Phase I Dose-Escalation Bioavailability Study of Oral Triapine in Combination With Concurrent Chemoradiation for Locally Advanced Cervical Cancer (LACC) and Vaginal Cancer
Phase: PHASE1
Conditions: Advanced Cervical Adenocarcinoma, Advanced Cervical Adenosquamous Carcinoma, Advanced Cervical Squamous Cell Carcinoma, Advanced Vaginal Adenocarcinoma, Advanced Vaginal Adenosquamous Carcinoma, Advanced Vaginal Squamous Cell Carcinoma, Stage IB2 Cervical Cancer AJCC v6 and v7, Stage II Cervical Cancer AJCC v7, Stage II Vaginal Cancer AJCC v6 and v7, Stage III Vaginal Cancer AJCC v6 and v7, Stage IIIB Cervical Cancer AJCC v6 and v7, Stage IVA Cervical Cancer AJCC v6 and v7, Stage IVA Vaginal Cancer AJCC v6 and v7
Sponsor: National Cancer Institute (NCI)

Page i of i 
 
 
 
SUMMARY OF CHANGES 
 
For Protocol Amendment #12: 
 
NCI Protocol #:  9892 
Local Protocol #: 15-157 
 
NCI Version Date:  01/12/2023  
Protocol Date:  01/12/2023 
 
 
# 
Section 
Change 
2. 
Administrative 
Throughout 
Updated section numbering. Corrected number formatting as well as 
updated the Table of Contents to reflect the updates. 
3. 
Study Team 
Removed statistician Dan Normolle, and updated to:  
Hong Wang, PhD 
UPMC Cancer Pavilion 
POB2, Suite 4C  
5150 Centre Ave  
Telephone: 412-383-1588 
Email: how8@pitt.edu 
 
4. 
5.4.1 
Clarified Dose Escalation criteria:  
Enrollment will not be time-limited but will be limited to patients with 
a histologically confirmed diagnosis of locally advanced cervical or 
vaginal carcinoma not amenable to curative surgical resection alone to 
facilitate achievement of secondary objectives. 
5. 
10 
Update made to STUDY CALENDAR to ensure all screening 
evaluations and drug can be ready within window: 
Baseline evaluations are to be conducted within 10 14 days prior to 
start of protocol therapy. 
6. 
10 
Update made to STUDY CALENDAR for secondary objective 1.2.2 
analysis: 
Follow up for progression and survival status will occur via medical 
record review or phone call and should occur every 6 months (+/- 2 
weeks) for a total of 5 years from the off treatment date.  
 
 
 

 
 
NCI Protocol #: 
9892 
 
Local Protocol #: 
HCC# 15-157 
 
ClinicalTrials.gov Identifier: NCT02595879 
 
TITLE: Phase I Dose-Escalation Bioavailability Study of Oral Triapine in Combination with 
Concurrent Chemoradiation for Locally Advanced Cervical Cancer (LACC) and Vaginal Cancer 
 
 
Corresponding Organization:   LAO-PA015 / UPMC Hillman Cancer Center LAO 
 
 
Principal Investigator: 
 
Sarah E. Taylor, MD 
Assistant Professor 
Division of Gynecology Oncology 
Magee-Womens Hospital of UPMC 
300 Halket St, Suite 2130 
Pittsburgh, PA 15213 
Phone: 412-641-1153 
Fax: 412-641-5417 
E-mail: taylorse2@mail.magee.edu 
 
Participating Organizations: 
 
LAO-11030 / University Health Network Princess Margaret Cancer Center LAO 
LAO-CA043 / City of Hope Comprehensive Cancer Center LAO 
LAO-CT018 / Yale University Cancer Center LAO 
LAO-MA036 / Dana-Farber - Harvard Cancer Center LAO 
LAO-MD017 / JHU Sidney Kimmel Comprehensive Cancer Center LAO 
LAO-OH007 / Ohio State University Comprehensive Cancer Center LAO 
LAO-TX035 / University of Texas MD Anderson Cancer Center LAO 
LAO-NCI / National Cancer Institute LAO 
EDDOP / Early Drug Development Opportunity Program 
For the ex-US participating institutions, Triapine exportation by the Pharmaceutical 
Management Branch/CTEP is contingent on approval by the pharmaceutical 
collaborator. 

NCI Protocol #:  9892 
Version Date:  January 12, 2023 
Page 2 of 84 
 
 
 
Statistician 
Hong Wang, PhD 
UPMC Cancer Pavilion 
POB2, Suite 4C  
5150 Centre Ave  
Telephone: 412-383-1588 
Email: how8@pitt.edu 
 
Study Coordinator 
Julie Urban, PhD 
5150 Centre Ave, Suite 301  
Pittsburgh, PA 15232  
Telephone: 412-623-7396  
Fax: 412-647-0949  
Email: ETCTN9892@upmc.edu  
 
 
NCI-Supplied Agent(s):  3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, 
triapine, NSC #663249) 
 
 
Commercial Agent(s): cisplatin (platinol®, NSC #119875) 
 
IND #:  
 
IND Sponsor: DCTD, NCI 
 
Protocol Type / Version # / Version Date:  Original / Version #1/ 06/09/15 
Original / Version #2/ 07/27/15 (Response to 
consensus review dated, July 6, 2015) 
Original / Version #3/ 09/04/15 (Response to 
consensus review follow-up, dated August 
18, 2015) 
Original/Version #4 / 12/07/15 (Response to CIRB 
reviewer 
comments, 
dated 
11/23/15) 
Original/Version #5 / 01/21/16 (Response to CTEP 
reviewer 
comments, 
dated 
12/22/15) 
Original/Version #6 / 03/21/16 (Response to CIRB 
reviewer 
comments/Outcome 
Letter, 
CIRB 
meeting held on 03/15/16) 
Amendment 1/Version #7/03/15/2018 (CTCAE 
version change, study coordinator change) 
Amendment 2/Version #8/ 09/10/2018 [Response 
to 
RRA 
from 
Dr. 
Charles 
Kunos 
(charles.kunos@nih.gov)] 
Amendment 3/Version #9/ 11/09/2018 (Response 
to Comments dated 10/11/18 from Dr. Charles 
Kunos following Amendment 2 Disapproval on 
10/10/2018) 
Amendment 4/Version #10/ 01/16/2019 [Response 
to Comments dated 01/04/2019 from Dr. Charles 
Kunos (charles.kunos@nih.gov)] 
Amendment 5/Version #11/ 02/21/2019 (Response 

NCI Protocol #:  9892 
Version Date:  January 12, 2023 
Page 3 of 84 
 
to CIRB Stipulations dated 02/07/2019) 
Amendment 6/Version #12/ 05/17/2019 [Response 
to 
an 
RA 
from 
Dr. 
Charles 
Kunos 
(charles.kunos@nih.gov)] 
Amendment 7/Version #13/08/27/2020 (Changes 
made to align with a Corrective Action Plan for 
study enrollment requested from CTEP and in 
response to an RA from CTEP) 
Amendment 8/Version #14/11/03/2020 (Response 
to comments dated 09/03/2020 from Dr. Charles 
following 
Amendment 
7 
Disapproval 
on 
09/04/2020 and response to CIRB stipulations dated 
10/21/2020) 
Amendment 9/Version #15/03/17/2021 (Response 
to CTEP Review Comments and a CTEP 
Amendment Request, and changes elicited by the 
University of Pittsburgh) 
Amendment 10/Version #16/ 06/13/2022 (MTD 
addition, response to CTEP comments, & other 
minor changes)  
Amendment 11/Version #17/ 06/29/2022 (TRIAD 
removal and responses to CTEP comments) 
Amendment 
12/Version 
#18 
01/12/2023 
(Administrative 
formatting 
updates, 
clarified 
eligibility for expansion cohort, follow up period, 
baseline evaluation window and study team 
update.) 
 

NCI Protocol #:  9892 
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SCHEMA 
 
 
Dose Escalation Schema 
 
 
Radiation Therapy 
Dose 
Level 
IV Cisplatin 
Weekly 
PO Triapine* 
Pelvic RT + 
Brachytherapy 
(+/- Extended 
-2 
40 mg/m2 
50 mg D1, 3, 5 
-1 
40 mg/m2 
50 mg QD x 5 
1 
40 mg/m2 
100 mg QD x 5 
2 
40 mg/m2 
150 mg QD x 5 
3 
40 mg/m2 
200 mg QD x 5 
*1 of the planned 25 doses of triapine will be delivered IV (day 1) at a fixed dose of 
50 mg to allow PK and PD studies.

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TABLE OF CONTENTS 
 
 
 
SCHEMA................................................................................................................................... 4 
1. 
OBJECTIVES .................................................................................................................... 7 
1.1 
Primary Objectives ................................................................................................. 7 
1.2 
Secondary Objectives ............................................................................................. 7 
1.3 
Exploratory Endpoints ............................................................................................ 7 
2. 
BACKGROUND ............................................................................................................... 7 
2.1 
Locally Advanced Cervical Cancer (LACC) ......................................................... 7 
2.2 
CTEP Agent: Triapine ............................................................................................ 8 
2.3 
Rationale for the combination of triapine with concurrent chemoradiation .......... 9 
2.4 
Correlative Studies Background ............................................................................. 9 
3. 
PATIENT SELECTION .................................................................................................. 10 
3.1 
Eligibility Criteria ................................................................................................. 10 
3.2 
Exclusion Criteria ................................................................................................. 12 
3.3 
Inclusion of Women and Minorities ..................................................................... 12 
4. 
REGISTRATION PROCEDURES ................................................................................. 13 
4.1 
Investigator and Research Associate Registration with CTEP ............................ 13 
4.2 
Site Registration.................................................................................................... 14 
4.3 
Patient Registration ............................................................................................... 15 
4.4 
General Guidelines ............................................................................................... 17 
5. 
TREATMENT PLAN ...................................................................................................... 18 
5.1 
Agent Administration ........................................................................................... 20 
5.2 
Radiation therapy: ................................................................................................. 30 
5.3 
Chemotherapy ....................................................................................................... 33 
5.4 
Duration of Study ................................................................................................. 34 
5.5 
Definition of Dose-Limiting Toxicity .................................................................. 35 
5.6 
General Concomitant Medication and Supportive Care Guidelines .................... 36 
5.7 
Duration of Therapy ............................................................................................. 36 
5.8 
Duration of Follow Up ......................................................................................... 37 
5.9 
Criteria for Removal from Study .......................................................................... 37 
6. 
DOSING DELAYS/DOSE MODIFICATIONS ............................................................. 38 
6.1 
Nausea/vomiting ................................................................................................... 38 
6.2 
Diarrhea ................................................................................................................ 38 
6.3 
Neutropenia ........................................................................................................... 39 
6.4 
Thrombocytopenia ................................................................................................ 39 
6.5 
Non-hematologic toxicity ..................................................................................... 39 
6.6 
Methemoglobinemia ............................................................................................. 40 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ......................... 40 
7.1 
Comprehensive Adverse Events and Potential Risks List(s) (CAEPRs) ............. 41 
7.2 
Adverse Event Characteristics .............................................................................. 45 
7.3 
Expedited Adverse Event Reporting .................................................................... 45 
7.4 
Routine Adverse Event Reporting ........................................................................ 48 
7.5 
Secondary Malignancy ......................................................................................... 48 
7.6 
Second Malignancy .............................................................................................. 48 
8. 
PHARMACEUTICAL INFORMATION ....................................................................... 49 

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8.1 
Triapine NSC 663249 ........................................................................................... 49 
8.2 
Cisplatin (NSC #119875) ..................................................................................... 52 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ..................................... 54 
9.1 
Integrated Laboratory Studies - Secondary objective .......................................... 54 
9.2 
Special Studies ...................................................................................................... 56 
10. STUDY CALENDAR ..................................................................................................... 60 
11. MEASUREMENT OF EFFECT ..................................................................................... 62 
11.1 
Antitumor Effect – Solid Tumors ......................................................................... 62 
12. DATA REPORTING / REGULATORY REQUIREMENTS ........................................ 69 
12.1 
Study Oversight .................................................................................................... 69 
12.2 
Data Reporting ...................................................................................................... 69 
12.3 
CTEP Multicenter Guidelines .............................................................................. 71 
12.4 
Collaborative Agreements Language ................................................................... 71 
13. STATISTICAL CONSIDERATIONS ............................................................................ 73 
13.1 
Study Design/Endpoints ....................................................................................... 73 
13.2 
Sample Size/Accrual Rate .................................................................................... 75 
13.3 
Data Analysis ........................................................................................................ 76 
REFERENCES ........................................................................................................................ 78 
APPENDIX A ..................................................................................... PERFORMANCE STATUS 
CRITERIA ............................................................................................................................... 80 
APPENDIX B ................................................................... PHARMACOKINETIC SHEET DAY 
1-2 81 
APPENDIX C ................................................................... PHARMACOKINETIC SHEET DAY 
8-9 82 
APPENDIX D PATIENT MEDICATION DIARY – TRIAPINE ......................................... 83 
 
 

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1. OBJECTIVES 
 
1.1 Primary Objectives 
 
1.1.1 
To determine the Maximum Tolerable Dose (MTD) and Recommended Phase II Dose 
(RP2D) of oral triapine when used in combination with cisplatin plus radiation therapy. 
 
1.1.2 
To determine the oral bioavailability of triapine. 
 
1.1.3 
To describe the pharmacokinetics (PK) of oral and intravenous triapine. 
 
1.2 Secondary Objectives 
 
1.2.1 
To determine whether the metabolic complete response (mCR) rate of oral triapine in 
combination with cisplatin chemoradiation using 18F-FDG-PET/CT at posttherapy (3-month) is 
at least 70%. 
1.2.2 
To determine clinical overall response rate, progression-free survival, and overall survival. 
1.2.3 
 To determine the correlation of methemoglobin proportion (%) and triapine pharmacokinetic 
exposure. 
 
1.3 Exploratory Endpoints 
 
1.3.1 
To determine whether active human immunodeficiency virus (HIV) antiretroviral therapy 
impacts the antitumor activity of triapine. 
 
 
2. BACKGROUND 
 
2.1 Locally Advanced Cervical Cancer (LACC) 
 
In the United States, cervical cancer is the third most common gynecologic cancer with 
approximately 12,000 new cases and 4,000 succumbing to disease per year. 1 There is no 
curative surgical option for this patient cohort, and since 1999, concurrent chemoradiation with 
cisplatin 40 mg/m2 weekly has been widely adopted as standard of care for this cohort of 
patients.2 While the majority of women are diagnosed with early-stage disease, women with 
locally advanced cervical cancer (LACC, stage IB2 to IVA) have a 5-year survival rate ranging 
from 80% (stage IB) to 30% (stage III), and it is this subgroup that accounts for the large 
majority of deaths associated with cervical cancer.3 As a result, there remains an urgent need to 
identify novel agents and/or combination regimens to improve overall survival in patients with 
locally advanced cervical cancer. 
 

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2.2 CTEP Agent: Triapine 
 
2.2.1 
IV Triapine 
 
NCI-CTEP has supported a phase I trial (NCI 7336, clinicaltrials.gov NCT00335998) and a 
phase II trial (NCI 8327, clinicaltrials.gov NCT00941070) evaluating the safety and clinical 
efficacy of intravenous triapine combined with cisplatin chemoradiation for the management of 
IB2-IVA cancer of the uterine cervix6, 7. Triapine is a 500-to-1000-fold more potent inhibitor of 
ribonucleotide reductase (RNR) M2 and M2b than hydroxyurea, which has previously shown 
clinical activity in cervical cancer9. The half-life of triapine is approximately 2 hours, suggesting 
that repeat dosing is needed within one treatment week to optimize clinical efficacy. Cervical 
cancer cells treated at human pharmacokinetic (PK) concentrations and exposure times survive at 
a rate of 80% after triapine alone, 40% after triapine plus cisplatin, and 10% after 3-AP plus 
cisplatin plus radiation10, 11. In phase I and II trials, intravenous triapine (25 mg/m2) was given 
three times weekly co-administered with weekly cisplatin (40 mg/m2) and daily radiation (50.4 
Gy in 28 fractions) plus brachytherapy (35-40 Gy) in 35 patients with advanced stage cervical 
and vaginal cancer6, 7. This regimen was well-tolerated as a total of 500 (95%) of 525 2-hour 3- 
AP infusions were administered with the most common side effects being grade 2 diarrhea, grade 
2 electrolyte imbalance, grade 2 fatigue, and infrequent grade 3 pancytopenia. In the IV trial 
(NSC 3663249), 90% of toxicity for this combined regimen occurred within the first 5 weeks of 
treatment, there is no currently known cumulative risk of toxicity associated with triapine (C. 
Kunos, MD, personal communication). With respect to the secondary objectives of this trial, 3- 
month metabolic complete responses (mCRs), as determined by PET-CT, were observed in 23 
(96%) of 24 patients in whom images were obtained in the phase II study6. To date, 29 of 35 
(86%) locally advanced cervical cancer patients are alive and disease-free at a median follow-up 
of 24 months. Four of 35 (11%) patients have died from extra-pelvic disease progression. Based 
on these findings, a randomized phase II trial of IV triapine in combination with concurrent 
cisplatin and radiation therapy was initiated (clinicaltrials.gov NCT01835171; Target accrual 188; 
opened 01/15/2016). 
 
2.2.2 
Oral Triapine 
 
While the clinical activity of IV triapine in combination with standard chemoradiation therapy 
appears to be promising, it is quite time-intensive to perform a 2-hour infusion 3 times a week. 
Additionally, the PK data from IV triapine indicated that peak serum concentrations occur 1-2 
hours after a 2-hour infusion, suggesting only a potential transient therapeutic benefit. It is 
conceivable, therefore, that daily dosing of triapine may yield greater clinical benefit. Recently, a 
phase I trial evaluated single-agent oral triapine in patients with a wide range of advanced solid 
tumors, enrolling 20 patients, including 1 woman with cervical cancer. Treatment consisted of 
oral triapine administered every 12 hours for 5 consecutive doses on days 1-3, 8-10, and 15-17 of 
an every 28-day cycle. Triapine was initially dosed at 50 mg every 12 hours and then increased 
to dose levels of 100, 150, and 200 mg every 12 hours. On this trial, grade 3/4 adverse events 
were uncommon at the 50 mg (1 hypertensive episode) and at the 100 mg (1 anemia) dose levels. 
Three patients experienced (38%) grade 3 or 4 neutropenia at the 150 mg dose level. At the 200 
mg dose level, two grade 3-4 hypoxia events and grade 3-4 anemia, neutropenia, 

NCI Protocol #:  9892 
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thrombocytopenia, infection, fatigue, hepatic enzyme elevation, and anorexia adverse events 
were observed rarely. The recommended phase II dose was 150 mg every 12 hours for five 
consecutive doses on days 1–3, 8–10, and 15–17 of each 28-day cycle. Ultimately, 8 patients 
were treated at the 150 mg dose level with 1 DLT observed. Pharmacokinetic (PK) analysis 
suggested that the 150 mg dose achieved a minimum inhibitory concentration of RNR for six 
hours, which is similar to what is observed with IV dosing12. In addition, the PK data suggested 
that the population average bioavailability of triapine was approximately 55-70%. 
 
2.3 Rationale for the combination of triapine with concurrent chemoradiation 
 
Ribonucleotide reductase (RNR) is the rate-limiting enzyme in the synthesis and repair of DNA, 
and it is directly involved in the cellular response to radiation, making RNR-targeted therapy 
to enhance radiation treatment a rational therapeutic strategy. Inhibition of this pathway may 
be both radiosensitizing and chemosensitizing, thereby making investigation of combination 
therapy with chemoradiation a promising therapeutic strategy. There is an unmet therapeutic 
need to improve complete metabolic response during definitive chemoradiation in patients with 
locally advanced disease who are at high risk for recurrence. 
 
