethylformamide at 24 
mg/mL. It has a melting point of 207° C. 
Mechanism of Action
Cisplatin crosslinks with the purine bases on the DNA and interferes with DNA repair mechanisms, 
causes DNA damage, and subsequently induces apoptosis in cancer cells. Although this drug seems to 
act as an alkylating agent, there are data to indicate that its mode and sites of action are different from 
those of nitrogen mustard and the standard alkylating agents.
Metabolism
Plasma concentrations of the parent compound, cisplatin, decay monoexponentially with a half- life of 
about 20 to 30 minutes following bolus administrations of 50 or 100 mg/m2 doses. Monoexponential 
decay and plasma half-lives of about 0.5 hour are also seen following 2-hour or 7-hour infusions of 100 
mg/m2. After the latter, the total-body clearances and volumes of distribution at steady-state for cisplatin 
are about 15 to 16 L/h/m2 and 11 to 12 L/m2. 
Due to its unique chemical structure, the chlorine atoms of cisplatin are more subject to chemical 
displacement reactions by nucleophiles, such as water or sulfhydryl groups, than to enzyme- catalyzed 
metabolism. At physiological pH in the presence of 0.1M NaCl, the predominant molecular species are 
cisplatin and monohydroxymonochloro cis-diammine platinum (II) in nearly equal concentrations. The 
latter, combined with the possible direct displacement of the chlorine atoms by sulfhydryl groups of amino 
acids or proteins, accounts for the instability of cisplatin in biological matrices. The ratios of cisplatin to 
total free (ultrafilterable) platinum in the plasma vary considerably between patients and range from 0.5 to 

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1.1 after a dose of 100 mg/m2. Cisplatin does not undergo the instantaneous and reversible binding to 
plasma proteins that is characteristic of normal drug-protein binding. However, the platinum from cisplatin, 
but not cisplatin itself, becomes bound to several plasma proteins, including albumin, transferrin, and 
gamma globulin. Three hours after a bolus injection and two hours after the end of a three-hour infusion, 
90% of the plasma platinum is protein bound. The complexes between albumin and the platinum from 
cisplatin do not dissociate to a significant extent and are slowly eliminated with a minimum half-life of five 
days or more. 
Following cisplatin doses of 20 to 120 mg/m2, the concentrations of platinum are highest in liver, prostate, 
and kidney; somewhat lower in bladder, muscle, testicle, pancreas, and spleen; and lowest in bowel, 
adrenal, heart, lung, cerebrum, and cerebellum. Platinum is present in tissues for as long as 180 days 
after the last administration. With the exception of intracerebral tumors, platinum concentrations in tumors 
are generally somewhat lower than the concentrations in the organ where the tumor is located. Different 
metastatic sites in the same patient may have different platinum concentrations. Hepatic metastases have 
the highest platinum concentrations, but these are similar to the platinum concentrations in normal liver. 
Maximum red blood cell concentrations of platinum are reached within 90 to 150 minutes after a 100 
mg/m2 dose of cisplatin and decline in a biphasic manner with a terminal half-life of 36 to 47 days. 
Over a dose range of 40 to 140 mg cisplatin/m2 given as a bolus injection or as infusions varying in length 
from 1 hour to 24 hours, from 10% to about 40% of the administered platinum is excreted in the urine in 
24 hours. Over five days following administration of 40 to 100 mg/m2 doses given as rapid, 2- to 3-hour, 
or 6- to 8-hour infusions, a mean of 35% to 51% of the dosed platinum is excreted in the urine. Similar 
mean urinary recoveries of platinum of about 14% to 30% of the dose are found following five daily 
administrations of 20, 30, or 40 mg/m2/day. Only a small percentage of the administered platinum is 
excreted beyond 24 hours post-infusion and most of the platinum excreted in the urine in 24 hours is 
excreted within the first few hours. Platinum-containing species excreted in the urine are the same as 
those found following the incubation of cisplatin with urine from healthy subjects, except that the 
proportions are different. The parent compound, cisplatin, is excreted in the urine and accounts for 13% 
to 17% of the dose excreted within one hour after administration of 50 mg/m2. The mean renal clearance 
of cisplatin exceeds creatinine clearance and is 62 and 50 mL/min/m2 following administration of 100 
mg/m2 as 2-hour or 6- to 7-hour infusions, respectively. 
The renal clearance of free (ultrafilterable) platinum also exceeds the glomerular filtration rate indicating 
that cisplatin or other platinum-containing molecules are actively secreted by the kidneys. The renal 
clearance of free platinum is nonlinear and variable and is dependent on dose, urine flow rate, and 
individual variability in the extent of active secretion and possible tubular reabsorption. 
There is a potential for accumulation of ultrafilterable platinum plasma concentrations whenever cisplatin 
is administered on a daily basis but not when dosed on an intermittent basis. 
No significant relationships exist between the renal clearance of either free platinum or cisplatin and 
creatinine clearance. 
Although small amounts of platinum are present in the bile and large intestine after administration of 
cisplatin, the fecal excretion of platinum appears to be insignificant. 
Contraindications
Cisplatin is contraindicated in patients with preexisting renal impairment. Cisplatin should not be 
employed in myelosuppressed patients, or in patients with hearing impairment.  Cisplatin is 
contraindicated in patients with a history of allergic reactions to cisplatin or other platinum-containing 
compounds. 