RNR is the only enzyme responsible for conversion of ribonucleoside diphosphate to 
deoxyribonucleotide diphosphate (dNDP), the key building blocks for DNA synthesis. RNR 
is composed of a heterodimeric tetramer comprised of two dimers M1∙M2 or M1∙M2b. When 
RNR is inhibited, the supply of dNDPs and dNTPs is reduced. Inhibition of key nucleotide 
precursors for DNA biosynthesis results in a protracted repair of damaged DNA, which in turn, 
enhances the potential cytotoxic effects of chemotherapy and radiation therapy. Cervical cancer 
preferentially overexpresses the RNR M2b and M2 subunits, and this overexpression is associated 
with resistance to cisplatin-based chemoradiotherapy5. As such, RNR inhibitors have been 
developed as potential radiation sensitizers over the past 30 years. While the initial data was 
promising, the older inhibitor compounds had displayed mixed clinical effectiveness, and they 
were associated with significant toxicity. However, there was sufficient proof of concept to 
suggest that a RNR inhibitor may be efficacious when used in combined modality therapy. Newer 
RNR inhibitors have increased potency and improved binding characteristics, which has 
significantly renewed interest in their clinical development. The RNR inhibitor 3-aminopyridine-
2- carboxaldehyde-thiosemicarbazone (3-AP, triapine, NSC#663249) was developed by the 
Sartorelli laboratory at the Yale Cancer Center, and extensive pre-clinical studies have shown it 
this agent to be an equipotent inhibitor of M2b and M26-8.  
 
2.4 Correlative Studies Background 
 
2.4.1 
Pharmacokinetics  
 
Previous studies of a different oral formulation have shown that triapine may have an oral 
bioavailability of 67% (range 35-128%). As the oral dose of triapine is escalated in this trial, it 
will be possible to determine oral bioavailability, within and between subject variability in 
bioavailability and clearance, and linearity of absorption. Assay methodology has been 
developed and validated by Dr. Jan Beumer at the University of Pittsburgh Cancer 
Pharmacokinetics and Pharmacodynamics Facility (CPPF): LC-MS/MS assay for the quantitation 
of the ribonucleotide reductase inhibitor triapine in human plasma. Matsumoto J, et al. J Pharm 

NCI Protocol #:  9892 
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Page 10 of 84 
 
Biomed Anal. 2017; 146: 154-160. PMID: 28881312. 
 
2.4.2 
FDG-PET/CT Imaging as Biomarker of Response  
 
Prior studies have demonstrated that metabolic response can be determined by positron emission 
tomography (PET) using 18F-fluorodeoxyglucose (FDG) obtained within 10-16 weeks after the 
completion of therapy to predict clinical response of cervical cancer13-15. The current 
recommendations by the National Comprehensive Cancer Network (NCCN) is imaging based on 
symptoms or suspicious examination findings or a one-time PET-CT at 3-6 months following 
treatment in LACC can be used to suggest early or asymptomatic persistence/recurrence. This 
study provides the opportunity to further assess 18F-FDG-PET/CT metabolic response rate as an 
early surrogate endpoint in cancer clinical trials. 
 
Complete metabolic response, defined as 18F-FDG-PET/CT with no evidence of local or distant 
disease, is approximately 70% after completion of cisplatin-based chemoradiation13, 14. Early 
determination of durable chemoradiation therapy response is an important objective in oncologic 
care. 
 
2.4.3 
Methemoglobinemia 
Previous studies of triapine have shown methemoglobinemia as a potential side-effect. 
Therefore, we will perform studies to monitor the % of methemoglobinemia on specific PK and  
PD days, which will allow us to correlate this effect with e.g. exposure. 
 
 
3. PATIENT SELECTION 
 
3.1 Eligibility Criteria 
 
3.1.1 
Patient has a new, untreated histologic diagnosis of stage IB2 (> 5 cm), II, IIIB, IIIC or IVA 
squamous, adenocarcinoma, or adenosquamous carcinoma of the uterine cervix or stage II-IVA 
squamous, adenocarcinoma, or adenosquamous carcinoma of the vagina not amenable to curative 
surgical resection alone. The presence or absence of lymph node metastasis will be based on pre-
therapy 18F-FDG PET/CT. The patient must be able to tolerate imaging requirements of an 18F-
FDG PET/CT scan. 
 
3.1.2 
Age ≥18 years old. 
 
3.1.3 
ECOG performance status score of 0, 1, or 2. See Appendix A 
 
3.1.4 
Life expectancy greater than 6 months. 
 
3.1.5 
Normal organ and marrow function as defined below: 
-Absolute neutrophil count (ANC) ≥ 1.5 x 109/L 
-Platelets ≥ 100 x 109/L 
-Hemoglobin (Hgb) ≥ 10.0 g/dL (blood transfusions to reach this amount are 
allowed) 
-Serum creatinine ≤ 1.5 mg/dL to receive weekly cisplatin 

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 If serum creatinine is between 1.5 and 1.9 mg/dL, patients are eligible for cisplatin if 
the estimated creatinine clearance (CCr) is > 30 ml/min (for the purpose of estimating 
the CCr, the formula of Cockcroft and Gault for females should be used) 
-Total serum bilirubin ≤ 1.5 x ULN (in patients with known Gilbert Syndrome, a 
total bilirubin ≤ 3.0 x ULN, with direct bilirubin ≤ 1.5 x ULN) 
-AST and ALT ≤ 2.5 x ULN 
 
3.1.6 
Able to take oral medication. 
 
3.1.7 
Not pregnant and not breastfeeding. The effects of triapine on the developing human fetus 
are 
unknown. 
For 
this 
reason, 
as 
well 
as 
because 
heterocyclic 
carboxaldehydethiosemicarbazones and radiation are known to be teratogenic, women of 
child-bearing potential and men must agree to use two forms of contraception (hormonal or 
barrier method of birth control; abstinence) prior to study entry and for the duration of study 
participation. Patient must have documented negative urine pregnancy test must be resulted 
within 7 days before initiating protocol therapy. Should a woman become pregnant or 
suspect she is pregnant while participating in this study, she should inform her treating 
physician immediately. Because there is an unknown but potential risk for adverse events in 
nursing infants secondary to treatment of the mother with triapine, breastfeeding should be 
discontinued if the mother is treated with triapine. These potential risks may also apply to 
other agents used in this study. 
 
3.1.8 
For HIV and HEPB/C: 
• HIV-infected patients on effective anti-retroviral therapy with undetectable viral load 
within 6 months are eligible for the dose escalation portion of this trial. For those patients 
who are enrolled in the HIV+ expansion cohort, they must be HIV infected and be on 
retroviral therapy with an undetectable viral load within 6 months of enrollment. 
• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral 
load must be undetectable on suppressive therapy, if indicated. 
• Patients with a history of hepatitis C virus (HCV) infection must have been treated and 
cured. For patients with HCV infection who are currently on treatment, they are eligible 
if they have an undetectable HCV viral load. 
 
3.1.9 
Able to understand and willingness to sign a written informed consent document. 

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3.2 Exclusion Criteria 
 
3.2.1 
Patient has had a prior invasive malignancy diagnosed within the last three years (except [1] 
non-melanoma skin cancer or [2] prior in situ carcinoma of the cervix);  
 
 
3.2.2 
Patients are excluded if they have received prior pelvic radiotherapy for any reason that 
would contribute radiation dose that would exceed tolerance of normal tissues at the discretion 
of the treating physician. 
 
3.2.3 
Patients receiving any other investigational agents 
 
3.2.4 
Patients with known glucose-6-phosphate dehydrogenase deficiency (G6PD) are excluded 
due to an inability to administer the antidote for methemoglobinemia, methylene blue. Pre-
registration testing for G6PD is at the investigator’s discretion and is not required for study 
enrollment. 
 
3.2.5 
Patients who are taking any medication associated with methemoglobinemia, see “5.6 
General Concomitant Medication and Supportive Care Guidelines” for examples. Medication 
must be discontinued and must have a washout period of 4 halflives or 4 weeks, whichever is 
shorter.   
 
3.2.6 
History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to triapine or cisplatin. 
 
3.2.7 
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection; 
symptomatic congestive heart failure; unstable angina pectoris; cardiac arrhythmia; known 
inadequately controlled hypertension; significant pulmonary disease including dyspnea at 
rest, patients requiring supplemental oxygen, or poor pulmonary reserve; or psychiatric 
illness/social situations that would limit compliance with study requirements. 
 
3.2.8 
Patients with uncontrolled diabetes mellitus (fasting blood glucose controlled by 
medication, ≤ 200 mg/dL allowed) 
 
3.2.9 
Patients who have had a hysterectomy or are planning to have an adjuvant hysterectomy 
following radiation as part of their cervical cancer treatment are ineligible 
 
3.2.10 Patients scheduled to be treated with adjuvant consolidation chemotherapy at the conclusion 
of their standard chemoradiation 
 
 
3.3 Inclusion of Women and Minorities 
 
This clinical trial will not exclude potential subjects from participating in this or any study solely 
on the basis of ethnic origin or socioeconomic status. Every attempt will be made to enter all 
eligible patients in this protocol to address the study objectives in a population representative of 
the entire cervical cancer population treated by any of the participating institutions. (See Planned 
Enrollment Table in Section 13.2) 

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4. REGISTRATION PROCEDURES 
 
4.1 Investigator and Research Associate Registration with CTEP 
 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy require 
all individuals contributing to NCI-sponsored trials to register and to renew their registration 
annually.  To register, all individuals must obtain a Cancer Therapy Evaluation Program (CTEP) 
Identity and Access Management (IAM) account at https://ctepcore.nci.nih.gov/iam.  In addition, 
persons with a registration type of Investigator (IVR), Non-Physician Investigator (NPIVR), or 
Associate Plus (AP) must complete their annual registration using CTEP’s web-based Registration 
and Credential Repository (RCR) at https://ctepcore.nci.nih.gov/rcr.    
RCR utilizes five person registration types. 
• IVR:  MD, DO, or international equivalent, 
• NPIVR:  advanced practice providers (e.g., NP or PA) or graduate level researchers (e.g., 
PhD), 
• AP:  clinical site staff (e.g., RN or CRA) with data entry access to CTSU applications such 
as the Roster Update Management System (RUMS), OPEN, Rave, acting as a primary site 
contact, or with consenting privileges,  
• Associate (A):  other clinical site staff involved in the conduct of NCI-sponsored trials, and 
• Associate Basic (AB):  individuals (e.g., pharmaceutical company employees) with limited 
access to NCI-supported systems. 
RCR requires the following registration documents: 
Documentation Required 
IVR 
NPIVR 
AP 
A AB 
FDA Form 1572 
✔ 
✔ 
Financial Disclosure Form 
✔ 
✔ 
✔ 
NCI Biosketch (education, training, employment, license, 
and certification) 
✔ 
✔ 
✔ 
GCP training 
✔ 
✔ 
✔ 
Agent Shipment Form (if applicable) 
✔ 
CV (optional) 
✔ 
✔ 
✔ 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all 
CTEP and Cancer Trials Support Unit (CTSU) websites and applications.  In addition, IVRs and 
NPIVRs must list all clinical practice sites and Institutional Review Boards (IRBs) covering their 
practice sites on the FDA Form 1572 in RCR to allow the following: 
• Addition to a site roster, 
• Assign the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN, 
• Act as the site-protocol Principal Investigator (PI) on the IRB approval, and 

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In addition, all investigators act as the Site-Protocol PI, consenting/treating/drug shipment, or as 
the CI on the DTL must be rostered at the enrolling site with a participating organization (i.e., 
Alliance).  
Additional information is located on the CTEP website at 
https://ctep.cancer.gov/investigatorResources/default.htm.  For questions, please contact the RCR 
Help Desk by email at RCRHelpDesk@nih.gov. 
 
4.2 Site Registration 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
IRB Approval   
Sites participating with the NCI Central Institutional Review Board (NCI CIRB) must submit the 
Study Specific Worksheet (SSW) for Local Context to the CIRB using IRBManager to indicate 
their intent to open the study locally.  The NCI CIRB’s approval of the SSW is automatically 
communicated to the CTSU Regulatory Office, but sites are required to contact the CTSU 
Regulatory Office at CTSURegPref@ctsu.coccg.org to establish site preferences for applying NCI 
CIRB approvals across their Signatory Network.  Site preferences can be set at the network or 
protocol level.  Questions about establishing site preferences can be addressed to the CTSU 
Regulatory Office by emailing the email address above or calling 1-888-651-CTSU (2878). 
In addition, the Site-Protocol PI (i.e., the investigator on the IRB/REB approval) must meet the 
following criteria to complete processing of the IRB/REB approval record to be completed: 
• Holds an Active CTEP status, 
• Active status at the site(s) on the IRB/REB approval (applies to US and Canadian sites 
only) on at least one participating organization’s roster, 
• If using NCI CIRB, active on the NCI CIRB roster under the applicable CIRB Signatory 
Institution(s) record, 
• Includes the IRB number of the IRB providing approval in the Form FDA 1572 in the RCR 
profile,  
• Lists all sites on the IRB/REB approval as Practice Sites in the Form FDA 1572 in the RCR 
profile; and 
• Holds the appropriate CTEP registration type for the protocol.  
 
Additional Requirements 
Additional site requirements to obtain an approved site registration status include: 
• An active Federalwide Assurance (FWA) number, 
• An active roster affiliation with the Lead Protocol Organization (LPO) or a Participating 
Organization,  
• An active roster affiliation with the NCI CIRB roster under at least one CIRB Signatory 
Institution (US sites only); and 
• Compliance with all protocol-specific requirements (PSRs). 
 
4.2.1 
Downloading Site Registration Documents 
Download the site registration forms from the protocol-specific page located on the CTSU 

NCI Protocol #:  9892 
Version Date:  January 12, 2023 
Page 15 of 84 
 
members’ website.  Permission to view and download this protocol and its supporting 
documents is restricted to institutions and its associated investigators and staff  on a 
participating roster.  To view/download site registration forms: 
• Log on to the CTSU members’ website (https://www.ctsu.org) using your CTEP-IAM 
username and password, 
• Click on Protocols in the upper left of your screen 
o Enter the protocol number in the search field at the top of the protocol tree, or 
o Click on the By Lead Organization folder to expand, then select LAO-PA015, 
and protocol number 9892, 
Click on Documents, Protocol Related Documents, and use the Document Type filter and 
select Site Registration, to download and complete the forms provided.  (Note:  For sites 
under the CIRB initiative, IRB data will load automatically to the CTSU as described 
above.) 
 
4.2.2 
Submitting Regulatory Documents 
 
Submit required forms and documents to the CTSU Regulatory Office via the Regulatory 
Submission Portal on the CTSU website members’ website.  
To access the Regulatory Submission Portal, log on to the CTSU members’ website, go to 
the Regulatory section, and select Regulatory Submission. 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal 
should alert the CTSU Regulatory Office immediately at by phone or email: 1-866-651-
CTSU (2878), or CTSURegHelp@coccg.org in order to receive further instruction and 
support. 
 
4.2.3 
Checking Site Registration Status 
 
Site’s registration status may be verified on the CTSU website.  
 
• Click on Regulatory at the top of the screen, 
• Click on Site Registration, and  
• Enter the site’s 5-character CTEP Institution Code and click on Go. 
o Additional filters are available to sort by Protocol, Registration Status, 
Protocol Status, and/or IRB Type. 
 
Note:  The status shown only reflects institutional compliance with site registration 
requirements as outlined within the protocol.  It does not reflect compliance with protocol 
requirements for individuals participating on the protocol or the enrolling investigator’s 
status with NCI or their affiliated networks. 
 
4.3 Patient Registration 
 
4.3.1 
OPEN / IWRS 

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Version Date:  January 12, 2023 
Page 16 of 84 
 
 
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system 
available on a 24/7 basis.  OPEN is integrated with CTSU regulatory and roster data and with 
the LPOs registration/randomization systems or Theradex Interactive Web Response System 
(IWRS) for retrieval of patient registration/randomization assignment.  OPEN or IWRS will 
populate the patient enrollment data in NCI’s clinical data management system, Medidata 
Rave. 
 
Requirements for OPEN access:   
• A valid CTEP-IAM account. 
• To perform enrollments or request slot reservations:  Must be on an LPO roster, 
ETCTN Corresponding roster, or Participating Organization roster with the role 
of Registrar.  Registrars must hold a minimum of an Associate Plus (AP) 
registration type. 
• Have an approved site registration for a protocol prior to patient enrollment. 
 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, drug shipment (IVR only), or receiving investigator for a patient 
transfer in OPEN, the IVR or NPIVR must list the IRB number used on the site’s IRB 
approval on their Form FDA 1572 in RCR. 
Prior to accessing OPEN, site staff should verify the following: 
• Patient has met all eligibility criteria within the protocol stated timeframes, and  
• All patients have signed an appropriate consent form and Health Insurance 
Portability and Accountability Act (HIPAA) authorization form (if applicable). 
Note:  The OPEN system will provide the site with a printable confirmation of registration 
and treatment information.  IWRS system also sends an email confirmation of the 
registration.  You may print this confirmation for your records.  
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU members’ 
website.  Further instructional information is in the OPEN section of the CTSU website at 
https://www.ctsu.org or https://open.ctsu.org.  For any additional questions, contact the 
CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
Patient enrollment for this study will be facilitated using the Slot Reservation System in 
conjunction with the registration system in OPEN.  Prior to discussing protocol entry with 
the patient, all site staff must use the CTSU OPEN Slot Reservation System to ensure that 
a slot on the protocol is available to the patient.  Once a slot reservation confirmation is 
obtained, site staff may then proceed to enroll the patient to this study. 
 
4.3.2 
OPEN/IWRS Questions? 
 
Further instructional information on OPEN is provided on the OPEN tab of the CTSU 
website at https://www.ctsu.org or at https://open.ctsu.org.  For any additional questions 
contact the CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com.  
 
Theradex has developed a Slot Reservations and Cohort Management User Guide, which is 
available on the Theradex website:  

NCI Protocol #:  9892 
Version Date:  January 12, 2023 
Page 17 of 84 
 
http://www.theradex.com/clinicalTechnologies/?National-Cancer-Institute-NCI-11. This 
link to the Theradex website is also on the CTSU website OPEN tab. For questions about 
the use of IWRS for slot reservations, contact the Theradex Helpdesk at 855-828-6113 or 
Theradex main number 609-799-7580; CTMSSupport@theradex.com. 
 
 
4.4 General Guidelines 
Following registration, patients should begin protocol treatment within 7 days.  Issues that would 
cause treatment delays should be discussed with the Principal Investigator.  If a patient does not 
receive protocol therapy following registration, the patient’s registration on the study may be 
canceled.  The Study Coordinator should be notified of cancellations as soon as possible.

NCI Protocol #:  9892 
Version Date:  January 12, 2023 
Page 18 of 84 
 
 
5. TREATMENT PLAN 
 
 
*Correlative blood sample collections on these days (see protocol Appendix B and C) 
**EBRT make-up is permissible. See Section 5.2 
 
 
 
 
ENROLLMENT 
Primary Locally Advanced Cervical or Vaginal Carcinoma 
Baseline 18F-FDG-PET/CT 
Treatment Schedule 
Week 
Day 1* 
Day 2* 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
1 
 
EBRT 
Triapine (IV) 
EBRT 
Triapine (PO)
CISPLATIN 
 
EBRT 
Triapine (PO) 
 
EBRT 
Triapine (PO) 
 
EBRT 
Triapine (PO) 
 
OFF DAY 
 
OFF DAY 
2 
Day 8* 
Day 9* 
Day 10 
Day 11 
Day 12 
Day 13 
Day 14 
 
EBRT 
Triapine (PO) 
EBRT 
Triapine (PO)
CISPLATIN 
 
EBRT 
Triapine (PO) 
 
EBRT 
Triapine (PO) 
 
EBRT 
Triapine (PO) 
 
OFF DAY 
 
OFF DAY 
3 
Day 15 
Day 16 
Day 17 
Day 18 
Day 19 
Day 20 
Day 21 
 
EBRT 
Triapine (PO) 
EBRT 
Triapine (PO)
CISPLATIN 
 
EBRT 
Triapine (PO) 
 
EBRT 
Triapine (PO) 
 
EBRT 
Triapine (PO) 
 
OFF DAY 
 
OFF DAY 
4 
Day 22 
Day 23 
Day 24 
Day 25 
Day 26 
Day 27 
Day 28 
EBRT 
Triapine (PO) 
EBRT 
Triapine (PO)
CISPLATIN 
EBRT 
Triapine (PO) 
EBRT 
Triapine (PO) 
EBRT 
Triapine (PO) 
 
OFF DAY 
 
OFF DAY 
5** 
Day 29 
Day 30 
Day 31 
Day 32 
Day 33 
Day 34 
Day 35 
EBRT 
Triapine (PO) 
EBRT 
Triapine (PO)
CISPLATIN 
EBRT 
Triapine (PO) 
EBRT 
Triapine (PO) 
EBRT 
Triapine (PO) 
 
OFF DAY 
 
OFF DAY 
Brachytherapy (see Section 5.2) 
END OF THERAPY 

NCI Protocol #:  9892 
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1 MONTH FOLLOW-UP 
3 MONTH FOLLOW-UP 
Response Assessment 
18F-FDG-PET/CT 

NCI Protocol #:  9892 
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5.1 Agent Administration 
 
 
Chemotherapy and Radiation Regimen 
Agenta 
Pre-medications; 
Precautions 
Dose 
Route 
Schedule 
Pelvic external 
beam radiation 
Skin, antiemetic, or 
anti-diarrheal 
medications may be 
administered 
as 
needed. 
1.8 Gy/ day 
N/A 
Days 1 to 5 
(Mon-Fri), 
Weekly x 5 
weeks (25 
treatments) 
Pelvic 
brachytherapy 
(See 
Section 
5.2) 
Antiemetic 
and 
anti-diarrheal 
medication may be 
administered 
as 
needed. 
30 to 40 Gy in one 
or 
multiple 
fractions 
using 
LDR or HDR 
techniques 
N/A 
IV Triapine 
(See Section 
5.3.3 
for 
required clinical 
monitoring) 
All patients will 
receive 
dexamethasone IV 
prior to each IV 
triapine 
(3-AP) 
infusion. 
 