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Formulation, Appearance, Packaging, and Labeling
Cisplatin is supplied as a clear, colorless, sterile aqueous solution available in amber vials. Each 50 mL or 
100 mL amber vial of infusion concentrate contains: 1 mg/mL cisplatin, 9 mg/mL sodium chloride, 
hydrochloric acid and sodium hydroxide to approximate pH of 4.0, and water for injection to a final volume 
of 50 mL or 100 mL, respectively. Cisplatin injection infusion concentrate must be further diluted prior to 
intravenous administration. 
Availability
Cisplatin is being obtained as commercial supply. 
Storage and handling
Cisplatin is stored at the UCSF investigational pharmacy. Reconstituted solution of cisplatin is stable for 
20 hours when stored at 27°C and should be protected from light if not used within 6 hours. The vials and 
injection should not be refrigerated. Cisplatin has been shown to react with aluminum needles, producing 
a black precipitate within 30 minutes.
Side Effects
Complete and updated adverse event information is available in the product package insert. 
4.2
 Accountability Records for Investigational Product(s)
UCSF Investigational Drug Services (IDS) will manage drug accountability records for UCSF.
4.3
Ordering Investigational Product(s)
Cisplatin and sodium thiosulfate will be obtained via commercial supply. 
5
Treatment Plan
5.1
Dosage and Administration
Treatment will be administered on an outpatient basis.

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Table 5.1
Regimen Description

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Investigational 
Product
Premedication; 
precautions
Dose
Route
Schedule
Cycle Length
 Cisplatin
(weekly)

Cisplatin can be 
given within 24 
hours of radiation 
therapy.  If 
radiation is held 
for more than 2 
days (for any 
reason), cisplatin 
may be held as 
well until radiation 
resumes.

Prophylactic anti-
emetic regimen 
will be given as 
per UCSF 
guidelines.

1 liter of isotonic 
fluid will be given 
intravenously 
prior to cisplatin 
infusion
40 mg/m2
Intravenously
Days 1, 8, 15, 
22, 29, 36, 
and 43
 Cisplatin
(every-3-weeks)

Cisplatin can be 
given within 24 
hours of radiation 
therapy.  If 
radiation is held 
for more than 2 
days (for any 
reason), cisplatin 
may be held as 
well until radiation 
resumes.

Prophylactic anti-
emetic regimen 
will be given as 
per UCSF 
guidelines.

1 liter of isotonic 
fluid will be given 
intravenously 
prior to cisplatin 
infusion
80-100 
mg/m2
 Intravenously 
Days 1, 22, 
and 43
*Sodium 
Thiosulfate
(weekly)
No contraindications
10 g/m2
Intravenously 
using a 
Mediport or a 
PICC line 
Between 4-5 
hours after 
each cisplatin 
infusion 
sodium 
thiosulfate will 
be 
Weekly or  every 
3 weeks 

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administered 
over 1-2 hours
*Sodium 
Thiosulfate
(every-3-week)
No contraindications
20 g/m2
Intravenously 
using a 
Mediport or a 
PICC line 
Between 4-5 
hours after 
each cisplatin 
infusion 
sodium 
thiosulfate will 
be 
administered 
over 1-2 hours
*Missed doses of sodium thiosulfate will not be replaced.
5.1.1 Radiation Therapy
Radiation therapy will be delivered according to the standard of care, in daily fractions of 1.8-2.2 
Gy per fraction, over at least 6 weeks and no more than 7 weeks. 
The maximum radiation dose to the cochlea should not exceed 45 Gy but every effort will be 
made to constrain the maximum dose to 35 Gy when possible without compromising tumor 
volume coverage. The maximum point doses and average doses delivered to the right cochlea 
and left cochlea will be recorded.
5.2
Dose Modifications for Cisplatin
5.2.1 Neutropenia: 
If on the day of scheduled treatment with cisplatin the absolute neutrophil count (ANC) is < 
1000/mm3, hold the second chemotherapy treatment but not the radiation until ANC ≥ 
1000/mm3, then treat at 100% dose.
5.2.2 Thrombocytopenia: 
If on the day of scheduled treatment with cisplatin the platelet count is < 75,000/mm3, hold the 
second chemotherapy treatment but not the radiation until platelets are ≥ 75,000/mm3, then treat 
at 100% dose.
5.2.3 Renal Adverse Events: 
Cisplatin dose should be based on the serum creatinine or creatinine clearance immediately prior to the 
second cisplatin dose using the following guidelines:
Note: If creatinine is > 1.5 mg/dl, creatinine clearance must be calculated (Cockcroft-Gault) in order to 
make dose adjustment. The cisplatin dose will be determined as follows:
Serum Creatinine Clearance Cisplatin Dose

≤ 1.5 mg/dl or > 50 ml/min full dose

1.5 mg/dl and < 50 ml/min Hold drug*
             *Cisplatin should be held (but the RT continued) and the creatinine measured weekly, until it is

< 1.5 mg/dl or the creatinine clearance is > 50 ml/min, and then the second dose of cisplatin
             can be given at the reduced dose by 50%.