Pre- 
medicate 
with 
antiemetic 
as 
needed for patients 
developing nausea 
or vomiting with a 
previous dose of 
triapine. 
Fixed dose – 
50 mg diluted in 
500 ml NS or 500 
ml 5% dextrose in 
water 
IV infusion over 120
+/- 10 minutes within
90 
minutes 
after
pelvic 
irradiation 
using DEHP-free low 
sorbing infusion set. 
 
Day 1 
Oral Triapine 
(See Section 
5.3.3 
for 
required clinical 
monitoring) 
No premedications 
needed. Antiemetic 
as 
needed 
for 
nausea or vomiting. 
As per assigned 
Dose Level (see 
“Dose-Escalation 
Schedule”, section 
5.1.1) 
PO taken within 90 
minutes 
of 
completion of pelvic 
external 
beam radiation 
treatment 
Days 2-5, 8-
12, 
15-19, 22-26, 
29-33 

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Cisplatin 
IV hydration before 
cisplatin 
and 
antiemetic 
and 
steroid prophylaxis 
pre-medication 
as 
per 
institution 
protocol. 
40 mg/m2 (70 mg 
maximum), 
diluted with 25g 
mannitol in 1L 
normal saline or 
per 
institutional 
practice. 
IV infusion over 60-
120 minutes or  as 
per 
institution 
protocol using non- 
aluminum 
administration 
sets. 
Following 
cisplatin, 
post- 
hydration 
therapy 
should 
be 
administered as per 
institution 
protocol. 
Once weekly 
x 5 weeks 
(Days 2, 9, 
16, 23, 30) 
aRadiation therapy (RT) and chemotherapy must be administered in the order provided in the 
above table (Chemotherapy and Radiation Regimen) 
 
 

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Treatment will be administered on an outpatient basis. Appropriate dose modifications are 
described in Section 6. No investigational or commercial agents or therapies other than those 
described below may be administered with the intent to treat the patient's malignancy. 
 
Radiation therapy will be standard of care with no dose variation (see Section 5.2). The cisplatin 
chemotherapy dose will remain stable at 40 mg/m2 to maximize standard of care effects. The 
dose of oral triapine will be escalated as per the Dose Escalation Schedule below. The dose 
escalation component will enroll any patients with stage IB2-IVA cervical cancer or stage II-
IVA vaginal cancer for which cisplatin chemoradiation would be standard of care treatment. 
If de- escalation to DL-2 is necessary, the protocol will be amended to escalate triapine doses 
on the D1,3,5 schedule (previously explored with the intravenous (IV) route). 
 
Reported adverse events and potential risks are described in Section 7. 
 
5.1.1 
Dose Escalation 
For the first dose level, 3 patients were enrolled without issues. Given the scarcity of patients and the 
thus far favorable toxicity profile, dose level 2 will be enrolled per an accelerated titration approach 
using a single patient cohort.  Dose escalation will revert to the standard 3+3 design if the patient on 
dose level 2 experiences a DLT or a ≥ grade 2 toxicity or when dose level 3 is reached.  The standard 
3+3 design is as follows: Escalation at 0/3 DLTs, dose-reduction if >1/3 DLT, and expansion to 
6 if 1/3 DLTs. The highest dose level at which <2/6 DLTs are observed will be declared the 
MTD. 
 
Dose Escalation Schedule 
 
Radiation Therapy 
Dose 
Level 
IV cisplatin 
weekly 
PO 
Triapine* 
Dose / Days / Weekly x5 
Pelvic RT + 
Brachytherapy 
(+/- Extended Field) 
-2 
40 mg/m2 
50 mg D1,3,5 
-1 
40 mg/m2 
50 mg QD x5 
1 
40 mg/m2 
100 mg QD x5 
2 
40 mg/m2 
150 mg QD x5 
3 
40 mg/m2 
200 mg QD x5 
*1 of the planned 25 doses of triapine will be delivered IV (day 1) at a fixed dose of 50 mg 
to allow PK and PD studies (assuming 60% bioavailability and a BSA of 1.73 m2). If DL-2 
needs to be explored, the PK-PD days will be rearranged to the first day of the first 2 weeks 
of treatment. 
 
5.1.2 
RP2D 
Once 6 evaluable patients have been enrolled at a dose-level that is determined to be the MTD 
(according to the criteria outlined in Section 13.1) the observation period will be extended by 30 
days in those 6 patients. If no more than 1 of 6 subjects experiences a DLT at this dose level, 
including in the extended observation window, the RP2D is equal to the MTD, and the expansion 
cohort will be treated at this dose level. If more than 1 of 6 subjects experiences a DLT at this 
dose level, including in the extended observation window, the expansion cohort will be enrolled 
in the next lower dose level to further confirm tolerability, which may then be declared the 

NCI Protocol #:  9892 
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RP2D. 
 
5.1.3 
Dose to be used for expansion 
 
Dose escalation has been completed as of Amendment 10. The dose to be used for expansion is 
100 mg triapine PO daily in combination with cisplatin based chemoradiation as described in this 
protocol. Data supporting this dose decision are detailed below and have been discussed with the 
CTEP Medical Monitor.  
  
5.1.3.1 Safety  
The addition of oral triapine to standard of care cisplatin based chemoradiation was safe. There 
were no treatment related deaths.  
  
5.1.3.2 Tolerability   
  
Evaluability/DLT Overview:  
Dose 
Level   
Triapine  
(mg QD)  
Subject ID   
Evaluable   
DLT   
1   
100  
PA015-001   
Y1  
N  
1   
100  
PA015-002   
Y2  
N  
1   
100  
PA015-003   
Y3  
N  
2   
150  
PA015-0004   
Y1  
Y1  
2   
150  
KY010-005   
Y2  
N  
2   
150  
NJ066-006   
N  
Y*  
2   
150  
KY010-007   
Y3  
Y2  
1   
100  
PA015-008   
Y4  
N  
1   
100  
PA015-009   
N  
N  
1   
100  
KY010-010   
Y5  
Y1  
1   
100  
KY010-011   
Y6  
N  
Y: Yes, N: No, *see below for details  
  
There were no reported dose limiting toxicities noted in the first three individuals enrolled at dose 
level 1 (PO triapine 100 mg). The first person on dose level 2 (PO triapine 150 mg) experienced a 
DLT with grade 4 neutrophil count decrease and grade 4 WBC decrease on her week 3 labs. 
Repeat labs the following day showed normalization of both. The third person on dose level 2 
experienced grade 3 methemoglobinemia. She started therapy and completed dosing with oral and 
IV triapine as scheduled without any signs or symptoms concerning for methemoglobinemia for 
the first three weeks of her therapy. At the end of treatment week 3 the patient noted dysuria. She 
was initially started on pyridium and then Bactrim was added. After 5 days of pyridium and 3 
days of Bactrim, the patient presented for start of week 4 therapy. After completion of treatment 
for week 4, day 2, the patient noted chest tightness and feeling lightheaded while ambulating. She 
had a pulse ox ranging between 85-88% on room air. She was placed on 4L oxygen via nasal 
cannula and her oxygen saturation came up to 90%. EKG showed sinus tachycardia, BP and 
temperature within normal limits. Patient denied shortness of breath, nausea, vomiting, diarrhea, 
loss of consciousness. Due to hypoxia and the requirement of supplemental oxygen, the patient 

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was sent to the ER. ABG revealed arterial P02 of 48 and methemoglobin of 17.2%. The patient 
was put on a non-rebreather mask and given methylene blue (100mg IV) for the reversal of 
methemoglobinemia. Repeat methemoglobin was drawn 30 minutes after dosing and improved to 
5.3%. ABG was repeated 1 hour after dosing, arterial P02 was 271. The following morning, the 
patient was put on room air and pulse ox was 92-94%. She was discharged home in stable 
condition without any further symptoms and no need for supplemental oxygen. It is clear from 
the clinical course that a grade 3 non-hematologic toxicity occurred. However, triapine, pyridium 
and Bactrim can all cause methemoglobinemia and there is data to support that combination of 
more than one causative agent can increase risk of methemoglobinemia. The patient received 
three full weeks of treatment with triapine without complications. Only after starting on the 
pyridium and Bactrim for treatment of a urinary tract infection, combined with week 4 triapine 
initiation, did toxicity result. It is therefore most likely that this toxicity was a consequence of the 
combined methemoglobinemic actions of all three agents. As a result, an amendment was made 
to the protocol to add a list of concomitant medications that should be avoided to decrease the 
risk of methemoglobinemia. Because of this, and after reviewing the clinical scenario with the 
drug monitor, the patient was considered inevaluable and replaced with another individual. This 
fourth person on dose level 2 also experienced a DLT with grade 4 lymphocyte count at the end 
of week 5 when labs were drawn in the setting for new onset fever. The patient was treated for a 
UTI (Urinary Tract Infection) and her final dose of triapine was held the following week. Given 
two individuals with DLTs at this dose level, the decision was made to cease enrollment at this 
level and drop back down to dose level 1 for expansion to 6 total evaluable patients. An 
additional four individuals were enrolled at dose level 1. One had no DLTs, one withdrew prior to 
treatment start so was not evaluable, and one experienced two DLTs, grade 4 neutrophil count 
decrease and grade 4 WBC decrease. The final individual presented with cystitis symptoms 
without systemic signs of infection (ie fever, chills) to the ED at the end of week 3. She had labs 
drawn that showed a grade 4 decreased lymphocyte count and grade 3 hypokalemia. She was 
given 40mEq of potassium in the ED and sent home with a prescription to treat a UTI.  On her 
standard of care labs at the beginning of week 4, her lymphocyte count had improved to grade 3 
and her potassium level was at a grade 1 toxicity level. She was evaluated by her physician and 
found to be medically suitable for continued therapy. After reviewing the clinical scenario with 
the drug monitor, it was felt that the patient could safely continue to with therapy, including PO 
triapine as the labs would not have otherwise been drawn for a simple UTI and did not meet 
criteria for DLT at the time the decision needed to be made for therapy the following week. She 
was able to complete the remainder of her therapy without any noted DLTs. Based on the 
summation of these findings, dose level 1, triapine at 100 mg PO given concurrently with external 
beam radiation 5 days a week for 5 weeks with weekly cisplatin at 40 mg/m2 is the maximum 
tolerated dose.   
  
Beyond the DLTs described above, the regimen was well tolerated with expected hematologic 
events in the context of known baseline toxicity data for standard of care cisplatin base 
chemoradiation. Among the nine evaluable patients, seven experienced at least one grade 3 toxicity, 
including lymphocyte decrease (n=7), anemia (n=4), neutrophil count decrease (n=4), white blood 
cell count decrease (n=4), platelet count decreased (n=1), hypertension (n=1), hyponatremia (n=1). 
A comprehensive list of adverse events is outlined in Table below.  
  
 
 

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Adverse Events by Frequency during the dose escalation of NCI 9892.  
AEFamily  
AETerm  
Grade1  
Grade2  Grade3  
Grade4  
Total  
GENERAL/ADM. SITE CONDITIONS  
Fatigue  
7 (70%)  
3 (30%)  
  
  
10 (100.0%  
GI DISORDERS  
Nausea  
10 (100%)  
  
  
  
10 (100.0%  
BLOOD/LYMPH DISORDERS  
Anemia  
  
4 (40%)  
5 (50%)  
  
9 (90.0%)  
GI DISORDERS  
Diarrhea  
7 (70%)  
2 (20%)  
  
  
9 (90.0%)  
INVESTIGATIONS  
Lymphocyte count decreased  
  
1 (10%)  
5 (50%)  
3 (30%)  
9 (90.0%)  
METABOLISM & NUTRITION  
Hypomagnesemia  
6 (60%)  
1 (10%)  
  
  
7 (70.0%)  
METABOLISM & NUTRITION  
Hyponatremia  
6 (60%)  
  
1 (10%)  
  
7 (70.0%)  
INVESTIGATIONS  
Neutrophil count decreased  
2 (20%)  
  
3 (30%)  
2 (20%)  
7 (70.0%)  
INVESTIGATIONS  
White blood cell decreased  
  
2 (20%)  
3 (30%)  
2 (20%)  
7 (70.0%)  
BLOOD/LYMPH DISORDERS  
Blood/Lymph - Other - 
Methemoglobinemia  
1 (10%)  
4 (40%)  
1 (10%)  
  
6 (60.0%)  
INVESTIGATIONS  
Platelet count decreased  
3 (30%)  
2 (20%)  
1 (10%)  
  
6 (60.0%)  
RENAL & URINARY DISORDERS  
Urinary frequency  
5 (50%)  
1 (10%)  
  
  
6 (60.0%)  
GI DISORDERS  
Gastroesophageal reflux disease  
2 (20%)  
3 (30%)  
  
  
5 (50.0%)  
METABOLISM & NUTRITION  
Hypocalcemia  
5 (50%)  
  
  
  
5 (50.0%)  
EAR & LABYRINTH  
Tinnitus  
5 (50%)  
  
  
  
5 (50.0%)  
GI DISORDERS  
Vomiting  
5 (50%)  
  
  
  
5 (50.0%)  
GI DISORDERS  
Constipation  
4 (40%)  
  
  
  
4 (40.0%)  
RENAL & URINARY DISORDERS  
Hematuria  
3 (30%)  
1 (10%)  
  
  
4 (40.0%)  
METABOLISM & NUTRITION  
Hyperglycemia  
4 (40%)  
  
  
  
4 (40.0%)  
METABOLISM & NUTRITION  
Hypokalemia  
3 (30%)  
  
1 (10%)  
  
4 (40.0%)  
METABOLISM & NUTRITION  
Anorexia  
3 (30%)  
  
  
  
3 (30.0%)  
GI DISORDERS  
Bloating  
3 (30%)  
  
  
  
3 (30.0%)  
NERVOUS SYSTEM  
Dizziness  
3 (30%)  
  
  
  
3 (30.0%)  
RESPIRATORY/THORACIC/MEDIASTINAL  Dyspnea  
2 (20%)  
1 (10%)  
  
  
3 (30.0%)  
GENERAL/ADM. SITE CONDITIONS  
Fever  
2 (20%)  
1 (10%)  
  
  
3 (30.0%)  
NERVOUS SYSTEM  
Headache  
3 (30%)  
  
  
  
3 (30.0%)  
VASCULAR DISORDERS  
Hypertension  
1 (10%)  
1 (10%)  
1 (10%)  
  
3 (30.0%)  
PSYCHIATRIC DISORDERS  
Insomnia  
3 (30%)  
  
  
  
3 (30.0%)  
RENAL & URINARY DISORDERS  
Renal & urinary disorders - Other - 
Dysuria  
3 (30%)  
  
  
  
3 (30.0%)  
GI DISORDERS  
Abdominal pain  
1 (10%)  
1 (10%)  
  
  
2 (20.0%)  
BLOOD/LYMPH DISORDERS  
Blood/Lymph - Other - 
Thrombocytopenia  
2 (20%)  
  
  
  
2 (20.0%)  
METABOLISM & NUTRITION  
Dehydration  
  
2 (20%)  
  
  
2 (20.0%)  
GENERAL/ADM. SITE CONDITIONS  
Edema limbs  
2 (20%)  
  
  
  
2 (20.0%)  
MUSCULOSKELETAL/CONNECTIVE 
TISSUE  
Generalized muscle weakness  
2 (20%)  
  
  
  
2 (20.0%)  
METABOLISM & NUTRITION  
Hypoalbuminemia  
2 (20%)  
  
  
  
2 (20.0%)  

NCI Protocol #:  9892 
Version Date:  January 12, 2023 
Page 26 of 84 
 
INVESTIGATIONS  
Investigations - Other, specify - 
Fogginess  
2 (20%)  
  
  
  
2 (20.0%)  
CARDIAC DISORDERS  
Sinus tachycardia  
1 (10%)  
1 (10%)  
  
  
2 (20.0%)  
INFECTIONS & INFESTATIONS  
Urinary tract infection  
  
1 (10%)  
1 (10%)  
  
2 (20.0%)  
RENAL & URINARY DISORDERS  
Urinary urgency  
2 (20%)  
  
  
  
2 (20.0%)  
REPRODUCTIVE & BREAST DISORDERS  Vaginal hemorrhage  
2 (20%)  
  
  
  
2 (20.0%)  
REPRODUCTIVE & BREAST DISORDERS  Vaginal pain  
2 (20%)  
  
  
  
2 (20.0%)  
INVESTIGATIONS  
Weight loss  
2 (20%)  
  
  
  
2 (20.0%)  
INVESTIGATIONS  
ALT increased  
1 (10%)  
  
  
  
1 (10.0%)  
MUSCULOSKELETAL/CONNECTIVE 
TISSUE  
Arthralgia  
1 (10%)  
  
  
  
1 (10.0%)  
MUSCULOSKELETAL/CONNECTIVE 
TISSUE  
Back pain  
1 (10%)  
  
  
  
1 (10.0%)  
RENAL & URINARY DISORDERS  
Bladder spasm  
1 (10%)  
  
  
  
1 (10.0%)  
BLOOD/LYMPH DISORDERS  
Blood/Lymph - Other - Increased 
Medthemoglobin Level  
  
1 (10%)  
  
  
1 (10.0%)  
BLOOD/LYMPH DISORDERS  
Blood/Lymph - Other - Increased 
Methemoglobin  
  
1 (10%)  
  
  
1 (10.0%)  
BLOOD/LYMPH DISORDERS  
Blood/Lymph - Other - 
Methameoglobinemia  
  
1 (10%)  
  
  
1 (10.0%)  
BLOOD/LYMPH DISORDERS  
Blood/Lymph - Other - 
Methemoglobin Increase  
  
1 (10%)  
  
  
1 (10.0%)  
BLOOD/LYMPH DISORDERS  
Blood/Lymph - Other - 
Methemoglobinemina  
  
1 (10%)  
  
  
1 (10.0%)  
EYE DISORDERS  
Blurred vision  
1 (10%)  
  
  
  
1 (10.0%)  
CARDIAC DISORDERS  
Cardiac disorders - Other - Chest 
Tightness  
1 (10%)  
  
  
  
1 (10.0%)  
CARDIAC DISORDERS  
Chest pain - cardiac  
1 (10%)  
  
  
  
1 (10.0%)  
GENERAL/ADM. SITE CONDITIONS  
Chills  
1 (10%)  
  
  
  
1 (10.0%)  
RENAL & URINARY DISORDERS  
Cystitis noninfective  
1 (10%)  
  
  
  
1 (10.0%)  
GI DISORDERS  
Dysphagia  
  
1 (10%)  
  
  
1 (10.0%)  
GENERAL/ADM. SITE CONDITIONS  
Edema face  
1 (10%)  
  
  
  
1 (10.0%)  
MUSCULOSKELETAL/CONNECTIVE 
TISSUE  
Flank pain  
1 (10%)  
  
  
  
1 (10.0%)  
VASCULAR DISORDERS  
Flushing  
1 (10%)  
  
  
  
1 (10.0%)  
GENERAL/ADM. SITE CONDITIONS  
General and admin site - Other - 
Light Headedness  
1 (10%)  
  
  
  
1 (10.0%)  
EAR & LABYRINTH  
Hearing impaired  
1 (10%)  
  
  
  
1 (10.0%)  
GI DISORDERS  
Hemorrhoids  
1 (10%)  
  
  
  
1 (10.0%)  
VASCULAR DISORDERS  
Hot flashes  
1 (10%)  
  
  
  