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5.2.4. Nausea and Vomiting: 
Maximum supportive therapy will be given, and cisplatin will be continued at full dose for ≤ 
grade 2 nausea and vomiting. 
For grade 3 nausea and vomiting refractory to supportive therapy, cisplatin will be held until 
recovery to < grade 2. No dose reductions will be made.
5.2.4 Mucositis: 
Significant mucositis (grade 3-4, NCI CTCAE, version 45.0) is expected from radiation and 
cisplatin and should not be a reason for a treatment break, unless it significantly interferes with 
fluid intake or nutrition.  Aggressive supportive care is encouraged.
If a participant experiences several adverse events and there are conflicting recommendations, 
the investigator should use the recommended dose adjustment that reduces the dose to the 
lowest level. 
5.2.5 Switching to weekly cisplatin from every-3-week cisplatin
If a participant experiences any of the above adverse events requiring dose modification, every-
3-week cisplatin can be switched to weekly cisplatin at least 3 weeks after the first dose of 
every-3-week cisplatin, at the treating physician’s discretion. All adverse events should be 
resolved to baseline or CTCAE grade  1 before weekly cisplatin can be resumed. If the 
switching happens, the participant can continue STS infusion at 10mg/m2 as outline in section 
5.1.  
5.3
Monitoring after Sodium Thiosulfate infusion
Because of potential hemodynamic instability following STS infusion, participates will be 
monitored for 30 minutes to 1 hour following completion of STS infusion. If participants manifest 
symptoms of hypotension (dizziness or orthostasis), IV hydration needs to be initiated following 
BP measurement, following the current standard of care. 
5.4
Stopping Rules
We will use Bayesian decision rules for the study to decide respectively early stop out of safety 
or feasibility concerns. We expect that at least 75% of patients would receive target cumulative 
cisplatin dose of 200 mg/m2 which is similar for both weekly and high dose cisplatin groups[15]. 
We assume that no more than 25% of patients would fail to receive cumulative cisplatin dose of 
200 mg/m2 in either cisplatin dose stratum. With the Beta prior distribution with parameters 2 
and 6, the prior expected rate is set at the targeted rate of 25%, and the prior probability of the 
risk greater than 25% is 45%. We apply this prior distribution to the observed number of patients 
experiencing high grade toxicity and compute the posterior (updated) probability of the risk of 
such toxicities greater than 25%. In each cisplatin dose stratum we will consider stopping 
treatment any time if the posterior probability is at least .70(Table 1).
Table 1. Stopping rule for safety
Stop, if there are this many patients who do not 
2
3
4
5
6

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complete cumulative cisplatin dose of 200 mg/m2
In this many patients
2-4
5-7
8-10
11-13
14-16
6
Study Procedures and Schedule of Events
The study-specific procedures and assessments are detailed in this section and outlined in the Study 
Calendar – Section 6.1.  
Screening assessments must be performed within 28 days prior to the first dose of investigational 
product, unless otherwise noted.  Any results falling outside of the reference ranges may be repeated at 
the discretion of the investigator.
Audiogram will be obtained following the institutional standards and will include air-conduction
thresholds at (minimally) octave intervals from 0.25 to 8 kHz.
All on-study visit procedures are allowed a window of ± 2 days unless otherwise noted.  Treatment or 
visit delays for public holidays or weather conditions do not constitute a protocol violation.

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6.1
Study Calendar 
Weekly cisplatin 
Period/Procedure
Screening
Cycle 1 and Future Cycles
End of 
Treatment
Long 
Term/Survival 
Follow-Up1
Study Day/
Visit Day
-28
1
(+/- 2 
days)
8
(+/- 2 
days)
15
(+/- 
2days)
22
(+/- 2 
days)
29
(+/- 2 
days)
36
(+/- 2 
days)
43*2
(+/- 2 days)
133
(+/- 30 
days)
Every 3 
months (+/- 
30 days)
Study Treatment/Drug Administration
Cisplatin
x
x
x
x
x
x
x
Sodium 
Thiosulfate
x
x
x
x
x
x
x
Clinical Assessments
Physical exam
x
x
x
x
x
x
x
x
x
Medical history 
x
Vital signs
x
x
x
x
x
x
x
x
x
Concomitant 
medications
x
x
x
x
x
x
x
x
x
AE assessment
x
x
x
x
x
x
x
x
1Long Term/Survival Follow-up will occur every 3 months via telephone calls up to 36 months. 
2 Day 43 can be omitted at the discretion of treating physician

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Period/Procedure
Screening
Cycle 1 and Future Cycles
End of 
Treatment
Long 
Term/Survival 
Follow-Up1
Study Day/
Visit Day
-28
1
(+/- 2 
days)
8
(+/- 2 
days)
15
(+/- 
2days)
22
(+/- 2 
days)
29
(+/- 2 
days)
36
(+/- 2 
days)
43*2
(+/- 2 days)
133
(+/- 30 
days)
Every 3 
months (+/- 
30 days)
Disease 
assessment 3
x
Performance 
status
x
x
x
x
x
x
x
x
x
Audiogram
x
x
Survival/Long-
term Follow-up 
x
Questionnaires
HHIA-S
x
x
x
*PRO-CTCAE
x
x§4
x
Laboratory Assessments
Hematology5
x
x
x
x
x
x
x
x
x
Chemistry6
x
x
x
x
x
x
x
x
x
3 Documentation of disease assessment using AJCC Cancer Staging Manual 8th edition 
4 §PRO-CTCAE can be obtained between days 14 and 23
5 Including CBC with differential and platelet count
6 Including alkaline phosphatase (ALP), aspartate aminotransferase/alanine aminotransferase (ALT/AST), total bilirubin, calcium, phosphorus, blood urea 
  nitrogen (BUN), creatinine, total protein, albumin, glucose, potassium, sodium, chloride, bicarbonate

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Period/Procedure
Screening
Cycle 1 and Future Cycles
End of 
Treatment
Long 
Term/Survival 
Follow-Up1
Study Day/
Visit Day
-28
1
(+/- 2 
days)
8
(+/- 2 
days)
15
(+/- 
2days)
22
(+/- 2 
days)
29
(+/- 2 
days)
36
(+/- 2 
days)
43*2
(+/- 2 days)
133
(+/- 30 
days)
Every 3 
months (+/- 
30 days)
Urine pregnancy 
test7
x
7 For women of child-bearing potential must have a negative urine pregnancy at screening.

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High dose Q3W cisplatin group
Period/Procedure
Screening
Cycle 1 and Future Cycles
End of 
Treatment
Long 
Term/Survival 
Follow-Up1
Study Day/
Visit Day
-28
1
(+/- 2 
days)
8
(+/- 2 
days)
15
(+/- 2 
days)
22
(+/- 2 
days)
29
(+/- 2 
days)
36
(+/- 2 
days)
43*2
(+/- 2 
days)
133
(+/- 30 
days)
Every 3 
months (+/- 
30 days)
Study Treatment/Drug Administration
Cisplatin
x
x
x
Sodium 
Thiosulfate
x
x
x
Clinical Assessments
Physical exam
x
x
x
x
x
Medical history 
x
Vital signs
x
x
x
x
x
Concomitant 
medications 
x
x
x
x
AE assessment
x
x
x
x
Disease 
assessment 3
x
1 Long Term/Survival Follow-up will occur every 3 months via telephone calls up to 36 months.
2 Day 43 can be omitted at the discretion of treating physician
3 Documentation of disease assessment using AJCC Cancer Staging Manual 8th edition

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Period/Procedure
Screening
Cycle 1 and Future Cycles
End of 
Treatment
Long 
Term/Survival 
Follow-Up1
Study Day/
Visit Day
-28
1
(+/- 2 
days)
8
(+/- 2 
days)
15
(+/- 2 
days)
22
(+/- 2 
days)
29
(+/- 2 
days)
36
(+/- 2 
days)
43*2
(+/- 2 
days)
133
(+/- 30 
days)
Every 3 
months (+/- 
30 days)
Performance 
status
x
x
x
x
x
Audiogram
x
x
Survival/Long-
term Follow-up
x
Questionnaires
HHIA-S
x
x
x
*PRO-CTCAE
x
x§4
x
Laboratory Assessments 
Hematology5 
x
x
x
x
x
Chemistry6
x
x
x
x
x
Urine pregnancy 
test7
x
4  §PRO-CTCAE can be obtained between days 14 and 23
5 Including CBC with differential and platelet count
6 Including alkaline phosphatase (ALP), aspartate aminotransferase/alanine aminotransferase (ALT/AST), total bilirubin, calcium, phosphorus, blood urea   
  nitrogen (BUN), creatinine, total protein, albumin, glucose, potassium, sodium, chloride, bicarbonate
7 For women of child-bearing potential must have a negative urine pregnancy at screening.

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6.2
Participant Registration
A written, signed, informed consent form (ICF) and a Health Insurance Portability and 
Accountability Act (HIPAA) authorization must be obtained before any study-specific 
assessments are initiated.  A copy of the signed ICF will be given to the subject and a copy will 
be filed in the medical record.  The original will be kept on file with the study records.  
All participants consented to the study will be registered in OnCore®, the UCSF Helen Diller 
Family Comprehensive Cancer Center Clinical Trial Management System (CTMS).  The system 
is password protected and meets HIPAA requirements.
6.3
Schedule of Procedures and Assessments
6.3.1 Pretreatment Period
6.3.1.1 Screening Assessments 
The Screening procedures and assessments must be completed within 28 days of initiating 
study treatment. 

Clinical Assessments
o
Documentation of disease assessment using AJCC Cancer 
Staging Manual 8th edition
o
Physical examination
o
Complete medical history
o
Vital signs
o
Concomitant medication review
o
Performance status
o
Audiologic assessments including audiogram
o
Questionnaires

A questionnaire based on PRO-CTCAE for selected oral, 
GI, neurologic and perceptual symptoms (dry mouth, 
difficulty swallowing, mouth/throat sores, taste changes, 
nausea, vomiting, numbness & tingling, and ringing in 
ears)

Hearing Handicap Inventory for Adults – Screening (HHIA-
S) 

Laboratory Assessments
o
Hematology labs - CBC with differential and platelet count 
o
Blood chemistry assessment, including: Alkaline phosphatase 
(ALP), aspartate aminotransferase/alanine aminotransferase 
(ALT/AST), total bilirubin, calcium, phosphorus, blood urea 
nitrogen (BUN), creatinine, total protein, albumin, glucose, 
potassium, sodium, chloride, bicarbonate
o
Urine Pregnancy Test - For women of child-bearing potential. 

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6.3.2 Treatment Period
6.3.2.1 Study Procedures on treatment days

Clinical Assessments
o
Physical examination
o
Vital signs
o
Concomitant medication review
o
AE assessment
o
Performance status
o
Questionnaires (On Day 22 only)

A questionnaire based on PRO-CTCAE for selected oral, 
GI, neurologic and perceptual symptoms (dry mouth, 
difficulty swallowing, mouth/throat sores, taste changes, 
nausea, vomiting, numbness & tingling, and ringing in 
ears)

Hearing Handicap Inventory for Adults – Screening (HHIA-
S) 

Laboratory Assessments (Days 1, 8, 15, 22, 29, 36 for subjects getting weekly cisplatin 
and days 1 and 22 for subjects getting every-3-week cisplatinDay 43 labs will only be 
collected if treatment occurs that day).  
o
Hematology labs - CBC with differential and platelet count
o
Blood chemistry assessment, including: Alkaline phosphatase 
(ALP), aspartate aminotransferase/alanine aminotransferase 
(ALT/AST), total bilirubin, calcium, phosphorus, blood urea 
nitrogen (BUN), creatinine, total protein, albumin, glucose, 
potassium, sodium, chloride, bicarbonate 