1 (10.0%)  
SKIN & SUBCUTANEOUS DISORDERS  
Hyperhidrosis  
1 (10%)  
  
  
  
1 (10.0%)  
VASCULAR DISORDERS  
Hypotension  
1 (10%)  
  
  
  
1 (10.0%)  
RESPIRATORY/THORACIC/MEDIASTINAL  Hypoxia  
  
  
1 (10%)  
  
1 (10.0%)  
INVESTIGATIONS  
Investigations - Other, specify - 
Increase Ldh  
1 (10%)  
  
  
  
1 (10.0%)  
INVESTIGATIONS  
Investigations - Other, specify - 
Methemoglobinemia  
  
1 (10%)  
  
  
1 (10.0%)  
PSYCHIATRIC DISORDERS  
Irritability  
1 (10%)  
  
  
  
1 (10.0%)  
MUSCULOSKELETAL/CONNECTIVE 
TISSUE  
Musculoskel/connect tissue -Other - 
Muscle Cramping  
1 (10%)  
  
  
  
1 (10.0%)  

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MUSCULOSKELETAL/CONNECTIVE 
TISSUE  
Musculoskel/connect tissue -Other - 
Pelvic Muscle Spasm  
1 (10%)  
  
  
  
1 (10.0%)  
MUSCULOSKELETAL/CONNECTIVE 
TISSUE  
Myalgia  
1 (10%)  
  
  
  
1 (10.0%)  
MUSCULOSKELETAL/CONNECTIVE 
TISSUE  
Pain in extremity  
1 (10%)  
  
  
  
1 (10.0%)  
REPRODUCTIVE & BREAST DISORDERS  Pelvic pain  
1 (10%)  
  
  
  
1 (10.0%)  
NERVOUS SYSTEM  
Peripheral sensory neuropathy  
1 (10%)  
  
  
  
1 (10.0%)  
RESPIRATORY/THORACIC/MEDIASTINAL  Productive cough  
1 (10%)  
  
  
  
1 (10.0%)  
RENAL & URINARY DISORDERS  
Proteinuria  
1 (10%)  
  
  
  
1 (10.0%)  
RENAL & URINARY DISORDERS  
Renal & urinary disorders - Other - 
Bladder Pain  
1 (10%)  
  
  
  
1 (10.0%)  
RENAL & URINARY DISORDERS  
Renal & urinary disorders - Other - 
Pyelonephritis  
  
  
1 (10%)  
  
1 (10.0%)  
RENAL & URINARY DISORDERS  
Renal & urinary disorders - Other - 
Urinary Pressure  
1 (10%)  
  
  
  
1 (10.0%)  
REPRODUCTIVE & BREAST DISORDERS  Reproductive and breast - Other - 
Dysuria  
1 (10%)  
  
  
  
1 (10.0%)  
REPRODUCTIVE & BREAST DISORDERS  Reproductive and breast - Other - 
Vaginal Bleeding  
1 (10%)  
  
  
  
1 (10.0%)  
PSYCHIATRIC DISORDERS  
Restlessness  
1 (10%)  
  
  
  
1 (10.0%)  
SKIN & SUBCUTANEOUS DISORDERS  
Skin & subcutaneous tissue -Other - 
Dermatitis  
1 (10%)  
  
  
  
1 (10.0%)  
SKIN & SUBCUTANEOUS DISORDERS  
Skin & subcutaneous tissue -Other - 
Parasthesia  
  
1 (10%)  
  
  
1 (10.0%)  
SKIN & SUBCUTANEOUS DISORDERS  
Skin & subcutaneous tissue -Other - 
Skin Patches  
1 (10%)  
  
  
  
1 (10.0%)  
RESPIRATORY/THORACIC/MEDIASTINAL  Sore throat  
1 (10%)  
  
  
  
1 (10.0%)  
GI DISORDERS  
Toothache  
1 (10%)  
  
  
  
1 (10.0%)  
RENAL & URINARY DISORDERS  
Urinary incontinence  
1 (10%)  
  
  
  
1 (10.0%)  
INJURY, POISONING & PROCEDURAL  
Vascular access complication  
  
  
1 (10%)  
  
1 (10.0%)  
Looking only at the highest grade for each Adverse Event experienced by a Patient, this report displays the number of 
patients that experienced each Adverse Event, by Grade, for each Organ Class and for each Preferred Term within an 
Organ Class. It also displays the percentage of treated patients in the study that experienced the Adverse Event with 
that Grade as their highest grade for that event.  
   
5.1.3.3 Pharmacokinetics  
 
Summary PK of triapine in the dose escalation is reported below. PK is comparable to earlier 
reports of triapine for both routes. PO bioavailability observed in this trial was 66%, which is also 
comparable to previous reports of 67% (Chao 2012). There was no discernable difference 
between triapine exposure at 100 vs 150 mg PO, and between patient variability at each dose 
level was substantial.  
  

NCI Protocol #:  9892 
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Page 28 of 84 
 
  
 
Pharmacokinetics of triapine at 50 mg IV (left), 100 mg PO (middle) or 150 mg PO (right).  
  
Pharmacokinetic parameters of triapine at 50 mg IV.  
PT  
(#')   
Cmax  
(ug/L)   
Tmax  
(h)   
HL  
(h)   
AUClast  
(h*ug/L)   
AUCINFobs 
(h*ug/L)   
Extrap  
(%)   
Cl_obs  
(L/h)   
Vss_obs  
(L)   
Vz_obs  
(L)   
Tlast  
(h)   
Geo 
Mean  
294  
1.6  
1.3  
718  
734  
2.0  
68  
119  
124  
10  
Geo SD  
1.2  
1.1  
1.3  
1.4  
1.4  
1.7  
1.4  
1.4  
1.3  
1.8  
N  
10  
10  
10  
10  
10  
10  
10  
10  
10  
10  
  
Pharmacokinetic parameters of PO triapine.  
PO_DOSE  
(mg)   
PT  
(#')   
Cmax  
(ug/L)   
Tmax  
(h)   
HL  
(h)   
AUClast  
(h*ug/L)   
AUCINFobs  
(h*ug/L)   
%Extrap  
(%)   
Cl_F_obs  
(L/h)   
Vz_F_obs  
(L)   
Tlast  
(h)   
100  
GeoMean  
520  
1.2  
1.3  
1187  
1209  
0.8  
83  
156  
14  
  
GeoSD  
2.5  
1.6  
1.2  
2.6  
2.5  
4.2  
2.5  
2.6  
1.9  
  
N  
6  
6  
6  
6  
6  
6  
6  
6  
6  
150  
GeoMean  
344  
1.5  
1.5  
990  
1034  
3.9  
145  
322  
10  
  
GeoSD  
1.9  
1.5  
1.3  
1.4  
1.4  
1.7  
1.4  
1.5  
1.7  
  
N  
4  
4  
4  
4  
4  
4  
4  
4  
4  
  
Bioavailability of triapine.  
PO_DOSE  
  
F  
100  
Geometric Mean  
0.75  
  
Geometric SD  
2.2  
  
N  
6  
150  
Geometric Mean  
0.54  
  
Geometric SD  
1.5  
  
N  
4  
Overall  
Geometric Mean  
0.66  
 
Geometric SD  
1.9  
 
N  
10 
  
5.1.3.4 Pharmacodynamics  
 
There was no obvious relationship between occurrence of DLT and triapine AUC. 
Methemoglobin levels were sampled at approximately 4 h after dosing on PK days, and the 
observed levels had a clear correlation with triapine exposure both when expressed as AUC and 
Cmax.  
 

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Relationship of triapine AUC and DLT.  
 
  
Relationship of triapine AUC and Cmax vs methemoglobin levels.  
  
5.1.3.5 Activity  
Eleven patients were enrolled into the dose escalation. One patient withdrew prior to treatment, 
so was not evaluable. Patient number 6, who experienced grade 3 methemoglobinemia during 
week 4 of treatment, was withdrawn from the study and was replaced by patient 7. Of the 
remaining nine patients, 6 had a documented complete metabolic response on 3-month post 
therapy PET-CT. One had documented stable disease on PET-CT but had complete resolution of 
her remaining disease on follow-up MRI imaging and remains disease-free 18 months after 
treatment. One patient had disease progression in her lung, but complete metabolic response 
within the treatment field. The individual most recently enrolled has not undergone PET-CT 
imaging yet. Patient 6 did complete therapy with standard of care cisplatin based chemoradiation 
without triapine and had a document partial response on her PET-CT; however, repeat imaging 
obtained 6 months later demonstrated no evidence of disease.  
  
5.1.3.6 Conclusion  
Based on the 3+3 design, 100 mg PO daily was determined to be the MTD with 1 out of 6 
evaluable patients experiencing a DLT, while 150 mg PO daily resulted in 2 out of 3 evaluable 
patients with a DLT. The side effect profile at 100 mg PO daily was considered acceptable and 
consistent with the expected side effect profile of the cisplatin chemoradiation therapy backbone. 
Exposures were comparable to previous reports (Chao 2012), patients treated at 150 mg did not 
achieve higher plasma exposures than at 100 mg PO, and patients with DLT did not appear to 
have markedly different exposures than patients that without DLT.  
In summary, 100 mg triapine PO daily in combination with cisplatin based chemoradiation is the 
appropriate dose to take forward into the expansion phase of this phase 1 trial.  

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5.2 Radiation therapy: 
 
5.2.1 
Radiation Therapy for Cervical Cancer or Vaginal Cancer 
Patients will receive 5 consecutive days of external beam radiation (EBRT) preferably given 
Monday-Friday, and repeated for 5 consecutive weeks. A three consecutive day parametrial 
may be given in the sixth week or in the week after completion of chemoradiation if treatment 
missed in days 1-35 has to be made up.  Radiation therapy must be completed within 56 ± 3 
days of its initiation (two (2) make-up weeks are permitted). 
 
External beam radiation will be delivered using a linear accelerator with a photon energy of 6 
MV or greater. Source-to-axis distance (SAD) of 100 cm is required. Intracavitary therapy could 
be delivered by low dose-rate (LDR) brachytherapy using 137cesium or high dose-rate (HDR) 
brachytherapy using 192iridium.  Intensity modulated radiation therapy (IMRT) is permitted on 
this study (see Section 5.2.1.1). 
 
Localization and Simulation: Patients to be simulated in the supine position with feet tied 
together for immobilization (may use vacuum-evacuated device if desired). CT simulation 
is required, if feasible with full and empty bladder (for generation of an internal target volume 
for the cervical contour when feasible) and an empty rectum. CT scan should extend at least 
4 cm above and below the target volumes with inter slice thickness of ≤ 3mm. Intravenous 
contrast may be used during simulation to help better define the vessels. 
 
Contouring: The lymph node Clinical target volume (CTV1) includes entire bilateral common 
iliac, external/internal iliac, upper pre-sacral (from S1-S3) and obturator regions. For patients 
with pelvic node positive and para-aortic node not surgically staged include the entire para-aortic 
nodal region up to renal vessels. For patients with para-aortic node positive include the entire 
para-aortic nodal region up to renal vessels or at least 2 cm above highest para-aortic node. The 
involved nodes are contoured as GTV and expanded by 5 to 7 mm with editing for the small 
bowel and duodenal region to create PTV2 for the concomitant boost or sequential boost. 
Involved nodes are defined as all lymph nodes ≥ 1cm in the short axis, those with a necrotic 
center and/or PET avidity 
 
The primary CTV2 included the entire gross tumor plus the entire cervix, uterus, parametria, and 
proximal ½ of the vagina (unless vaginal involvement where the entire vagina is included). 
CTV1 is expanded 5-7 mm to create nodal PTV.  CTV2 is expanded by 1.5-2 cm to account for 
target motion and set up uncertainty to create primary PTV. If ITV created, then 7-10 mm to 
ITV should be sufficient for primary PTV. Nodal PTV and Primary PTV is combined to create 
a final PTV1.  Involved node with 5 to 7 mm expansion as described would be PTV2.  Normal 
tissue structures will be contoured on the CT scan obtained with a full bladder since treatment 
will be delivered with a full bladder with the goal of reducing the volume of irradiated 
bowel. A description for the technique on how to contour these structures can be found at 
http://www.rtog.org/CoreLab/ContouringAtlases/FemaleRTOGNormalPelvisAtlas.aspx. 
Bladder will be outlined on every slice, including the portion inferior to the planning target 
volume. Rectum will be outlined on every slice, including the portion inferior to the planning 
target volume and superior to the level that it leaves the posterior pelvis around the region of the 
rectosigmoid. Bowel space will be outlined on every slice which has visible bowel, extending 

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Page 31 of 84 
 
2 cm above the planning target volume. Bowel space will include the volume surrounding loops 
of bowel out to the edge of the peritoneum because the bowel may lie within this space at any 
time throughout the course of treatment. Bowel space will include the ENTIRE bowel, 
including small bowel, colon and sigmoid, in one bowel bag contour. This contour will be 
named ‘bowel space’. The pelvic bone will be contoured as a surrogate for the bone marrow. 
The pelvic bone from the superior to the inferior aspect of the PTV can be auto-contoured. 
This can be accomplished with use of a CT-density–based auto-contouring algorithm. The 
femoral heads but not femoral necks should be included in the bone marrow contour. 
 
5.2.1.1 Intensity Modulated Radiation Therapy (IMRT) Dose Specifications 
 
Prescription dose shall be according to the following specifications: 
Planning target volume (PTV1) will receive 45Gy in 25 fractions. Patients will be treated once 
a day, 5 days a week with a daily fraction size of 1.8Gy. All targets will be treated 
simultaneously. The dose is prescribed to cover 97% of the PTV1. A volume of at least 0.03 
cc within any PTV 1 should not receive > 110% of the maximum prescribed dose. No volume 
within the PTV that is 0.03 cc or larger can receive a dose that is < 93% of its prescribed dose. 
Any contiguous volume of 0.03 cc or larger of the tissue outside the PTVs must not receive 
> 110% of the maximum prescribed dose to the PTV. If PTV2 is created, then it can receive 
concomitant boost of 55 to 57.5 Gy in 25 fractions or sequential boost to a total dose of 58-60Gy. 
 
IMRT Technical Factors: Megavoltage equipment capable of delivering static intensity 
modulation with a multileaf collimator or dynamic intensity modulation (using a multileaf 
collimator or tomotherapy) is required. VMAT is allowed. Six or more fields should be utilized 
with a minimum source-axis distance of 100 cm. The exception is the use of the tomotherapy 
unit that uses 80 cm. 6-10 MV energy photon beams should be used. 
 
3D EBRT technique: Four field technique with field borders 7 mm from PTV1 in all directions. 
Target dose is 45Gy in 25 fractions. The minimum dose to the dose specification point (isocenter 
or calculation point) is greater than or equal to 43.2Gy Maximum dose to a volume of ≥0.03 
cc of tissue within the convergence of the treatment fields should not exceed 107% of the 
prescription dose. The PTV2 if created would receive sequential boost to a total dose of 
58-60Gy. 
 
Parametrial Boost Fields:  The parametrial boost field is an anterior-posterior and posterior- 
anterior field arrangement. The superior border should be reduced to include only the true pelvis. 
The upper border of the true pelvis field is defined at the inferior aspect of the sacroiliac joint. 
The inferior border remains the same as in the pelvis fields or mid obturator foramen. A 
parametrial central field block is a minimum of 6 cm wide. The dose for parametrial boost is 
5.4Gy in 3 fractions. 
 
Dose constraints for IMRT (recommended but not mandated, as below). Priority should be given 
to PTV1 coverage IMRT arm: 
Bowel up to 30-40% receives 40Gy, 
Bladder up to 50-60% receives 40Gy 
Rectum up to 50-60% receives 40Gy  
Bone marrow up to 75-80% receives 

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20Gy 
Kidneys for extended field up to < 10%  receives 16Gy 
 
In patients with nodal boost V55 Gy for small bowel < 5-15cc and Duodenum V55 < 1cc 
 
Verification Requirements: Image should be performed at least weekly for patients treated on the 
IMRT and standard therapy arms, respectively. For patients treated with IMRT dose delivery, 
orthogonal films or CBCT to localize the isocenter placement shall be obtained. For patients 
treated with standard therapy, weekly port films should be obtained. The length of the treatment 
field shall be indicated on these films. These films will not be collected but should be held by the 
institution and available for review if requested. 
 
5.2.1.2 Intracavitary Brachytherapy: 
 
At the time of registration, institutions will select the one brachytherapy dose rate to be used for 
all accrued patients at that institution, either low-dose-rate (LDR) or high-dose-rate (HDR). 
 
Low Dose Rate (LDR) Brachytherapy: Following the completion of external beam RT, the 
patient will receive 4000cGy to Point A or 3D image based brachytherapy following GEC 
ESTRO guidelines by intracavitary tandem and ovoid implant with 137cesium. The patient may 
receive this in one or two applications at the discretion of the radiation oncologist. The first 
insertion should be performed promptly upon completion of external beam irradiation. If two 
implants are contemplated, the second implant should be completed within three weeks of the 
completion of external beam irradiation. 
 
High Dose Rate (HDR) Brachytherapy: 3D image based brachytherapy using MRI or CT based 
planning using GEC ESTRO guidelines. Dose of each brachytherapy fractions is 550- 600cGy 
for a total 5 or 700 cGy per fraction to total of 4 fractions. HDR brachytherapy should start at 
week 4 or 5. When HDR brachytherapy begins, at least one insertion will be performed per week 
with no external beam therapy given on the day of the insertion. If the majority of the external 
beam radiation has been given, then two o r  t h r e e  insertions per week could be done separated 
by at least 48 to 72 hours in order to complete all treatment within 56 ± 3 days. 
 
HDR Instruments: It is recommended that tandem and ovoids or tandem or ring or hybrid 
applicator be used for HDR brachytherapy for patients with cervical cancer.  Interstitial 
brachytherapy with a Vienna, a Venezia applicator or Syed template should be used for patients 
with vaginal cancer who are not candidates for intracavitary brachytherapy. 
 
HDR Dosimetry: The planned total dose to high risk clinical target volume (HRCTV) after 
summating for EBRT and brachytherapy should be EQ2 of 80-90Gy. Similarly total dose to 
bladder, rectum and sigmoid should be ≤ 80Gy, 65Gy and 70Gy respectively. If intracavitary 
brachytherapy cannot be performed, then interstitial or hybrid applicator brachytherapy can be 
performed as per standard institutional guidelines and practice. Reasons for not performing 
intracavitary brachytherapy should be documented for those patients with cervical cancer. 
 
5.2.1.3 Interstitial Brachytherapy 

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Interstitial brachytherapy such as with a Vienna, Venezia applicator or Syed template is allowed for 
those patients with vaginal cancer who are not candidates for intracavitary therapy or  if it is felt to 
be clinically imperative to change the plan after treatment start because of poor response of the 
tumor to external beam therapy. 
 
5.3 Chemotherapy 
 
5.3.1 
Cisplatin 
Cisplatin will be given by IV infusion at a dose of 40 mg/m2 on days 2, 9, 16, 23, and 30 (Tues) 
for a total of 5 weekly cycles. It will also be permitted to include a 6th cycle of cisplatin 
during the parametrial boost or any make-up radiation treatment in a sixth week of 
external beam radiotherapy. Patients will be strongly encouraged to increase oral hydration 
24 hours prior and after chemotherapy administration. Normal saline will be infused IV as pre- 
and post-hydration to cisplatin infusion as per institutional standard protocol and investigator 
discretion. Standard premedication with antiemetic, steroid, and H2 blocker will be administered 
as per institution protocol. Cisplatin 40 mg/m2 (maximum dose, 70 mg) may be mixed with 
mannitol 25 g in 1L normal saline, but sites may also follow institutional practice.  It will be 
infused over 60-120 minutes or per institutional protocol.  All patients receive weekly cisplatin 
on this protocol. 
 
5.3.2 
Intravenous Triapine 
 
Triapine 50 mg intravenous infusion over 120 +/- 10 minutes is administered once during the 
study within 90 minutes after pelvic irradiation, on day 1 to obtain PK data.  Triapine 50 mg is 
diluted in 500 mL normal saline or 500 mL 5% dextrose in water and administered using DEHP-
free low sorbing infusion set.  All patients will receive dexamethasone IV prior to each IV triapine 
infusion.  Premedicate with antiemetic as needed for patients developing nausea or vomiting with 
a previous dose of triapine. 
 