Treatment with cisplatin and sodium thiosulfate
6.3.3 Post-treatment/Follow-Up 
Participants will be followed at least once around 3 months +/- 2 weeks after discontinuing study 
treatment.  The following procedures will be performed at the Follow Up visit:

Clinical Assessments
o
Physical examination
o
Vital signs
o
Concomitant medication review
o
AE assessment
o
Performance status
o
Audiologic assessments including audiogram
o
Questionnaires

A questionnaire based on PRO-CTCAE for selected oral, 
GI, neurologic and perceptual symptoms (dry mouth, 

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difficulty swallowing, mouth/throat sores, taste changes, 
nausea, vomiting, numbness & tingling, and ringing in 
ears) 

Hearing Handicap Inventory for Adults – Screening (HHIA-
S) 

Laboratory Assessments
o
Hematology labs - CBC with differential and platelet count 
o
Blood chemistry assessment, including: Alkaline phosphatase 
(ALP), aspartate aminotransferase/alanine aminotransferase 
(ALT/AST), total bilirubin, calcium, phosphorus, blood urea 
nitrogen (BUN), creatinine, total protein, albumin, glucose, 
potassium, sodium, chloride, bicarbonate
6.3.4 Long Term/Survival Follow-up 
After completing the follow-up period, participants can be contacted by telephone every 3 
months (+/- 30 days) up to 3 years to assess for event free survival and overall survival after 
initiation of treatment to confirm that there is no reduced efficacy of cisplatin when administered 
prior to sodium thiosulfate (STS) and to assess for survival/anti-cancer therapy status until 
death, withdrawal of consent, or the end of the study, whichever occurs first. 
6.4
Use of Concurrent/Concomitant Medications
Participants should receive anti-emetic therapy based on UCSF guidelines at the treating 
physician’s discretion. Use of growth factors is not allowed for patients getting weekly cisplatin , 
but can be allowed at the treating physician’s discretion for patients gettingevery-3-week 
cisplatin.
7
Reporting and Documentation of Results
7.1
Evaluation of Safety
7.1.1 Definitions
Evaluable for toxicity
All participants will be evaluable for toxicity from the time of their first treatment with sodium 
thiosulfate.
7.1.2 Evaluation of Safety
The safety parameters for this study include all laboratory tests and hematological 
abnormalities, physical findings, and spontaneous reports of adverse events reported to the 
investigator by participants.
Toxicity will be assessed according to the NCI CTCAE version 5.0. Safety analyses will be 
performed for all participants who received at least one dose of sodium thiosulfate.

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7.2
Definitions of Adverse Events 
7.2.1 Adverse Event
An adverse event (also known as an adverse experience) is defined as any untoward medical 
occurrence associated with the use of a drug in humans, whether or not considered drug 
related.  More specifically, an adverse event (can be any unfavorable and unintended sign (e.g., 
an abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
drug, without any judgment about causality.  An adverse event can arise from any use of the 
drug (e.g., off-label use, use in combination with another drug) and from any route of 
administration, formulation, or dose, including an overdose. 
7.2.2 Adverse Reaction
An adverse reaction is defined as any adverse event caused by the use of a drug.  Adverse 
reactions are a subset of all suspected adverse reactions for which there is reason to conclude 
that the drug caused the event.
7.2.3 Suspected Adverse Reaction
A suspected adverse reaction is defined as any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event. For the purposes of IND safety reporting, 
“reasonable possibility” indicates that there is evidence to suggest a causal relationship 
between the drug and the adverse event.  A suspected adverse reaction implies a lesser degree 
of certainty about causality than an adverse reaction.
7.2.3.1
Unexpected 
An adverse event or suspected adverse reaction is considered unexpected if it is not listed 
in the investigator brochure or package insert(s), or is not listed at the specificity or severity 
that has been observed, or, if an investigator brochure is not required or available, is not 
consistent with the risk information described in the general investigational plan or 
elsewhere in the current application. 
“Unexpected,” as used in this definition, also refers to adverse events or suspected adverse 
reactions that are mentioned in the investigator brochure as occurring with a class of drugs 
or as anticipated from the pharmacological properties of the drug, but are not specifically 
mentioned as occurring with the particular drug under investigation.
Adverse events that would be anticipated to occur as part of the disease process are 
considered unexpected for the purposes of reporting because they would not be listed in the 
investigator brochure.  For example, a certain number of non-acute deaths in a cancer trial 
would be anticipated as an outcome of the underlying disease, but such deaths would 
generally not be listed as a suspected adverse reaction in the investigator brochure.
Some adverse events are listed in the Investigator Brochure as occurring with the same 
class of drugs, or as anticipated from the pharmacological properties of the drug, even 
though they have not been observed with the drug under investigation.  Such events would 
be considered unexpected until they have been observed with the drug under investigation. 
For example, although angioedema is anticipated to occur in some participants exposed to 
drugs in the angiotensin-converting enzymeinhibitor class and angioedema would be 
described in the investigator brochure as a class effect, the first case of angioedema 
observed with the drug under investigation should be considered unexpected for reporting 
purposes.