5.3.3 
Oral triapine 
 
Oral triapine will be given at the assigned phase I dose level (see 5.1.1 Dose Escalation 
Schedule). Patients will be asked to fast (except for water) for 2 hours prior to dosing and for 
1 hour after ingesting the oral dose (triapine complexes strongly with iron ions). Patients 
will ingest one dose of triapine in the clinic within 90 minutes after each daily radiation 
treatment, starting with the first radiation treatment through the last day of radiation treatment 
(completion of EBRT). Each oral triapine dose will be administered in the clinical area within 
90 minutes of each daily RT dose. Triapine will not be administered on days that radiation is 
not given (Sat- Sun, holidays) or on the days that radiation is missed or held. Study staff 
will observe and document triapine administration and will document dosing time in the patient’s 
record. The patient will be requested to maintain a medication diary of each dose of medication 
(see APPENDIX D PATIENT MEDICATION DIARY – TRIAPINE).  The medication diary 
will be reviewed by clinic staff each week.   
 
5.3.3.1 
Clinical Monitoring for Methemoglobin 
 

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Patients should be observed clinically during the first week of treatment. 
 
Test 
Frequency 
IV Triapine, Days 1 
PO Triapine, Days 2-5 
Blood 
pressure 
Pulse 
Respiratory rate 
O2 
saturation 
(pulse oximeter) 
Pre-dose, 
then every 60 minutes x 3 
Pre-dose, 
then every 60 minutes x 3 
EKG 
Only if patient is hypotensive or dyspneic 
 
If patient is symptomatic or has hypoxia (<92%) requiring oxygen, obtain “spot” methemoglobin 
level and serial sampling as clinically indicated (based on symptoms such as but not limited 
to skin discoloration, cyanosis, coma, dysrhythmia, levels can be repeated every 6-8 hours 
until levels <20%). A repeat spot methemoglobin should be obtained prior to the next triapine 
dose to determine whether dose modification or further treatment is indicated. Supportive care 
should be provided as clinically indicated. 
 
Starting week 2, if no changes in O2 saturation are seen during the treatment and observation 
periods noted in the table above, the patient may be discharged immediately post subsequent 
triapine dosing. 
 
See Section 6 for dose modification instructions for methemoglobinemia 
 
5.4 Duration of Study 
 
Patients are considered on study from the date of enrollment until the completion of the 
secondary endpoint, the 3-month post-treatment 18F-FDG-PET/CT scan ( 90 days +/- 7 days 
from completion of therapy). 
 
5.4.1 
Expansion cohorts 
An expansion cohort will be treated at the MTD or the dose below that as stipulated above. 
Subjects will be enrolled into a non-HIV+ cohort (n=12) to further expand pharmacokinetic 
investigations and provide additional safety information or a 28-patient cohort of regionally 
advanced stage HIV+ uterine cervix cancer patients on active retroviral therapy.  (Subject 
enrolled into this cohort may include such patients enrolled as part of the MTD 
determination.)  Enrollment will not be time-limited but will be limited to patients with a 

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histologically confirmed diagnosis of locally advanced cervical or vaginal carcinoma not 
amenable to curative surgical resection alone to facilitate achievement of secondary 
objectives.   
 
 
 
5.5 Definition of Dose-Limiting Toxicity 
DLTs are defined as the following adverse events if considered at least “possibly related” to a 
component of the study therapy and which occur from the start of treatment until completion of 
EBRT, prior to initiation of brachytherapy (i.e. the first 5 weeks if no treatments are missed): 
 
• 
Any nausea, vomiting, diarrhea and elevation of serum creatinine level Grade 3 
toxicity not resolved with maximal intervention to Grade 0-2 over 7 days 
(except alopecia and fatigue); 
• 
Any nausea, vomiting, diarrhea and elevation of serum creatinine level Grade 
4 toxicity 
• 
Any other non-hematologic toxicity ≥Grade 3; 
• 
Any hematologic toxicity of  ≥ Grade 4; 
• 
Grade ≥3 dyspnea; 
• 
Inability to deliver at least 20 of the scheduled 25 administrations of triapine at 
the planned dose, allowing for 2 weeks to make up missed radiation days. 
• 
Inability to deliver at least 4 of the scheduled 5 administrations of IV cisplatin at 
the planned dose. 
 
Dose escalation will proceed within each cohort according to the following schema, unless stated 
otherwise. 
 
 
0 out of 3 
Enroll 3 patients at the next dose level. 
≥2 
Dose escalation will be stopped. This dose level will be 
declared the maximally administered dose (highest dose 
administered).  Three additional patients will be enrolled 
at the next lowest dose level if only 3 patients were 
treated previously at that dose. 
1 out of 3 
Enter at least 3 more patients at this dose level. 
• If 0 of these 3 patients experience DLT, proceed to 
the next dose level. 
• If 1 or more of this group suffer DLT, then dose 
escalation is stopped, and this dose is declared the 
maximally administered dose.  Three (3) additional 
patients will be enrolled at the next lowest dose level 
if only 3 patients were treated previously at that dose. 
Number of Patients with DLT at a 
Given Dose Level 
 
Escalation Decision Rule 

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≤1 out of 6 at highest dose level 
below the maximally administered 
dose 
This is generally the Recommended Phase 2 Dose 
(RP2D). At least 6 patients must be enrolled at the 
RP2D (section 5.1.2). 
 
 
 
5.6 General Concomitant Medication and Supportive Care Guidelines 
 
Because there is a potential for interaction of intravenous and oral triapine with other 
concomitantly administered drugs, the case report form must capture the concurrent use of all 
other drugs, over-the-counter medications, or alternative therapies. 
 
The following medications or drug classes listed should be avoided while taking triapine in order 
to minimize the risk for signs and symptoms of methemoglobinemia.  This is not an all-inclusive 
list and should be utilized along with clinical judgement and other patient risk factors, if applicable: 
 
• Amino salicylic acid (also called p-aminosalicylic acid or 4-aminosalicylic acid) 
• Chloroquine 
• Dapsone 
• Local anesthetics, topical sprays and creams including benzocaine, lidocaine, and 
prilocaine 
• Methylene Blue (used for treatment but it is also a risk in certain high risk populations like 
G6PD deficiency)  
• Metoclopramide 
• Nitroglycerin 
• Phenazopyridine 
• Primaquine 
• Rasburicase 
• Quinones 
• Sulfonamide 
 
5.6.1 
Supportive care 
 
IV Triapine: pre-treatment glucocorticoids (IV dexamethasone); antiemetic therapy* 
Oral Triapine: antiemetic therapy* 
Cisplatin: steroid prophylaxis and antiemetic therapy* 
Pelvic External Beam Radiation (EBRT): skincare; antiemetic therapy; and anti-diarrheal 
medication* 
Pelvic Brachytherapy: antiemetic therapy and anti-diarrheal medication* 
* Per institutional policy. 
 
5.7 Duration of Therapy 
 
In the absence of treatment delays due to adverse event(s), treatment will continue until the 
completion of brachytherapy.  Two-weeks to make up missed EBRT doses are allowable. 
Therapy may continue until one of the following criteria applies: 

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• Disease progression 
 
• Intercurrent illness that prevents further administration of treatment 
 
• Unacceptable adverse event(s) 
 
• Patient decides to withdraw from the study 
 
• General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator. 
 
5.8 Duration of Follow Up 
 
All patients will be followed until completion of 3-month post-treatment PET-CT scan (90 days 
+/- 7 days from completion of therapy). Patients removed from study for unacceptable adverse 
event(s) should also be followed until resolution or stabilization of the adverse event. Long term 
follow up will begin after post-treatment PET-CT-scan and will occur every six months (+/- 2 
weeks) for a total of 5 years.  
 
5.9 Criteria for Removal from Study 
 
Patients will be removed from treatment when any of the criteria listed in Section 5.7 apply, or 
once they have completed follow-up as described in Section 5.8. The reasons for treatment 
discontinuation and study removal and the associated dates must be documented in the Case 
Report Form. 

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6. DOSING DELAYS/DOSE MODIFICATIONS 
 
Dose Level 
PO Triapine Dose 
-2 
50 mg D1,3,5 Weekly x5 
-1 
50 mg  QD D1-5 Weekly x5 
1 
100 mg QD D1-5 Weekly x5 
2 
150 mg QD D1-5 Weekly x5 
3 
200 mg QD D1-5 Weekly x5 
 
6.1 Nausea/vomiting 
Nausea/vomiting Management/Next Dose for 
Triapine 
Management/Next Dose for 
Cisplatin 
≤ Grade 2 
No change in dose 
Treat with antiemetics. 
No change in dose 
Treat with antiemetics. 
Grade 3 
Holda until ≤ Grade 2. 
Resume at one dose level lower, if 
indicatedb 
Treat with antiemetics. 
Holda week-to-week until ≤ Grade 2. 
Treat with antiemetics. 
Grade 4 
Off protocol therapyc 
Off protocol therapyc 
aPatients should hold triapine if N/V refractory to anti-emetic therapy. 
bIf appropriate antiemetic treatment does not resolve toxicity down to grade 2 or less within 72 
hours. 
cOff protocol therapy and continue standard of care treatment per treating physician. 
Recommended management:  antiemetics. 
• External-beam pelvic radiation should be held until Grade 3 toxicity is ≤Grade 2. 
 
6.2 Diarrhea 
Diarrhea 
Management/Next Dose for 
Triapine 
Management/Next Dose for 
Cisplatin 
≤ Grade 2 
No change in dose 
Treat with antidiarrheal therapy. 
No change in dose 
Treat with antidiarrheal therapy. 
Grade 3 
Treat with antidiarrheal therapy. 
Holda until ≤Grade 2. 
Resume at one dose level lower, if 
indicatedb 
Holda week-to-week until ≤ Grade 2. 
Treat with antidiarrheal therapy 
Grade 4 
Off protocol therapyc 
Off protocol therapyc 
aPatients should hold triapine if diarrhea refractory to anti-diarrheal 
bIf appropriate antidiarrheal treatment does not resolve toxicity to ≤Grade 2 within 72 hrs. 
cOff protocol therapy and continue standard of care treatment per treating physician. 
Recommended management:  Loperamide antidiarrheal therapy 
Dosage schedule:  4 mg at first onset, followed by 2 mg with each loose motion until diarrhea- 
free for 12 hours (maximum dosage: 16 mg/24 hours) 
Adjunct anti-diarrheal therapy is permitted and should be recorded when used. 
• External-beam pelvic radiation should be held until Grade 3 toxicity is ≤ Grade 2. 

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6.3 Neutropenia 
Neutropenia 
Management/Next Dose for 
Triapine 
Management/Next Dose for 
Cisplatin 
≤ Grade 2 
No change in dose 
No change in dose 
Grade 3 
No change in dose 
Holda week-to-week until ≤ Grade 
2. 
Resume at same dose level 
Grade 4 
Off protocol therapyb 
Off protocol therapyb 
aPatients requiring a delay of >2 weeks should go off protocol therapy. 
bOff protocol therapy and continue standard of care treatment per treating physician. 
• G-CSF is not allowed during this therapy 
• External-beam pelvic radiation and Triapine dosing should continue while any or all 
courses of cisplatin are withheld. 
 
6.4 Thrombocytopenia 
Thrombocytopenia Management/Next Dose for 
Triapine 
Management/Next Dose for 
Cisplatin 
≤ Grade 1 
No change in dose 
No change in dose 
Grade 2 
No change in dose 
Holda week-to-week until ≤ Grade 
1.  Resume at same dose level. 
Grade 3 
No change in dose 
Holda week-to-week until < Grade 
2.  Resume at same dose level. 
Grade 4 
Off protocol therapyb 
Off protocol therapyb 
aPatients requiring a delay of >2 weeks should go off protocol therapy. 
bOff protocol therapy and continue standard of care treatment per treating physician. 
• External-beam pelvic radiation and Triapine dosing should continue while any or all 
courses of cisplatin are withheld. 
 
6.5 Non-hematologic toxicity 
Non-hematologic 
toxicity 
Management/Next Dose for 
Triapine 
Management/Next Dose for 
Cisplatin 
≤ Grade 1 
No change in dose 
No change in dose 
Grade 2 
Holdauntil ≤ Grade 1  (SEE NOTE) Holda until ≤ Grade 1.  (SEE 
NOTE) 
Grade 3 
Holda until < Grade 1  (SEE 
NOTE) 
Holda until < Grade 2.  (SEE 
NOTE) 
Grade 4 
Off protocol therapyb 
Off protocol therapyb 
aPatients requiring a delay of >2 weeks should go off protocol therapy. 
bOff protocol therapy and continue standard of care treatment per treating physician. 
€NOTE: Decision to maintain dose or resume at dose reduction must be reviewed with study PI 
• 
External-beam pelvic radiation should be held until Grade 3 toxicity is ≤Grade 2. 

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6.6 Methemoglobinemia 
 
If patients had prolonged methemoglobinemia or hypoxia requiring dose adjustment during any 
of the observation periods noted in the table above (5.3.3.1 Clinical Monitoring for 
Methemoglobin), follow the schema until stable. 
 
Please note, it is the trend in the O2 saturation that is of importance. Since pulse oximetry is 
known to be unreliable in the presence of significant methemoglobinemia, weight should not be 
given to a single value alone. In any case where there is significant doubt, serial spot 
methemoblobins should be obtained (as clinically indicated based on symptoms such as but not 
limited to skin discoloration, cyanosis, coma, or dysrhythmia and levels can be repeated every 6- 
8 hours until levels <20%) and consultation as needed. 
 
It is expected that all patients will show a transient rise in methemoglobin (up to 10-15%) while 
on study but unless accompanied by hypoxia, or symptoms (e.g., dyspnea), no changes to 
treatment or dose may be required. However, for patients not fitting this pattern, the following 
guidelines should be followed: 
 
• If  methemoglobin  is  asymptomatic,  <20%,  and  NOT  accompanied  by  hypoxia 
(oxygen saturation <92%) : treat without change in dose. 
 
• IF methemoglobin >15% lasts more than 3 hours OR if methemoglobin >20% OR if 
oxygen saturation <92%, THEN: obtain arterial blood gases (a pO2 <80 should result in 
hospitalization and will be counted as DLT). If pO2 normalizes within 24 hours, 
retreatment at a lower dose level may be considered by the Principal Investigator at 
UPCI. 
 
Treatment options for methemoglobinemia could include methylene blue, 1-2 mg/kg IV over 
five minutes32. However, methylene blue is contraindicated in patients with glucose-6-phosphate 
deficiency, since its pharmacologic action as an electron carrier in the reduction of 
methemoglobin is itself dependent on the generation of NADPH by G6PD through the hexose 
monophosphate shunt33. Thus, methylene blue may be at best ineffective in such patients and 
may have the potential to complicate the clinical situation by provoking hemolysis, although this 
association is less clear33. In situations where the use of methylene blue may be contraindicated 
(e.g., in those individuals who are in the high-risk group (patients of African, Asian or 
Mediterranean origin/ancestry), who may have had a false negative G6PD deficiency test), the 
successful use of ascorbic acid (1000 mg IV q6h) has been described33. 
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS 
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial. For this 
trial, routine and expedited reporting will begin at the start of study therapy (i.e., with the first 
dose of triapine, cisplatin and/or radiation therapy). The following list of AEs (Section 7.1) and 
the characteristics of an observed AE (Section 7.2) will determine whether the event requires 
expedited reporting via the CTEP Adverse Event Reporting System (CTEP-AERS) in addition 
to routine reporting. 

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7.1 Comprehensive Adverse Events and Potential Risks List(s) (CAEPRs) 
 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a 
single list of reported and/or potential adverse events (AE) associated with an agent 
using a uniform presentation of events by body system. In addition to the 
comprehensive list, a subset of AEs, the Specific Protocol Exceptions to Expedited 
Reporting (SPEER), appears in a separate column and is identified with bold and 
italicized text.  The SPEER is a list of events that are protocol- specific exceptions 
to expedited reporting to NCI (except as noted below). Refer to the 'CTEP, NCI 
Guidelines: 
Adverse 
Event 
Reporting 
Requirements'  
http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm 
for 
further 
clarification. 
 
 
NOTE:  The highest grade currently reported is noted in parentheses next to the AE 
in the SPEER.  Report ONLY AEs higher than this grade expeditiously.  If this 
CAEPR is part of a combination protocol using multiple investigational agents and 
has an AE listed on different SPEERs, use the lower of the grades to determine if 
expedited reporting is required. 
 
7.1.1 
CAEPRs for CTEP IND Agent 
 
7.1.1.1 CAEPR for for Triapine® (NSC 663249) 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
Triapine® (NSC 663249) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported and/or 
potential adverse events (AE) associated with an agent using a uniform presentation of events by body system. 
In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to Expedited Reporting 
(SPEER), appears in a separate column and is identified with bold and italicized text. This subset of AEs 
(SPEER) is a list of events that are protocol specific exceptions to expedited reporting to NCI (except as noted 
below). Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for further clarification. 
Frequency is provided based on 182 patients. Below is the CAEPR for Triapine®. 
 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to 
the AE in the SPEER. If this CAEPR is part of a combination protocol using multiple investigational 
agents and has an AE listed on different SPEERs, use the lower of the grades to determine if 
expedited reporting is required. 
 
 
 
 
 
 
 
 
 
 

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Version 2.6, March 19, 20191 
 
 Adverse Events with Possible  
 Relationship to Triapine® 
 (CTCAE 5.0 Term) 
[n= 182] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER) 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
Anemia 
 
 
 Anemia (Gr 3) 
 
Febrile neutropenia 
 
 Febrile neutropenia (Gr 2) 
 
 
Hemolysis 
 Hemolysis (Gr 3) 
 
Methemoglobinemia 
 
 Methemoglobinemia (Gr 2) 
CARDIAC DISORDERS 
  
 
Cyanosis 
 
 Cyanosis (Gr 2) 
 
 
Left ventricular systolic 
dysfunction 
  
GASTROINTESTINAL DISORDERS 
  
 
Colitis 
 
 Colitis (Gr 2) 
 
Constipation 
 
  
 
Diarrhea 
 
 Diarrhea (Gr 2) 
 
Dyspepsia 
 
 Dyspepsia (Gr 2) 
 
Mucositis oral 
 
 Mucositis oral (Gr 2) 
Nausea 
 
 
 Nausea (Gr 2) 
Vomiting 
 
 
 Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Chills 
 
 Chills (Gr 2) 
Fatigue 
 
 
 Fatigue (Gr 2) 
Fever 
 
 
 Fever (Gr 2) 
 
Injection site reaction 
 
 Injection site reaction (Gr 2) 
INFECTIONS AND INFESTATIONS 
  
 
Infection2 
 
 Infection2 (Gr 3) 
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased 
 
 Alanine aminotransferase increased 
(Gr 2) 
 
Alkaline phosphatase increased  
 Alkaline phosphatase increased (Gr 
2) 
 
Aspartate aminotransferase 
increased 
 
 Aspartate aminotransferase 
increased (Gr 2) 
 
Blood bicarbonate decreased 
 
 Blood bicarbonate decreased (Gr 2) 
 
Blood bilirubin increased 
 
 Blood bilirubin increased (Gr 2) 
 
Creatinine increased 
 
 Creatinine increased (Gr 2) 
 
Electrocardiogram QT corrected 
interval prolonged 
 
 Electrocardiogram QT corrected 
interval prolonged (Gr 2) 
 
Investigations - Other (Elevated 
ST and T wave changes) 
 
 Investigations - Other (Elevated ST 
and T wave changes) (Gr 2) 
 
Lipase increased 
 
 Lipase increased (Gr 2) 
 
Lymphocyte count decreased 
 
  
Neutrophil count decreased  
 
 Neutrophil count decreased (Gr 4) 
Platelet count decreased 
 
 
 Platelet count decreased (Gr 4) 
 
Weight loss 
 
 Weight loss (Gr 2) 
White blood cell decreased 
 
 
 White blood cell decreased (Gr 4) 
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia (Gr 2) 
 
Dehydration 
 
 Dehydration (Gr 2) 
 
Hypercalcemia 
 
 Hypercalcemia (Gr 2) 

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 Adverse Events with Possible  
 Relationship to Triapine® 
 (CTCAE 5.0 Term) 
[n= 182] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER) 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
Hyperkalemia 
 
 Hyperkalemia (Gr 2) 
 
Hypoalbuminemia 
 
 Hypoalbuminemia (Gr 2) 
 
Hypokalemia 
 
 Hypokalemia (Gr 2) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Myalgia 
 
  
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
  
 
Dysgeusia 
 
 Dysgeusia (Gr 2) 
 
Headache 
 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
 Dyspnea (Gr 2) 
 
Hypoxia 
 
 Hypoxia (Gr 3) 
 
 
Pneumonitis 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Alopecia 
 
 Alopecia (Gr 2) 
 
Rash maculo-papular 
 
 Rash maculo-papular (Gr 2) 
VASCULAR DISORDERS 
  
 
Flushing 
 
 Flushing (Gr 2) 
 
Hypertension 
 
 Hypertension (Gr 2) 
 
Hypotension 
 
 Hypotension (Gr 2) 
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should be 
included in the e-mail. 
 
2Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
 
Adverse events reported on Triapine® trials, but for which there is insufficient evidence to suggest 
that there was a reasonable possibility that Triapine® caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other (spleen 
disorder); Blood and lymphatic system disorders - Other (monocytosis); Disseminated intravascular 
coagulation; Hemolytic uremic syndrome; Leukocytosis; Thrombotic thrombocytopenic purpura 
CARDIAC DISORDERS - Atrial fibrillation; Cardiac disorders - Other (cardiovascular edema); Cardiac 
disorders - Other (premature ventricular contraction); Myocardial infarction; Palpitations; Pericardial effusion; 
Restrictive cardiomyopathy; Sinus tachycardia; Ventricular tachycardia 
EAR AND LABYRINTH DISORDERS - Ear and labyrinth disorders - Other (ear congestion); Ear and 
labyrinth disorders - Other (hyperacusis); Ear pain; Hearing impaired; Middle ear inflammation; Tinnitus; 
Vertigo 
EYE DISORDERS - Dry eye; Watering eyes 
GASTROINTESTINAL DISORDERS - Abdominal pain; Ascites; Dry mouth; Dysphagia; Esophagitis; 
Flatulence; Gastrointestinal disorders - Other (glossitis); Gastrointestinal disorders - Other (leukoplakia of the 
mouth); Gastrointestinal disorders - Other (mouth ulceration); Gastrointestinal disorders - Other (salivary 
hypersecretion); Gastrointestinal disorders - Other (steatorrhea); Gastrointestinal disorders - Other (stool 
discoloration); Gastrointestinal disorders - Other (tongue discoloration); Hemorrhoids; Ileus; Oral 
hemorrhage; Pancreatitis; Rectal hemorrhage; Small intestinal obstruction 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Death NOS; Edema face; Edema 

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limbs; Flu like symptoms; General disorders and administration site conditions - Other (extravasation); 
Malaise; Non-cardiac chest pain; Pain; Sudden death NOS 
HEPATOBILIARY DISORDERS - Hepatobiliary disorders - Other (hepatomegaly); Hepatobiliary disorders - 
Other (jaundice); Hepatobiliary disorders - Other (liver tenderness) 
IMMUNE SYSTEM DISORDERS - Allergic reaction; Anaphylaxis; Cytokine release syndrome 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Infusion related reaction 
INVESTIGATIONS - Activated partial thromboplastin time prolonged; Blood lactate dehydrogenase 
increased; CPK increased; Cholesterol high; GGT increased; INR increased; Investigations - Other (BUN 
increased); Investigations - Other (C-reactive protein increased); Investigations - Other (NPN increased); 
Investigations - Other (PT decreased); Investigations - Other (sedimentation rate increased); Serum amylase 
increased; Weight gain 
METABOLISM AND NUTRITION DISORDERS - Acidosis; Alkalosis; Hyperglycemia; Hypernatremia; 
Hyperuricemia; Hypocalcemia; Hypoglycemia; Hypomagnesemia; Hyponatremia; Hypophosphatemia; Iron 
overload; Metabolism and nutrition disorders - Other (hypoproteinemia); Tumor lysis syndrome 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Arthritis; Back pain; Bone 
pain; Chest wall pain; Generalized muscle weakness; Musculoskeletal and connective tissue disorder - Other 
(hypertonia); Musculoskeletal and connective tissue disorder - Other (leg cramps); Musculoskeletal and 
connective tissue disorder - Other (myoglobin); Musculoskeletal and connective tissue disorder - Other 
(twitching); Pain in extremity 
NERVOUS SYSTEM DISORDERS - Amnesia; Cognitive disturbance; Depressed level of consciousness; 
Dysesthesia; Intracranial hemorrhage; Ischemia cerebrovascular; Lethargy; Nervous system disorders - 
Other (cerebellar toxicity); Nervous system disorders - Other (reflexes decreased); Paresthesia; Peripheral 
motor neuropathy; Peripheral sensory neuropathy; Seizure; Somnolence; Syncope; Tremor 
PSYCHIATRIC DISORDERS - Anxiety; Confusion; Delayed orgasm; Delirium; Depression; Insomnia; 
Personality change 
RENAL AND URINARY DISORDERS - Acute kidney injury; Cystitis noninfective; Hematuria; Urinary 
frequency; Urinary tract pain; Urine discoloration 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Erectile dysfunction; Genital edema; Vaginal 
hemorrhage 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress syndrome; 
Apnea; Epistaxis; Hiccups; Laryngospasm; Pleural effusion; Voice alteration 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Dry skin; Erythema multiforme; Hirsutism; 
Hyperhidrosis; Photosensitivity; Pruritus; Skin and subcutaneous tissue disorders - Other (Skin nodule); Skin 
ulceration; Stevens-Johnson syndrome 
VASCULAR DISORDERS - Hematoma; Phlebitis; Thromboembolic event; Vascular disorders - Other 
(pallor); Vascular disorders - Other (vasodilation) 
 
Note: Triapine® in combination with other agents could cause an exacerbation of any adverse event currently 
known to be caused by the other agent, or the combination may result in events never previously associated 
with either agent. 
 
 
7.1.2 
Adverse Event List for Cisplatin 
 
Leukopenia, thrombocytopenia, anemia, nausea, vomiting, nephrotoxicity, ototoxicity, peripheral 
neuropathy, electrolyte imbalance, hypocalcemia, hypomagnesemia, aminoglycoside ototoxicity, 
ocular toxicity, and allergic reactions. Infrequent: Cardiac abnormalities, anorexia, elevated SGOT, 
rash, alopecia and acute myeloid leukemia. NOTE: Aminoglycoside antibiotics given before, 
with, or after cisplatin may potentiate renal toxicity and should be avoided whenever possible. 
Severe renal toxicity can be largely avoided by induction of a diuresis before, during and after 
treatment. Mild renal dysfunction is a common complication (10%) of chronic therapy and may 
require discontinuation of therapy if creatinine> 1.5 x institutional upper limit normal (ULN) 
develop. Mild or severe electrolyte abnormalities may occur (5%) as acute or chronic 
complications, especially hypokalemia or hypomagnesemia. Monitoring of electrolytes and 

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electrolyte replacement will usually correct these abnormalities. Rarely, severe hypomagnesemia 
and hypocalcemia may require replacement therapy and discontinuation of treatment with 
cisplatin. Local necrosis and thrombophlebitis can be avoided by careful administration. 
Neurotoxicity may be related to cumulative dose and severe toxicity can be largely avoided by 
careful monitoring for evidence of paresthesias and timely discontinuation of treatment. Ataxia 
has been described. Ototoxicity may occur. NOTE: Eighth (VIII) nerve toxicity resulting in 
hearing loss and (less commonly) vestibular symptoms is a well-documented complication of 
cisplatin treatment and is usually related to total cumulative dose. It is advised that patients 
placed on cisplatin, whether as a single agent therapy or combination, be questioned concerning 
hearing loss. Patients with a history of hearing loss should be considered for pre-treatment 
audiometry with follow-up audiometry as clinically indicated. It is recommended that patients be 
queried concerning hearing loss before each course of cisplatin. Refer to package insert for 
additional information. 
 
Allergic reactions are rare. If accompanied by respiratory symptoms, allergic reactions require 
discontinuation of treatment. Patch or skin tests are recommended for patients with suspected 
allergy to cisplatin. An emergency set for the treatment of allergic reactions should be available 
in the treatment area. 
 
 
7.2 Adverse Event Characteristics 
 
• CTCAE term (AE description) and grade: The descriptions and grading scales found in 
the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 
will be utilized for AE reporting. All appropriate treatment areas should have access to a 
copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 can be downloaded 
from 
the 
CTEP 
web 
site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
• For expedited reporting purposes only: 
- 
AEs for the agent that are bold and italicized in the CAEPR (i.e., those listed in the 
SPEER column, Section 7.1.1) should be reported through CTEP-AERS only if the 
grade is above the grade provided in the SPEER. 
- 
Other AEs for the protocol that do not require expedited reporting are outlined in 
section 7.3.4. 
 
• Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
7.3 Expedited Adverse Event Reporting 
 
7.3.1 
CTEP-AERS 
 

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Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse Event Reporting 
System), accessed via the CTEP website (https://eapps-ctep.nci.nih.gov/ctepaers).  The 
reporting procedures to be followed are presented in the “NCI Guidelines for Investigators: 
Adverse Event Reporting Requirements for DCTD (CTEP and CIP) and DCP INDs and IDEs” 
which 
can 
be 
downloaded 
from 
the 
CTEP 
website 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm).  
These requirements are briefly outlined in the tables below (Section 7.3.3). 
 
In the rare occurrence when Internet connectivity is lost, a 24-hour notification is to be made 
to CTEP by telephone at 301-897-7497.  Once Internet connectivity is restored, the 24-hour 
notification phoned in must be entered electronically into CTEP-AERS by the original 
submitter at the site. 
 
 
7.3.2 
Distribution of Adverse Event Reports 
 
CTEP-AERS is programmed for automatic electronic distribution of reports to the following 
individuals:  Principal Investigator and Adverse Event Coordinator(s) (if applicable) of the 
Corresponding Organization or Lead Organization, the local treating physician, and the 
Reporter and Submitter.  CTEP-AERS provides a copy feature for other e-mail recipients.  
 
 
7.3.3 
Expedited Reporting Guidelines 
 
Use the NCI protocol number and the protocol-specific patient ID assigned during trial 
registration on all reports. 
 
Note:  A death on study requires both routine and expedited reporting, regardless of 
causality.  Attribution to treatment or other cause must be provided. 
 
Death due to progressive disease should be reported as Grade 5 “Disease progression” in the 
system organ class (SOC) “General disorders and administration site conditions.”  Evidence 
that the death was a manifestation of underlying disease (e.g., radiological changes suggesting 
tumor growth or progression: clinical deterioration associated with a disease process) should 
be submitted. 
 
Phase 1 and Early Phase 2 Studies:  Expedited Reporting Requirements for Adverse Events 
that Occur on Studies under an IND/IDE within 30 Days of the Last Administration of the 
Investigational Agent/Intervention 1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not 
they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  

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6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or subject 
and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. 
(FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via electronic 
submission within the timeframes detailed in the table below. 
Hospitalization 
de 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting 
in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 Calendar Days 
Not 
resulting 
in 
Hospitalization  
≥ 24 hrs 
Not required 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR. 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 5 Calendar Days” - The AE must initially be submitted electronically within 24 hours of learning of 
the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted electronically within 10 
calendar days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 3, 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, rounded 
UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above applies after this 
reporting period. 
Effective Date:  May 5, 2011 
 
 
7.3.4 
Additional Protocol-Specific Expedited Adverse Event Reporting Exclusions 
 
For this protocol only, the AEs/grades listed below do not require expedited reporting via 
CTEP-AERS.  However, they still must be reported through the routine reporting 
mechanism (Section 7.4): 
 
CTCAE SOC 
Adverse Event 
Grade 
≥24h Hospitalizationa 
Skin and subcutaneous 
tissue disorders 
Alopecia 
2 
No 
Gastrointestinal disorders 
Diarrhea 
2 
No 

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Gastrointestinal disorders 
Nausea 
Vomiting 
2 
No 
a Indicates that an adverse event required hospitalization for ≥24 hours or prolongation of 
hospitalization by ≥24 hours of a patient. 
 
 
 
7.4 Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions.  AEs reported 
expeditiously through CTEP-AERS must also be reported in routine study data submissions. 
 
Adverse event data collection and reporting, which are required as part of every clinical trial, are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in 
future studies using similar agents.  AEs are reported in a routine manner at scheduled times during 
the trial using Medidata Rave. For this trial the Adverse Event CRF is used for routine AE 
reporting in Rave. 
 
7.5 Secondary Malignancy 
 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm. 
 
CTEP requires all secondary malignancies that occur following treatment with an agent under an 
NCI IND/IDE be reported expeditiously via CTEP-AERS.  Three options are available to describe 
the event: 
 
• Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML]) 
• Myelodysplastic syndrome (MDS) 
• Treatment-related secondary malignancy 
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol. 
 
 
7.6 Second Malignancy 
 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies require ONLY routine AE 
reporting unless otherwise specified. 

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8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational or commercial 
agents administered in this study can be found in Section 7.1. 
 
8.1 Triapine NSC 663249 
 
Chemical Name:  
3-aminopyridine-2-carboxaldehyde thiosemicarbazone 
 
Other Names:  
3-AP 
 
Classification:  
Triapine®, an α-heterocyclic carboxaldehyde thiosemicarbazone (HCT), is a 
ribonucleotide reductase (RNR) inhibitor that acts on the M2 (R2) subunit. The 
HCTs are the most potent RNR inhibitors, being 65 -5,000 times more potent 
than hydroxyurea. 
 
Mechanism of Action:  
Ribonucleotide reductase (RNR) inhibitor  
 
CAS Registry Number: 
143621-35-6 
 
Molecular Formula:  
C7H9N5S 
 
 
M.W.: 195 
 
Approximate Solubility: 
Water = 0.1 mg/mL 
 
 
 
 
Ethanol = 1.25 mg/mL 
 
 
 
 
PEG-300 = 15 mg/mL 
 
Potential Drug Interactions:  In in vitro cellular and subcellular liver studies, triapine was not 
metabolized by glucuronyltransferases, FMO, AO/XO, MAO-A/B, or NAT-1/2, but was metabolized 
by CYP450s. CYP1A2 accounted for most of the depletion of triapine. Triapine reduced CYP1A2 
activity and increased CYP2C19 activity. (Joshi et al. Cancer Chemotherapy and Pharmacology (2020) 
86:633–640) 
 
8.1.1 
Triapine Injection 
 
How Supplied: 
Triapine® Injection is supplied by DCTD, NCI and distributed by the CTEP, 
DCTD, NCI.  Triapine® Injection is supplied in 10 mL amber vials containing 
10 mL of a clear yellowish slightly viscous, sterile, non-aqueous solution for 
IV administration.  Each 10 mL vial contains 50 mg of Triapine® (5 mg/mL), 
60 mg of citric acid, anhydrous, 10 mg of L-ascorbic acid, 3 mL of ethyl 
alcohol, and 7 mL of polyethylene glycol 300. 
 
Preparation:   
Withdraw the Triapine dose volume from the vial and add to 0.9% sodium 
chloride or 5% dextrose in water to a final concentration of 0.01 to 2 mg/mL. 
Triapine infusion should be a clear, yellow solution with no discernible haziness. 
If haziness appears or persists after dilution, do not use the product.  
 

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Dilutions of Triapine® must be performed in glass bottles, or in plastic IV 
bags that do not contain di (ethylhexyl) phthalate (DEHP), since the 
nonaqueous solvents in Triapine® injection have been shown to extract 
DEHP.  
 
Storage: 
 
Store Triapine® injection between 2-8°C (36-46°F).  Do not freeze.   
 
 
If a storage temperature excursion is identified, promptly return Triapine® 
injection to refrigerated temperature and quarantine the supply. Provide a 
detailed report of the excursion (including documentation of temperature 
monitoring and duration of the excursion) to PMBAfterHours@mail.nih.gov 
for determination of suitability. 
 
Stability: 
When diluted with 0.9% sodium chloride or 5% dextrose in water, to a final 
concentration of 0.01 to 2 mg/mL, Triapine® infusions have been found to be 
stable for 8 hours at room temperature or at 2 - 8ºC.  Do not freeze. Do not 
expose diluted solutions of Triapine® injection to direct sunlight or 
temperatures above 25°C (77°F). 
 
Shelf life stability studies of Triapine® injection vials are on-going. 
 
Route of Administration: 
 Intravenous 
 
Method of Administration: Infuse intravenously over 120 +/- 10 minutesusing a DEHP-free (e.g., 
polyethylene) low sorbing infusion set on day 1. 
 
8.1.2 
Triapine Capsules 
 
How Supplied:  Triapine® Capsules are supplied by Nanopharmaceutics, LLC and distributed by the 
CTEP, DCTD, NCI.  Each Triapine® Capsule contains 50 mg of Triapine® in combination with 
Starch 1500 and Magnesium Stearate in a size 1, hard gelatin, white, opaque capsule.  Each bottle 
contains 30 capsules. 
 
Storage: Store Triapine® Capsules at room temperature 25ºC, excursions permitted to 15ºC to 30ºC. 
 
If a storage temperature excursion is identified, promptly return Triapine® Capsules to between 
15 and 30°C and quarantine the supplies.  Provide a detailed report of the excursion (including 
documentation 
of 
temperature 
monitoring 
and 
duration 
of 
the 
excursion) 
to 
PMBAfterHours@mail.nih.gov for determination of suitability. 
 
Stability: Shelf-life stability studies of Triapine® Capsules are on-going. 
 
Route of Administration: Oral administration per the protocol treatment schedule.  No oral 
administration on day 1 when triapine is delivered intravenously.   
 
Method of Administration:  Patients will be asked to fast (except for water) for 2 hours prior to 
dosing and for 1 hour after ingesting the oral dose (triapine complexes strongly with iron ions).  

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Patients will ingest one dose of triapine in the clinic within 90 minutes after each daily radiation 
treatment, starting with the first radiation treatment through the last day of radiation treatment 
(completion of EBRT).  Each oral triapine dose will be administered in the clinical area within 90 
minutes of each daily RT dose.  Triapine will not be administered on days that radiation is not given 
(Sat- Sun, holidays) or on the days that radiation is missed or held. Study staff will observe and 
document triapine administration and will document dosing time in the patient’s record. 
 
8.1.3 
Agent Ordering and Agent Accountability 
 
Availability:  Triapine is an investigational agent supplied to investigators by the Division of Cancer 
Treatment and Diagnosis (DCTD), NCI. 3-AP is provided to the NCI under a Collaborative 
Agreement between the Pharmaceutical Collaborator and the DCTD, NCI (see Section 12.3). In 
general, sites may order initial agent supplies when a subject is being screened for enrollment onto 
the study. 
 
Agent Ordering: 
NCI-supplied agents may be requested by eligible participating Investigators 
(or their authorized designee) at each participating institution.  The CTEP-assigned protocol number 
must be used for ordering all CTEP-supplied investigational agents.  The eligible participating 
investigators at each participating institution must be registered with CTEP, DCTD through an 
annual submission of FDA Form 1572 (Statement of Investigator), NCI Biosketch, Agent Shipment 
Form, and Financial Disclosure Form (FDF).  If there are several participating investigators at one 
institution, CTEP-supplied investigational agents for the study should be ordered under the name 
of one lead participating investigator at that institution. 
 
Submit agent requests through the PMB Online Agent Order Processing (OAOP) application.  
Access to OAOP requires the establishment of a CTEP Identity and Access Management (IAM) 
account and the maintenance of an “active” account status, a “current” password, and active person 
registration status.  For questions about drug orders, transfers, returns, or accountability, call or email 
PMB any time.  Refer to the PMB’s website for specific policies and guidelines related to agent 
management.   
 
Agent Inventory Records – The investigator, or a responsible party designated by the investigator, 
must maintain a careful record of the receipt, dispensing and final disposition of all agents received 
from the PMB using the appropriate NCI Investigational Agent (Drug) Accountability Record 
(DARF) available on the CTEP forms page.  Store and maintain separate NCI Investigational Agent 
Accountability Records for each agent, strength, formulation and ordering investigator on this 
protocol. 
 
8.1.4 
Investigator Brochure Availability 
The current versions of the IBs for the agents will be accessible to site investigators and 
research staff through the PMB OAOP application.  Access to OAOP requires the 
establishment of a CTEP IAM account and the maintenance of an “active” account status, a 
“current” password and active person registration status.  Questions about IB access may be 
directed to the PMB IB Coordinator via email. 
 
8.1.5 
Useful Links and Contacts 
• CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/ 

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• NCI CTEP Investigator Registration:  RCRHelpDesk@nih.gov 
• PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm  
• 
PMB Online Agent Order Processing (OAOP) application:  
https://ctepcore.nci.nih.gov/OAOP 
• CTEP Identity and Access Management (IAM) account: 
https://ctepcore.nci.nih.gov/iam/  
• CTEP IAM account help:  ctepreghelp@ctep.nci.nih.gov  
• IB Coordinator:  IBCoordinator@mail.nih.gov  
• PMB email:  PMBAfterHours@mail.nih.gov 
• PMB phone and hours of service: (240) 276-6575 Monday through Friday between 
8:30 am and 4:30 pm (ET) 
 
8.2 Cisplatin (NSC #119875) 
 
Formulation: 
PLATINOL®-AQ (cisplatin injection) infusion concentrate is 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. 
 
Supplier: 
Commercially  available.  Refer  to  individual  FDA-approved  package 
insert. 
 
Preparation: 
PLATINOL®-AQ (cisplatin injection) infusion concentrate (1 mg/mL) 
must be further diluted prior to administration. Cisplatin (40 mg/m2) will 
be diluted in 250 mL of normal saline. 
 
NOTE: Aluminum reacts with cisplatin causing precipitation formation 
and loss of potency, therefore, needles or intravenous sets containing 
aluminum parts that may come in contact with the drug must not be used 
for the preparation or administration of cisplatin. 
 
Storage: 
Store at 15° to 25°C (59° to 77°F). Do not refrigerate. Protect unopened 
container from light. 
 
Stability: 
The cisplatin remaining in the amber vial following initial entry is stable 
for 28 days protected from light or for 7 days under fluorescent room light. 
 
Administration: 
Once weekly intravenous cisplatin (40 mg/m2) is administered. 1000 mL 
of normal saline should be infused intravenously one hour before cisplatin. 
Increased oral intake should be encouraged starting the day before. 
Additional fluid may be given as needed for symptomatic support. The 
solution should be infused at a rate of 1 mg/min, usually over a total of 60 
to 120 minutes. The cisplatin dose will not exceed 70 mg maximum. 
Immediately after completion of the cisplatin infusion, an additional 1000 

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mL of normal saline should be given. 

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9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
9.1 Integrated Laboratory Studies - Secondary objective 
 
9.1.1 
Pharmacokinetics  
 
General 
Blood samples to be obtained through a peripheral or central line blood draw.  Samples should 
be drawn from the opposite arm if infusion is a peripheral infusion.  Samples should NOT be 
drawn from the infusion line. 
 
Drawing and Processing 
Document exact start and stop times of each infusion and drug dose and exact times of blood 
draws per Appendix B-C. 
1. Collect in a ~4 mL (3-5) mL purple top tube (e.g. BD vacutainer 367861 plastic 13 x 75 4 
mL tube). 
2. Invert the vacutainer tubes several times to mix blood with EDTA anticoagulant and 
immediately place on ice. 
3. Processing should begin within 30 minutes of collection. 
4. Samples should be centrifuged for 10 min at approximately 1000 x g in a refrigerated 
tabletop centrifuge so as to produce plasma. 
5. The resulting plasma should be aspirated from the tubes, placed into appropriately-
labeled microcentrifuge tubes, and stored at -70 °C until shipment. 
 
Pharmacokinetics of IV triapine 
To assess oral bioavailability, IV triapine at a fixed dose of 50 mg for all dose levels will be given 
on day 1. On the day when IV triapine is administered, oral triapine will not be given. 
 
Day 1: 
EDTA anti-coagulated blood samples will be obtained at the following timepoints: 
prior to IV triapine infusion 
30 (±5) min after start of infusion 
60 (±5) min after start of infusion 
90 (±5) min after start of infusion 
110 (±5) min after start of infusion 
2 h 30 min (±10 min) after start of infusion 
3 h (±10 min) after start of infusion 
4 h (±10 min) after start of infusion 
6 h (±15 min) after start of infusion 
8 h (±30 min) after start of infusion 
24 h (±2 h) after start of infusion 
 
Pharmacokinetics of PO triapine 
To assess oral bioavailability, blood samples will be obtained on 1 day of PO triapine. 

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Day 8: 
EDTA anti-coagulated blood samples will be obtained at the following timepoints: 
 
prior to PO triapine dose 30 
(±5) min after dose 
60 (±5) min after dose 
90 (±10) min after dose 
110 (±10) min after dose 
2 h 30 min (±10 min) after dose 
3 h (±10 min) after dose 
4 h (±10 min) after dose 
6 h (±15 min) after dose 
8 h (±30 min) after dose 
24 h (±2 h) after dose 
 
 
9.1.1.1 Shipping of Specimen(s) 
 
Preparing the shipment 
• Samples should be stored in cardboard boxes (5 1/8” x 5 1/8” x 2”, L x W x H). 
• Please organize the samples by Patient and Time point in the box. 
• Do not store in plastic bags (they break on dry-ice and labels will detach). 
• A copy of each of the pharmacokinetic sample collection forms (Appendix B-C) for the 
respective patients should be included with each shipment.  If applicable, to prevent 
problems with illegible writing on tubes, consider numbering them and numbering 
samples on the sample sheet. 
• *Note the study number, PI, and the drugs used/to be measured. 
• *A name, phone number, and email address should be included with the samples so that 
receipt can be acknowledged. 
• Please notify the lab by email (PITT-PK@UPMC.EDU), telephone (412-623-3248) or 
fax (412-623-1212) at least 24 hours prior to shipment. 
 
Shipping 
*All samples should be shipped via overnight express courier in insulated containers with 
enough dry ice to maintain the samples in a frozen state (if samples are to be shipped frozen). 
All specimens are to be shipped on either Monday, Tuesday or Wednesday to: 
 
Cancer Pharmacokinetics and Pharmacodynamics Facility 
UPMC Hillman Cancer Center 
Room G27 Hillman Research Laboratories 5117 Centre Avenue 
Pittsburgh, PA 15213. 
 
Regulations 
Shipment of samples must comply with appropriate regulations as specified by the carrier. At a 

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minimum, all samples must be packaged within two containers with absorbent material between 
containers to control any spill or leakage. The outer container must be puncture-resistant (e.g. 
cardboard mailing tube, corrugated cardboard box). A biohazard sticker must be affixed to both 
the inner and outer containers. 
 
Contact Information for Assistance 
Lab phone:  412-623-3248 
Lab fax:  412-623-1212 
PK Lab email: PITT-PK@upmc.edu  
PK director email: beumerjh@upmc.edu 
 
9.2 Special Studies 
 
9.2.1 
18F-FDG-PET/CT 
 
9.2.1.1 Subject Preparation 
 
Prior to Arrival 
-Subjects must fast (except for water) for at least 4 hours before administration of 
18F-FDG for the PET/CT exam. 
-Subjects should avoid strenuous exercise for 24 hours before the FDG injection 
to minimize uptake of the radiotracer in muscles. 
 
Upon Arrival 
-Upon arrival at the PET facility, confirm subject compliance with pre-procedure 
instructions, particularly that the fasting requirement was met. 
-The subject’s weight and height shall be measured and recorded (not verbally 
relayed by the subject). 
-The pre-injection blood glucose level must be < 200 mg/dL (measured ideally 
within one hour of FDG injection).  If the serum glucose is > 200 mg/dL, the 
study should be rescheduled.  The referring physician or primary physician of the 
subject should be contacted to optimize blood glucose control. 
-A large-bore intravenous line (typically, a 20 or 22 gauge angiocatheter) or a 
butterfly needle in a vein of the participant’s arm. 
-Prior to positioning the subject on the PET scanner the subjects should be asked 
to urinate. 
-Use of a Foley catheter and a single furosemide administration per institutional 
policy is permitted.   
 
Injection of 18F-FDG 
-The dose of FDG to be administered is 10-20 mCi. 
-The exact time of calibration of the dose should be recorded and the exact time 
of injection noted to permit correction of the administered dose for radioactive 
decay.  In addition, the dose remaining in the tubing or syringe, or that was spilled 
during injection should be recorded.  The injection should be performed through 
an intravenous catheter. 
 

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FDG-PET/CT Imaging Procedure 
-The time between the injection of FDG and PET emission scan start (tracer 
uptake time) should begin between 50-70 minutes after injection. 
-The injection to start of imaging time for the 3-month post therapy PET/CT scans 
should be within 10 minutes of that for the baseline study.   
-The CT component of the PET/CT study will be performed for attenuation 
correct and anatomical localization (AC, AL). 
-All participants must void prior to imaging to ensure clearance of bladder 
activity. 
-A Foley catheter and a single furosemide administration per institutional policy 
is permitted. 
-Participants will be positioned with their arms above their head or on their chest 
if unable to keep their arms above the head. 
 
9.2.1.2 Typical acquisition parameters for the low-dose CT scan for attenuation correction should 
be: kVp = 120; effective mAs = 30–80 (participant dependent); gantry rotation time ≤ 0.5 sec; 
maximum reconstructed width = 3–5 mm without overlap. The parameters should use the 
standard reconstruction algorithm, without any iodinated intravenous contrast agent. Dilute 
oral contrast is acceptable, if part of typical institutional practice. 
 
9.2.1.3 18F-FDG PET/CT Reporting: Images will be evaluated on baseline and 3-month scans 
qualitatively for focal areas of abnormally increased 18F-FDG uptake in the primary tumor. 
This will be performed by visually identifying 18F-FDG uptake. Assessment of uptake in 
regional lymph nodes also will be performed by visual inspection. New sites of confirmed18F-
FDG PET/CT activity at 3-months post therapy will be classified as progressive metabolic 
disease. Local institution nuclear medicine reports should be submitted (section 12.1). Local 
institution investigators will resolve discrepancies by teleconference. 
 
9.2.1.4 Semi-quantitative18F-FDG PET/CT Reporting of Standardized Uptake Value (SUV): 
Images will be evaluated quantitatively for abnormally increased 18F-FDG uptake in the 
primary tumor by measurement of the maximum standardized uptake value normalized for 
body mass (SUVmax). As a second metric, SUV normalized by lean body mass (SUL) will be 
calculated. On the baseline, 3-month scans, the SUVmax and SUL within the primary cancer 
will be recorded. The PET/CT Form recording this data must accompany pre-therapy and 3-
month data submissions. As a secondary analysis, an 18F-FDG PET/CT post therapy: pre-
therapy SUVmax ratio will be calculated. Ratios greater than 1.25 will be classified as 
progressive metabolic disease. Ratios of 0.76 to 1.25 will be classified as stable metabolic 
disease. Ratios of 0.34 to 0.75 will be considered partial metabolic response. Ratios lower than 
0.33 will be marked as complete metabolic response. Ratios indistinguishable from cardiac or 
liver blood pool activity because of complete resolution of tumor 18F-FDG uptake (i.e., a 
cervix indistinguishable from surrounding normal tissue on post therapy imaging) will be 
labeled also as quantitative metabolic complete response. 
 
9.2.1.5 Evaluation of 18F-FDG PET CT Target: 
Complete Response (CR): A metabolic complete response on PET/CT will be defined 
as greater than -66% reduction in tumor FDG uptake at sites of abnormal tumor FDG 
uptake noted on pre-treatment FDG-PET study (considering normal cardiac or liver 
blood pool). 

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Partial Response (PR): A metabolic partial response on PET/CT will be defined as -
25% to -66% reduction in tumor FDG uptake at sites of abnormal tumor FDG uptake 
noted on pre-treatment FDG-PET study (considering normal cardiac or liver blood 
pool).   
  
Progressive Disease (PD): Progressive metabolic disease on PET/CT is classified as 
an increase in tumor FDG uptake greater than +25% within the tumor region defined 
on baseline scan (considering normal cardiac or liver blood pool), or appearance of 
new FDG uptake in new metastatic lesions. 
  
Stable Disease (SD): Stable metabolic response will be defined as a change in tumor 
FDG uptake by less than +25% (increase) or by less than -25% (decrease) at sites of 
abnormal tumor FDG uptake (considering normal cardiac or liver blood pool) when 
compared to pre-treatment FDG-PET study. 
  
Patients with a global deterioration of health status requiring discontinuation of treatment 
or die without objective evidence of disease progression at that time should be reported to 
be off study treatment due to “symptomatic deterioration.”  Every effort should be 
made to document the objective progression even after discontinuation of treatment. 
 
9.2.1.5.1 Duration of Response 
Duration of overall response:  The duration of overall response is measured 
from the time measurement criteria are met for CR or PR (whichever is 
first recorded) until the first date that recurrent or progressive disease is 
objectively documented (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started). The duration 
of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that progressive disease is objectively 
documented. 
 
Duration of stable disease:  Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the 
smallest measurements recorded since the treatment started, including the 
baseline measurements. 
 
9.2.1.6 Outcome Measure 
18F-FDG-PET/CT to assess treatment response 
 
9.2.1.7 Assessment 
9.2.1.7.1 Method of Assessment 
standard of care total body scan (skull base to mid-thigh) 
9.2.1.7.2 Timing of Assessment 
2 scans: pre-treatment and 3-month post-treatment (90 days +/- 7 days from 
completion of therapy)  for acquiring the scans 
 
 
9.2.2 
Methemoglobin 

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9.2.2.1 Outcome Measure 
% methemoglobin 
 
9.2.2.2 Assessment of methemoglobin 
9.2.2.2.1 Method of Assessment 
Per institutional clinical chemistry procedures 
 
9.2.2.2.2 Timing of Assessment 
-On PK days (1, 8) before triapine, 4 h after triapine and the next day before 
any treatment 
-Spot methemoglobin if clinically indicated. 
 
9.2.2.3 Handling of Specimens(s) 
Per institutional clinical chemistry procedures. Suggestion: 1-2 mL in heparinized 
blood gas syringe, analyzed within 30 minutes of being drawn. 

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10. STUDY CALENDAR 
 
Baseline evaluations are to be conducted within 14 days prior to start of protocol therapy. In the 
event that the patient’s condition is deteriorating, laboratory evaluations should be repeated within 
48 hours prior to start of protocol therapy. Scans and x-rays must be done <4 weeks prior to the 
start of therapy. 
Procedure/Test 
Pre- 
Study 
Week 
1 
Week 
2 
Week 
3 
Week 
4 
Week 
5 
Week 
6 
EOT 
1mo 
F/U 
3mo 
F/U 
L/T 
F/U 
Informed consent 
X 
Demographics 
X 
Concurrent meds 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medical history 
X 
Current nicotine use status P 
X 
Physical exam A,B 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs A,B,Q 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height and Weight A,B 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Performance status A,B 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CBC w/diff, plts A,B 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum chemistry A,B,C 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PTT/PT/INR D 
X 
EKG D 
X 
FDG-PET/CT, Whole body X 
X 
MRI, Pelvis E 
X 
X 
Tumor Measurements 
X 
X 
Baseline signs & symptoms X 
Methemoglobin monitoringF 
X 
X 
X 
X 
X 
Adverse event evaluation 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Triapine IV G 
X 
Triapine PO H, I 
X 
X 
X 
X 
X 
Cisplatin IV J 
X 
X 
X 
X 
X 
Radiation Therapy H,K 
X 
X 
X 
X 
X 
Brachytherapy L 
X 
Urine or serum B-
HCG (WOCBP) 
X 
XM 
Pharmacokinetic Sampling N 
X 
X 
Patient Diary ReviewO 
X 
X 
X 
X 
X 
Review of disease status and 
Survival R 
X 

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A. These procedures do not need to be repeated in Week 1 if done pre-study within 7 days prior to start of 
protocol therapy. 
B. The procedures must be repeated within 1 day prior to cisplatin each week in Weeks 2-5. 
C. Albumin, alkaline phosphatase, total bilirubin, direct bilirubin, bicarbonate, BUN, calcium, chloride, 
creatinine, glucose, potassium, total protein, SGOT [AST], SGPT [ALT], sodium, magnesium, phosphorus 
D. Required pre-study, then as clinically indicated 
E. This is optional. 
F. Clinical monitoring required Week 1; as clinically indicated Weeks 2-5 (See Section 5.3.3.1). Monitor the % of 
methemoglobinemia on specific PK and PD days to correlate effect with exposure (see Section 9.2.2) 
G. Day 1 
H. M-F (except holidays); Oral triapine dosing for Dose Level -2 is M/W/F. 
I. 
Not on the IV triapine day 
J. 
Tuesdays (Days 2, 9, 16, 23, 30). Weeks 3-5, cisplatin may be given on Monday or Tuesday. 
K. EBRT make-up is permissible (see Section 5.2). 
L. See Section 5.2.1.2 
M. Pregnancy test for women of childbearing potential (WOCBP) must be repeated within 24 hours prior to 
Cycle 1 Day 1. 
N. See Appendix B and C for detailed schedule. 
O. Study staff should review the patient medication diary each week. 
P. Current nicotine use status will be collected on C1D1. 
Q. Vital signs will have the following windows: +/- 5m for 60m post-dose and +/-10m for 120 and 180m post. 
R. Long term survival follow up: Follow up for progression and survival status will occur via medical record review 
or phone call and should occur every 6 months (+/- 2 weeks) for a total of 5 years from the off treatment date. 

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11. MEASUREMENT OF EFFECT 
 
Although the clinical benefit of oral triapine in combination with chemoradiation therapy has not 
yet been established, the intent of offering this treatment is to provide a possible therapeutic 
benefit, and thus the patient will be carefully monitored for tumor response and symptom relief in 
addition to safety and tolerability. Patients will be assessed by standard criteria.  For the purposes 
of this study, patients will undergo a clinical assessment every week while receiving 
chemotherapy and radiation therapy and at 1 month and 3 months post-treatment. Tumor response 
will be re-evaluated at the 3-month post-treatment 18F-FDG PET/CT scan (approximately 150 
days +/- 7 days following completion of all treatment). 
 
11.1 Antitumor Effect – Solid Tumors 
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) [Eur J Ca 45:228-247, 2009]. Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes 
are used in the RECIST criteria. 
 
11.1.1 Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their 
first treatment with triapine and cisplatin. 
 
Evaluable for objective response.  Only those patients, have received at least 3 cycles of 
therapy (cisplatin + triapine), and have had their disease re-evaluated (with a 3 month post 
treatment PET-CT) will be considered evaluable for response.  These patients will have 
their response classified according to the definitions stated below.  (Note:  Patients who 
exhibit objective disease progression prior to the end of cycle 1 will also be considered 
evaluable.) 
 
Evaluable Non-Target Disease Response.  Patients who have lesions present at baseline 
that are evaluable but do not meet the definitions of measurable disease, have received at 
least one cycle of therapy, and have had their disease re-evaluated will be considered 
evaluable for non-target disease.  The response assessment is based on the presence, 
absence, or unequivocal progression of the lesions. 
 
11.1.2 Disease Parameters 
 
Measurable disease. Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as ≥20 mm (≥2 cm) 
by chest x-ray or as ≥10 mm (≥1 cm) with CT scan, MRI, or calipers by clinical exam. 
All tumor measurements must be recorded in millimeters (or decimal fractions of 
centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area might or might not be 

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considered measurable.  If the investigator thinks it appropriate to include them, the 
conditions under which such lesions should be considered must be defined in the protocol. 
 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm (≥1.5 cm) in short axis when assessed by CT scan (CT scan 
slice thickness recommended to be no greater than 5 mm [0.5 cm]).  At baseline and in 
follow-up, only the short axis will be measured and followed. 
 
Non-measurable disease. All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm [<1 cm] or pathological lymph nodes with ≥10 to <15 mm [≥1 
to <1.5 cm] short axis), are considered non-measurable disease.  Bone lesions, 
leptomeningeal 
disease, 
ascites, 
pleural/pericardial 
effusions, 
lymphangitis 
cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by CT 
or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should 
not be considered as malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non- cystic 
lesions are present in the same patient, these are preferred for selection as target lesions. 
 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target lesions 
and recorded and measured at baseline.  Target lesions should be selected on the basis of 
their size (lesions with the longest diameter), be representative of all involved organs, but 
in addition should be those that lend themselves to reproducible repeated measurements.  
It may be the case that, on occasion, the largest lesion does not lend itself to reproducible 
measurement in which circumstance the next largest lesion which can be measured 
reproducibly should be selected.  A sum of the diameters (longest for non- nodal lesions, 
short axis for nodal lesions) for all target lesions will be calculated and reported as the 
baseline sum diameters.  If lymph nodes are to be included in the sum, then only the short 
axis is added into the sum.  The baseline sum diameters will be used as reference to further 
characterize any objective tumor regression in the measurable dimension of the disease. 
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable lesions 
over and above the 5 target lesions should be identified as non-target lesions and should 
also be recorded at baseline. Measurements of these lesions are not required, but the 
presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up. 
 