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7.2.3.2
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 participant and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition.  Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse.
7.2.3.3
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 participant at immediate risk 
of death. It does not include an adverse event or suspected adverse reaction that, had it 
occurred in a more severe form, might have caused death. 
7.2.4 Recording of Adverse Events
Refer to the Data Safety Monitoring Plan, located in Appendix 2.
7.2.5 Follow-up of Adverse Events
All participants who experience adverse events will be followed with appropriate medical 
management until resolved or stabilized, as determined by the investigator, or until the initiation 
of new anti-cancer therapy, whichever occurs first.  For selected adverse events for which 
administration of the investigational product was stopped, a re-challenge of the subject with the 
investigational drug may be conducted if considered both safe and ethical by the investigator.
7.2.6 Adverse Events Monitoring
Refer to the Data Safety Monitoring Plan, located in Appendix 2.
7.2.7 Expedited Reporting 
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 last 
administration of the study drug(s) and it is determined to be related either to the study drug(s) 
or to a study procedure, the Investigator or his/her designee must notify the DSMC Chair (or 
qualified alternate) within 1 business day of knowledge of the event.  The contact may be by 
phone or e-mail.
Reporting to Institutional Review Board

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The UCSF PI must report events to the UCSF IRB according to institutional guidelines.
UCSF IRB website for guidance in reporting adverse events: https://irb.ucsf.edu/adverse-event
Expedited Reporting to the FDA
If the study is being conducted under an IND, the Sponsor (or the Sponsor-Investigator) is 
responsible for determining whether or not the suspected adverse reaction meets the criteria for 
expedited reporting in accordance with federal regulations (21 CFR §312.32). 
The Sponsor (or Sponsor-Investigator) must report in an IND safety report any suspected 
adverse reaction that is both serious and unexpected. The Sponsor needs to ensure that the 
event meets all three definitions: 

Suspected adverse reaction 

Unexpected 

Serious 
If the adverse event does not meet all three of the definitions, it should not be submitted as an 
expedited IND safety report.
The timeline for submitting an IND safety report to FDA is no later than 15 calendar days after 
the Investigator determines that the suspected adverse reaction qualifies for reporting (21 CFR 
312.32(c)(1)). 
Any unexpected fatal or life-threatening suspected adverse reaction will be reported to FDA no 
later than 7 calendar days after the Investigator’s initial receipt of the information (21 CFR 
312.32(c)(2)). 
Any relevant additional information that pertains to a previously submitted IND safety report will 
be submitted to FDA as a Follow-up IND Safety Report without delay, as soon as the 
information is available (21 CFR 312.32(d)(2)). 
8
Statistical Considerations and Analysis Plan
Feasibility will be evaluated as the successful completion of 5 weekly cisplatin or 2 every-3-
week cisplatin without any extended treatment related delays more than 7 days by at least 75% 
of patients. Safety will be measured by:

Frequency of drug related adverse events occurring up to 7 days after the last dose of STS 

Frequency of serious adverse events occurring up to 7 days after the last dose of STS

Frequency of clinical laboratory test abnormalities by worst toxicity grade using NCI CTCAE 
version 5.0 
8.1
Accrual Estimates
A total of 16 patients are going to be enrolled. Estimated accrual is 2-3 per month. Projected 
completion of accrual from the activation of the study is 9 months and last patient follow-up will 
be completed in 12 months from the activation. 

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8.2
Sample Size Considerations
This is a phase II study that aims to obtain preliminary evidence of feasibility. The proposed 
sample of n=16 would allow estimating the rates with margins of error of 0.345 at 95% 
confidence level. 
8.3
Interim Analyses and Stopping Rules
There is no plan for interim analyses in this phase II study. Stopping rules are illustrated in 
section 5.3. 
8.4
Analyses Plans
We will report the proportion of patients experiencing high-grade toxicity with exact binomial 
95% confidence intervals. We will also describe patient experiences with respect to feasibility as 
defined above. All other adverse events will be similarly summarized by type and grade.
9
Study Management
9.1
Pre-study Documentation
This study will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki as stated in 21 CFR §312.120(c)(4); consistent with GCP and all 
applicable regulatory requirements.
Before initiating this trial, the PI 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 participants before any protocol related 
procedures are performed on any participants.  
The PI must comply with the applicable regulations in Title 21 of the Code of Federal 
Regulations (21 CFR §50, §54, and §312), GCP/ICH guidelines, and all applicable regulatory 
requirements.  The IRB must comply with the regulations in 21 CFR §56 and applicable 
regulatory requirements.
The clinical investigation will not begin until either FDA has determined that the study under the 
Investigational Drug Application (IND) is allowed to proceed or the FDA has determined that the 
study is exempt from IND requirements. 
9.2
Institutional Review Board Approval
The protocol, the proposed informed consent form, and all forms of participant-facing 
materialsrelated to the study (e.g. advertisements used to recruit participants) will be reviewed 
and approved by the UCSF 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.  
9.3
Informed Consent
All participants must be provided a consent form describing the study with sufficient information 
for each participant to make an informed decision regarding their participation.  Participants 
must sign the IRB -approved informed consent form prior to participation in any study specific 

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procedure.  The participant must receive a copy of the signed and dated consent document.  
The original signed copy of the consent document must be retained in the medical record or 
research file. 
9.4
Changes in the Protocol
Once the protocol has been approved by the UCSF IRB, any changes to the protocol must be 
documented in the form of an amendment.  The amendment must be signed by the PI and 
approved by PRC and the IRB prior to implementation.  
If it becomes necessary to alter the protocol to eliminate an immediate hazard to participants, an 
amendment may be implemented prior to IRB approval.  In this circumstance, however, the PI 
must then notify the IRB according to institutional requirements.  
9.5
Handling and Documentation of Clinical Supplies
The PI will maintain complete records showing the receipt, dispensation, return, or other 
disposition of all investigational drugs at the site.  The date, quantity and batch or code number 
of the drug, and the identification of participants to whom the investigational product has been 
dispensed by participant number and initials will be included.  
The PI shall not make the investigational drug available to any individuals other than to qualified 
study participants.  Furthermore, the PI will not allow the investigational product to be used in 
any manner other than that specified in this protocol.
9.6
Case Report Forms (CRFs)
The PI and/or 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.  Study personnel 
will complete the CRFs; the PI 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 participant’s medical records maintained by 
study personnel.  All source documentation should be kept in separate research files for each 
participant. 
In accordance with federal regulations, the PI 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. 
The PI 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 PI and the trial statistician.
All source documentation and CTMS data will be available for review/monitoring by the UCSF 
DSMC and regulatory agencies.   
9.7
Oversight and Monitoring Plan
The UCSF Helen Diller Family Comprehensive Cancer Center DSMC will be the monitoring 
entity for this study.  The UCSF DSMC will monitor the study in accordance with the NCI-

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approved Data and Safety Monitoring Plan (DSMP).  The DSMC will routinely review all adverse 
events and suspected adverse reactions considered “serious”.  The DSMC will audit study-
related activities to ensure that the study is conducted in accordance with the protocol, local 
standard operating procedures, FDA regulations, and Good Clinical Practice (GCP).  Significant 
results of the DSMC audit will be communicated to the IRB and the appropriate regulatory 
authorities at the time of continuing review, or in an expedited fashion, as applicable.  See 
Appendix 2 - Data and Safety Monitoring Plan.
9.8
Record Keeping and Record Retention
The PI 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 PI 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.
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 participant 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 PI shall retain records for a period of 2 years following 
the date a marketing application is approved for the drug for the indication for which it is being 
investigated; or, if no application is to be filed or if the application is not approved for such 
indication, until 2 years after the investigation is discontinued and FDA is notified.

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10
References
1.
Brock, P.R., et al., Sodium Thiosulfate for Protection from Cisplatin-Induced Hearing 
Loss. N Engl J Med, 2018. 378(25): p. 2376-2385.
2.
Blanchard, P., et al., Meta-analysis of chemotherapy in head and neck cancer (MACH-
NC): a comprehensive analysis by tumour site. Radiother Oncol, 2011. 100(1): p. 33-40.
3.
Gillison, M.L., et al., Radiotherapy plus cetuximab or cisplatin in human papillomavirus-
positive oropharyngeal cancer (NRG Oncology RTOG 1016): a randomised, multicentre, non-
inferiority trial. Lancet, 2019. 393(10166): p. 40-50.
4.
Teft, W.A., et al., Predictors of cisplatin-induced ototoxicity and survival in 
chemoradiation treated head and neck cancer patients. Oral Oncol, 2019. 89: p. 72-78.
5.
Frisina, R.D., et al., Comprehensive Audiometric Analysis of Hearing Impairment and 
Tinnitus After Cisplatin-Based Chemotherapy in Survivors of Adult-Onset Cancer. J Clin Oncol, 
2016. 34(23): p. 2712-20.
6.
Drug Approval Package: Sodium thiosulfate injection, 250 mg/mL, U.F.D. Administration, 
Editor. 2012: Silver Spring, MD.
7.
Gandara, D.R., et al., Cisplatin rescue therapy: experience with sodium thiosulfate, 
WR2721, and diethyldithiocarbamate. Crit Rev Oncol Hematol, 1990. 10(4): p. 353-65.
8.
Pfeifle, C.E., et al., High-dose cisplatin with sodium thiosulfate protection. J Clin Oncol, 
1985. 3(2): p. 237-44.
9.
Ang, K.K., et al., Human papillomavirus and survival of patients with oropharyngeal 
cancer. N Engl J Med, 2010. 363(1): p. 24-35.
10.
Zuur, C.L., et al., Ototoxicity in a randomized phase III trial of intra-arterial compared 
with intravenous cisplatin chemoradiation in patients with locally advanced head and neck 
cancer. J Clin Oncol, 2007. 25(24): p. 3759-65.
11.
Ishikawa, E., et al., Protective effects of sodium thiosulfate for cisplatin-mediated 
ototoxicity in patients with head and neck cancer. Acta Otolaryngol, 2015. 135(9): p. 919-24.
12.
Freyer, D.R., et al., Effects of sodium thiosulfate versus observation on development of 
cisplatin-induced hearing loss in children with cancer (ACCL0431): a multicentre, randomised, 
controlled, open-label, phase 3 trial. Lancet Oncol, 2017. 18(1): p. 63-74.
13.
Dickey, D.T., et al., Protection against cisplatin-induced toxicities by N-acetylcysteine 
and sodium thiosulfate as assessed at the molecular, cellular, and in vivo levels. J Pharmacol 
Exp Ther, 2005. 314(3): p. 1052-8.
14.
A Phase 3 Clinical Trial of Intravenous Sodium Thiosulfate in Acute Calciphylaxis 
Patients (CALISTA). 2019  [cited 2019 Oct 9]; Available from: 
https://clinicaltrials.gov/ct2/show/NCT03150420.
15.
Lee, S.Y., et al., Comparison of standard-dose 3-weekly cisplatin and low-dose weekly 
cisplatin for concurrent chemoradiation of patients with locally advanced head and neck 
squamous cell cancer: A multicenter retrospective analysis. Medicine (Baltimore), 2018. 97(21): 
p. e10778.

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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 Phase II or III Institutional Study
1.         Oversight and Monitoring Plan 
The UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC) Data and Safety 
Monitoring Committee (DSMC) is responsible for auditing data quality and participant safety for 
all HDFCCC institutional clinical trials.  A summary of DSMC activities for this trial includes:  

Semiannual auditing (depending on trial accrual) 

Review of serious adverse events 

Minimum of biennial regulatory auditing 
2. Monitoring and Reporting Guidelines 
Investigators will conduct a continuous review of data and participant safety at monthly site 
committee meetings where the results of each participant’s treatment are discussed and 
documented in the site committee minutes.   
All institutional Phase II and III therapeutic trials are audited on a semiannual basis, with all data 
from twenty percent of the enrolled participants audited by the DSMC 
Monitor/Auditor.  The assigned DSMC Monitor/Auditor will review no more than a total of 
10 participant charts during the course of auditing this trial. DSMC Monitor/Auditors will send a 
follow-up report to the study team within 20 business days after the auditing visit is complete for 
the PI and the study team to resolve all action items from this report within 20 business 
days.  An abbreviated regulatory review (i.e., reviewing protocol and consent versions, SAEs, 
PVs, DOA logs, 1572 forms, etc.) will occur at each participant monitoring review; however, a 
full regulatory review will occur on a biennially basis by the DSMC for regulatory compliance. 
Auditing of all enrolled participants in these trials will be complete after 20% of enrolled 
participants have been audited through five cycles of treatment.  However, regulatory reviews of 
the trial, safety reviews (i.e., Serious Adverse Event (SAE) reviews and Protocol Violation (PV) 
reviews), and audit/inspection preparation (as applicable) will continue until the trial is closed by 
the IRB.   
3. Review and Oversight Requirements 
3.1 Adverse Event Monitoring  
All Grade 3-5 adverse events (AEs), whether or not considered to be expected or unexpected 
and whether or not considered to be associated with the use of the investigational agent(s) 
or study procedure, will be entered into OnCore®, UCSF’s Clinical Trial Management System.   
Adverse events are graded according to the Common Terminology Criteria for Adverse Events 
(CTCAE) as developed and revised by the Common Therapy Evaluation Program (CTEP) of the 
National Cancer Institute.  Adverse events are further given an assignment of attribution or 
relationship to investigational agent or study procedure.  Attribution categories are: 
• Definite – The adverse event is clearly related to the investigational agent(s) 
or study procedure. 
• Probable – The adverse event is likely related to the investigational agent(s) 
or study procedure. 

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• Possible – The adverse event may be related to the investigational agent(s) 
or study procedure. 
• Unrelated – the adverse event is clearly not related to the investigational agent(s) 
or study procedure. 
All Grade 3-5 adverse events entered into OnCore® will be reviewed on a monthly basis at the 
Site Committee meetings.  The Site Committee will review and discuss the selected toxicity, the 
toxicity grade, and attribution assignment. 
3.2 Serious Adverse Event Reporting  
By definition, an adverse event is defined as a serious adverse event (SAE) according to the 
following criteria: 
• Death. 
• Life-threatening (i.e., results in an immediate risk of death). 
• Requires inpatient hospitalization or prolongation of existing hospitalization, 
• Permanent or significant disability/incapacity 
• Gives rise to a congenital anomaly/birth defect, or cancer, or any experience that suggests a 
significant hazard, contraindication, side effect, or precaution that may require medical or 
surgical intervention to prevent one of the outcomes listed above.  
• Event occurring in a gene therapy study. 
• Event that changes the risk/benefit ratio of a study. 
• Any other event the Principal Investigator judges to be serious or which would suggest a 
significant hazard, contraindication, side effect, or precaution. 
Serious adverse event reporting will be in accordance with all IRB regulations. For trials 
conducted under an investigational new drug (IND) application, the SAE will be reported in 
accordance with Code of Federal Regulation Title 21 Part 312.32 and will be reported on a Med 
Watch form.   
UCSF IRB website for guidance in reporting serious adverse events: 
https://irb.ucsf.edu/adverse-event  
Med Watch forms and information: 
www.fda.gov/medwatch/getforms.htm 
All serious adverse events are entered into OnCore®, as well as submitted to the IRB (per IRB 
guidelines).  The SAEs are reviewed and monitored by the Data and Safety Monitoring 
Committee on an ongoing basis and discussed at DSMC meetings, which take place every six 
weeks.  The date the SAE is sent to all required reporting agencies will be documented in 
OnCore®.  
If the SAE involves a subject death, and is determined to be possibly, probably or definitely 
related to the investigational drug or any research related procedure, the event must be 
reported to the DSMC Chair (or Vice Chair) and DSMC Director within one business day.  

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3.3 Review of Adverse Event Rates 
If an increase in the frequency of Grade 3 or 4 adverse events (above the rate reported in the 
Investigator Brochure or package insert) is noted in the study, the Principal Investigator will 
notify the DSMC via report at the time the increased rate is identified.  The report will indicate if 
the incidence of adverse events observed in the study is above the range stated in the 
Investigator Brochure or package insert. 
If at any time the Investigator voluntarily holds enrollment or stops the study due to safety 
issues, the DSMC Chair (or Vice Chair) and the DSMC Director must be notified within 
one business day and the IRB must be notified as per IRB reporting regulations. 
Data and Safety Monitoring Committee Contacts: 
 Katie Kelley, MD (DSMC Chair) 
 
 
  
 
  
 
  UCSF HDFCCC 
  San Francisco, CA 94158 
John McAdams (DSMC Director)  
 
 
 
UCSF HDFCCC 
San Francisco, CA 94143 
                                                                                       DSMP Monitoring Templates (version 12Oct2021)