11.1.3 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the treatment. 

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The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 
 
Clinical lesions  Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm (≥1 cm) diameter 
as assessed using calipers (e.g., skin nodules). In the case of skin lesions, documentation 
by color photography, including a ruler to estimate the size of the lesion, is recommended. 
 
Chest x-ray Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung. However, CT is preferable. 
 
Conventional CT and MRI  This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm (0.5 cm) or less. If CT scans 
have slice thickness greater than 5 mm (0.5 cm), the minimum size for a measurable lesion 
should be twice the slice thickness.  MRI is also acceptable in certain situations (e.g. for 
body scans). 
 
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement. Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the technical 
specifications of the scanning sequences used should be optimized for the evaluation of the 
type and site of disease. Furthermore, as with CT, the modality used at follow-up should 
be the same as was used at baseline and the lesions should be measured/assessed on the 
same pulse sequence. It is beyond the scope of the RECIST guidelines to prescribe specific 
MRI pulse sequence parameters for all scanners, body parts, and diseases. Ideally, the 
same type of scanner should be used and the image acquisition protocol should be followed 
as closely as possible to prior scans.  Body scans should be performed with breath-hold 
scanning techniques, if possible. 
 
PET-CT  At present, the low dose or attenuation correction CT portion of a combined 
PET-CT is not always of optimal diagnostic CT quality for use with RECIST 
measurements.  However, if the site can document that the CT performed as part of a PET-
CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), then 
the CT portion of the PET-CT can be used for RECIST measurements and can be used 
interchangeably with conventional CT in accurately measuring cancer lesions over time.  
Note, however, that the PET portion of the CT introduces additional data which may bias 
an investigator if it is not routinely or serially performed. 
 
Ultrasound Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement.  Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later date and, because they are operator dependent, it 
cannot be guaranteed that the same technique and measurements will be taken from one 
assessment to the next. If new lesions are identified by ultrasound in the course of the 

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study, confirmation by CT or MRI is advised.  If there is concern about radiation exposure 
at CT, MRI may be used instead of CT in selected instances. 
 
Endoscopy, Laparoscopy  The utilization of these techniques for objective tumor 
evaluation is not advised. However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint. 
 
Tumor markers  Tumor markers alone cannot be used to assess response. If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered 
in complete clinical response.  Specific guidelines for both CA-125 response (in recurrent 
ovarian cancer) and PSA response (in recurrent prostate cancer) have been published [JNCI 
96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 
2008]. 
In addition, the Gynecologic Cancer Intergroup has developed CA-125 
progression criteria which are to be integrated with objective tumor assessment for use in 
first-line trials in ovarian cancer [JNCI 92:1534-1535, 2000]. 
 
Cytology, Histology  These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or 
stable disease is mandatory to differentiate between response or stable disease (an 
effusion may be a side effect of the treatment) and progressive disease. 
 
FDG-PET  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease). New lesions on the basis 
of FDG-PET imaging can be identified according to the following algorithm: 
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG- 
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If 
the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal FDG-
PET scan).  If the positive FDG-PET at follow-up corresponds to a pre-existing site of 
disease on CT that is not progressing on the basis of the anatomic images, this is not 
PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy 
in cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring.  The use of FDG-PET in this circumstance should be prospectively described 
in the protocol and supported by disease-specific medical literature for the indication. 
However, it must be acknowledged that both approaches may lead to false positive CR 
due to limitations of FDG-PET and biopsy resolution/sensitivity. 
 

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Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 
 
11.1.4 Response Criteria 
 
11.1.4.1 Evaluation of Target Lesions 
 
Complete Response (CR): Disappearance of all target lesions. Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to <10 
mm (<1 cm). 
 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on study (this includes the baseline 
sum if that is the smallest on study).  In addition to the relative increase of 20%, the 
sum must also demonstrate an absolute increase of at least 5 mm (0.5 cm). (Note: the 
appearance of one or more new lesions is also considered progressions). 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
 
11.1.4.2 Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and normalization 
of tumor marker level. All lymph nodes must be non-pathological in size (<10 mm [<1 
cm] short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response. 
 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
 
Progressive Disease (PD): Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions. Unequivocal progression 
should not normally trump target lesion status. It must be representative of overall 
disease status change, not a single lesion increase. 
Although a clear progression of “non-target” lesions only is exceptional, the opinion 
of the treating physician should prevail in such circumstances, and the progression 
status should be confirmed at a later time by the review panel (or Principal 

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Investigator). 
 
11.1.4.3 Evaluation of 18F-FDG PET CT Target: 
Complete Response (CR): A metabolic complete response on PET/CT will be defined 
as greater than -66% reduction in tumor FDG uptake at sites of abnormal tumor FDG 
uptake noted on pre-treatment FDG-PET study (considering normal cardiac or liver 
blood pool). 
  
Partial Response (PR): A metabolic partial response on PET/CT will be defined as -
25% to -66% reduction in tumor FDG uptake at sites of abnormal tumor FDG uptake 
noted on pre-treatment FDG-PET study (considering normal cardiac or liver blood 
pool).   
  
Progressive Disease (PD): Progressive metabolic disease on PET/CT is classified as an 
increase in tumor FDG uptake greater than +25% within the tumor region defined on 
baseline scan (considering normal cardiac or liver blood pool), or appearance of new 
FDG uptake in new metastatic lesions. 
  
Stable Disease (SD): Stable metabolic response will be defined as a change in tumor 
FDG uptake by less than +25% (increase) or by less than -25% (decrease) at sites of 
abnormal tumor FDG uptake (considering normal cardiac or liver blood pool) when 
compared to pre-treatment FDG-PET study. 
 
Patients with a global deterioration of health status requiring discontinuation of 
treatment or die without objective evidence of disease progression at that time should 
be reported to be off study treatment due to “symptomatic deterioration.”  Every effort 
should be made to document the objective progression even after discontinuation of 
treatment. 
 
11.1.4.3.1 Duration of Response 
Duration of overall response:  The duration of overall response is measured from the 
time measurement criteria are met for CR or PR (whichever is first recorded) until the 
first date that recurrent or progressive disease is objectively documented (taking as 
reference for progressive disease the smallest measurements recorded since the 
treatment started). The duration of overall CR is measured from the time measurement 
criteria are first met for CR until the first date that progressive disease is objectively 
documented. 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements. 
 
11.1.4.4 Evaluation of Overall Response 
 
The overall response is the response recorded from the start of the treatment until the 
3-month post-treatment PET-CT. 

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For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target Lesions 
New Lesions* 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-PD/not 
evaluated 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
*See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**In exceptional circumstances, unequivocal progression in non-target lesions may be accepted 
as disease progression. 
Note:  Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.”  Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised 
 
 
 

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12. DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 
12.1 Study Oversight 
 
This protocol is monitored at several levels, as described in this section.  The Protocol Principal 
Investigator is responsible for monitoring the conduct and progress of the clinical trial, including the 
ongoing review of accrual, patient-specific clinical and laboratory data, and routine and serious adverse 
events; reporting of expedited adverse events; and accumulation of reported adverse events from other 
trials testing the same drug(s).  The Protocol Principal Investigator and statistician have access to the 
data at all times through the CTMS web-based reporting portal.   
 
For the Phase 1 portion of this study, all decisions regarding dose escalation/expansion/de-escalation 
require sign-off by the Protocol Principal Investigator through the CTMS/IWRS.  In addition, for the 
Phase 1 portion, the Protocol Principal Investigator will have at least monthly, or more frequently, 
conference calls with the Study Investigators and the CTEP Medical Officer(s) to review accrual, 
progress, and adverse events and unanticipated problems.  
 
All Study Investigators at participating sites who register/enroll patients on a given protocol are 
responsible for timely submission of data via Medidata Rave and timely reporting of adverse events for 
that particular study.  This includes timely review of data collected on the electronic CRFs submitted 
via Medidata Rave. 
 
All studies are also reviewed in accordance with the enrolling institution’s data safety monitoring plan. 
 
12.2 Data Reporting 
 
Medidata Rave is a clinical data management system being used for data collection for this 
trial/study.  Access to the trial in Rave is controlled through the CTEP-IAM system and role 
assignments.   
Requirements to access Rave via iMedidata: 
 
• 
A valid account, and  
• 
Assigned a Rave role on the LPO or PO roster at the enrolling site of:  Rave CRA, Rave 
Read Only, Rave CRA (LabAdmin), Rave SLA, or Rave Investigator.   
Rave role requirements: 
 
o Rave CRA or Rave CRA (Lab Admin) role, must have a minimum of an Associate 
Plus (AP) registration type, 
o Rave Investigator role, must be registered as an Non-Physician Investigator 
(NPIVR) or Investigator (IVR), and 

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o Rave Read Only role, site staff must have at a minimum an Associates (A) 
registration type. 
• 
Refer to https://ctep.cancer.gov/investigatorResources/default.htm for registration types 
and documentation required. 
 
Upon initial site registration approval for the study in Regulatory Support System (RSS), all 
persons with Rave roles assigned on the appropriate roster will be sent a study invitation email 
from iMedidata.  To accept the invitation, site staff must either click on the link in the email or log 
in to iMedidata via the CTSU members’ website  under Data Management > Rave Home and click 
to accept the invitation in the Tasks pane located in the upper right-corner of the iMedidata 
screen.  Site staff will not be able to access the study in Rave until all required Medidata and study 
specific trainings are completed.  Trainings will be in the form of electronic learnings (eLearnings) 
and can be accessed by clicking on the eLearning link in the Tasks pane located in the upper right 
corner of the iMedidata screen.  If an eLearning is required for a study and has not yet been taken, 
the link to the eLearning will appear under the study name in the Studies pane located in the center 
of the iMedidata screen; once the successful completion of the eLearning has been recorded, 
access to the study in Rave will be granted, and a Rave EDC link will replace the eLearning link 
under the study name.  
 
Site staff that have not previously activated their iMedidata/Rave account at the time of initial site 
registration approval for the study in RSS will receive a separate invitation from iMedidata to 
activate their account.  Account activation instructions are located on the CTSU website in the 
Data Management section under the Rave resource materials (Medidata Account Activation and 
Study Invitation Acceptance).  Additional information on iMedidata/Rave is available on the 
CTSU members’ website in the Data Management > Rave section at www.ctsu.org/RAVE/ or by 
contacting the CTSU Help Desk at 1-888-823-5923 or by e-mail at ctsucontact@westat.com.   
  
 
12.2.1 Method 
 
This study will be monitored by the Clinical Trials Monitoring Service (CTMS).  Data will 
be submitted to CTMS at least once every two weeks via Medidata Rave (or other modality 
if approved by CTEP).  Information on CTMS reporting is available at 
http://www.theradex.com/clinicalTechnologies/?National-Cancer-Institute-NCI-11.  On-
site audits will be conducted three times annually (one annual site visit and two data 
audits). For CTMS monitored studies, after users have activated their accounts, please 
contact the Theradex Help Desk at  (609) 619-7862 or by 
email at 
CTMSSupport@theradex.com for additional support with Rave and completion of CRFs. 
 
 
12.2.2 Responsibility for Data Submission 
 
For ETCTN trials, it is the responsibility of the PI(s) at the site to ensure that all 
investigators at the ETCTN Sites understand the procedures for data submission for each 
ETCTN protocol and that protocol specified data are submitted accurately and in a timely 

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manner to the CTMS via the electronic data capture system, Medidata Rave. 
 
Data are to be submitted via Medidata Rave to CTMS on a real-time basis, but no less than 
once every 2 weeks. The timeliness of data submissions and timeliness in resolving data 
queries will be tracked by CTMS.  Metrics for timeliness will be followed and assessed on 
a quarterly basis.  For the purpose of Institutional Performance Monitoring, data will be 
considered delinquent if it is greater than 4 weeks past due. 
 
Data from Medidata Rave and CTEP-AERS is reviewed by the CTMS on an ongoing basis 
as data is received.  Queries will be issued by CTMS directly within Rave. The queries 
will appear on the Task Summary Tab within Rave for the CRA at the ETCTN to resolve. 
Monthly web-based reports are posted for review by the Drug Monitors in the IDB, CTEP.  
Onsite audits will be conducted by the CTMS to ensure compliance with regulatory 
requirements, GCP, and NCI policies and procedures with the overarching goal of 
ensuring the integrity of data generated from NCI-sponsored clinical trials, as described 
in the ETCTN Program Guidelines, which may be found on the CTEP 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm 
)  and CTSU websites. 
 
CTMS will utilize a core set of eCRFs that are Cancer Data Standards Registry and 
Repository 
(caDSR) compliant (http://cbiit.nci.nih.gov/ncip/biomedical-informatics-  
resources/interoperability-and-semantics/metadata-and-models).  Customized eCRFs will 
be included when appropriate to meet unique study requirements.  The PI is encouraged 
to review the eCRFs, working closely with CTMS to ensure prospectively that all required 
items are appropriately captured in the eCRFs prior to study activation.  CTMS will 
prepare the eCRFs with built-in edit checks to the extent possible to promote data integrity. 
 
CDUS data submissions for ETCTN trials activated after March 1, 2014, will be carried 
out by the CTMS contractor, Theradex.  CDUS submissions are performed by Theradex 
on a monthly basis.  The trial’s lead institution is responsible for timely submission to 
CTMS via Rave, as above. 
 
Further information on data submission procedures can be found in the ETCTN Program 
Guidelines (http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_   
events.htm). 
 
 
12.3 CTEP Multicenter Guidelines 
N/A 
 
12.4 Collaborative Agreements Language 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI under 
a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical Company(ies) 
(hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer Treatment and 
Diagnosis.  Therefore, the following obligations/guidelines, in addition to the provisions in the 
“Intellectual 
Property 
Option 
to 
Collaborator” 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 

NCI Protocol #:  9892 
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terms of award, apply to the use of the Agent(s) in this study: 
 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can Agent(s) 
be transferred or licensed to any party not participating in the clinical study. Collaborator(s) 
data for Agent(s) are confidential and proprietary to Collaborator(s) and shall be maintained 
as such by the investigators.  The protocol documents for studies utilizing Agents contain 
confidential information and should not be shared or distributed without the permission of the 
NCI.  If a copy of this protocol is requested by a patient or patient’s family member 
participating on the study, the individual should sign a confidentiality agreement. A suitable 
model agreement can be downloaded from: http://ctep.cancer.gov. 
 
2. For a clinical protocol where there is an investigational Agent used in combination with 
(an)other Agent(s), each the subject of different Collaborative Agreements, the access to and 
use of data by each Collaborator shall be as follows (data pertaining to such combination use 
shall hereinafter be referred to as "Multi-Party Data”): 
 
a. NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NCI, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol. 
 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial 
by any other Collaborator solely to the extent necessary to allow said other Collaborator 
to develop, obtain regulatory approval or commercialize its own Agent. 
 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-Party 
Data solely for development, regulatory approval, and commercialization of its own 
Agent. 
 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available to Collaborator(s), the NCI, and the FDA, as appropriate and unless 
additional disclosure is required by law or court order as described in the IP Option to 
Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm). 
Additionally, all Clinical Data and Results and Raw Data will be collected, used and 
disclosed consistent with all applicable federal statutes and regulations for the protection of 
human subjects, including, if applicable, the Standards for Privacy of Individually 
Identifiable Health Information set forth in 45 C.F.R. Part 164. 
 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the 
NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group 
studies, or PI for other studies) of Collaborator's wish to contact them. 
 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a 
DMC for this clinical trial. 
 

NCI Protocol #:  9892 
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6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the 
Group office for Cooperative Group studies or by the principal investigator for non- 
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review and 
comment prior to submission for publication. Collaborator(s) will have 30 days from the date 
of receipt for review.  Collaborator shall have the right to request that publication be delayed 
for up to an additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to Collaborator(s)’s intellectual property rights, are protected. 
Copies of abstracts must be provided to CTEP for forwarding to Collaborator(s) for courtesy 
review as soon as possible and preferably at least three (3) days prior to submission, but in any 
case, prior to presentation at the meeting or publication in the proceedings.  Press releases and 
other media presentations must also be forwarded to CTEP prior to release. Copies of any 
manuscript, abstract and/or press release/ media presentation should be sent to: 
 
Email:  ncicteppubs@mail.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 
 
 
 
13. STATISTICAL CONSIDERATIONS 
 
13.1 Study Design/Endpoints 
 
The primary safety endpoint of this study is DLT, and the first primary objective is the 
determination of the MTD and recommended phase II dose for oral triapine when used 
concomitantly with cisplatin chemoradiation. 
 
The primary PK endpoint of this study is oral bioavailability of triapine, which will be 
determined with sufficient precision that the 95% CI of the mean population bioavailability falls 
within 80-125% of that mean. Based on reported preliminary data and assuming a normal 
distribution at log base 10 level, a true bioavailability rate of 0.67, and a standard deviation of 
0.175 at log base 10 level, with 28 patients on RP2D, we will be able to establish the bioavailability 
with the 95% confidence interval of the population mean falling within 0.53-0.83. 
 
Other PK parameter, including AUC, Cmax, Tmax and T1/2 will be evaluated in the expansion cohort. 
Descriptive statistics will be used.  
 
The secondary efficacy endpoints include metabolic complete response (mCR) by FDG-PET/CT, 
clinical overall response (OR), overall survival (OS) and progression free survival (PFS). 
 
For the first dose level, 3 patients were enrolled without issues. Given the scarcity of patients and 
the thus far favorable toxicity profile, dose level 2 will be enrolled per an accelerated titration 
approach using a single patient cohort.  Dose escalation will revert to the standard 3+3 design if the 

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patient on dose level 2 experiences a DLT or a ≥ grade 2 toxicity or when dose level 3 is reached. 
The standard 3+3 design is as follows:  Escalation at 0/3 DLTs, dose-reduction if >1/3 DLT, and 
expansion to 6 if 1/3 DLTs. DLT is defined as the severe toxicity event that leads to the termination 
of the treatment as defined in section 5.5. The highest dose level where <2/6 DLTs are observed 
will be declared MTD. 
13.1.1 The RP2D will be determined as described in section 5.1.2. Once the RP2D is determined, 
two expansion cohorts will be enrolled. Subjects will be enrolled into a non-HIV+ cohort (n=12) 
to further expand pharmacokinetic investigations and provide additional safety information.  
Additionally, u p  t o  28 HIV+ cervical cancer patients (including the patients who were treated 
at the R P 2 D  during the dose escalation stage) will be treated on RP2D to determine whether 
active HIV antiretroviral therapy impacts the antitumor activity of triapine. A Bayesian 
continuous m o n i t o r i n g  will be used to ensure that the true DLT rate is controlled at 20%. 
To establish the stopping r u l e ,  a week prior distribution of DLT rate is set to be 
beta (=1, =5). If the posterior probability t h a t  the true underlying DLT rate exceeds 20% at 
RP2D is 70% or higher then the study a c cr u al  w i l l  be suspended and the toxicity data will 
be examined by the PI and the research team, who will subsequently decide on whether the 
trial should be terminated or not. 
 
The enrollment suspension rule using the Bayesian analysis mentioned above can be represented 
as a table of possible outcomes for DLTs, as shown below. 
Bayesian rule for suspending enrollment 
Suspend accrual if n patients experience a 
DLT 
in N patients treated 
2 
3-4 
3 
5-8 
4 
9-13 
5 
14-17 
6 
18-22 
7 
23-26 
8 
27 
 
 
The operating characteristics of this study design can be expressed in terms of probability of early 
suspending the enrollment at RD2P under the assumptions of various the true rates of DLT. The 
following table calculated these probabilities for a single dose level based on the simulation of 
10,000 hypothetical trials. 
 
 
Frequentist properties of Bayesian rule for suspending enrollment 
Probability of DLT 
Probability of suspending 
Median sample size for 

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the enrollment 
each dose level 
0.1 
0.10 
28 
0.17 
0.32 
28 
0.2 
0.45 
28 
0.25 
0.66 
13 
0.3 
0.83 
8 
 
 
 
13.2 Sample Size/Accrual Rate 
 
13.2.1 The number patients accrued to the study will depend on the MTD; an additional 12 cervical 
cancer patients may be treated at the RP2D to further define the spectrum of toxicities associated 
with the regimen and up to an additional 28 HIV+ patients will be enrolled to explore whether 
active (HIV) antiretroviral therapy impacts the antitumor activity of triapine .  Although unlikely 
to happen, for the worst-case scenario, we could have needed 6x6 =36 patients for the phase 
dose escalation portion of the protocol, 12 for the non-HIV+ expansion cohort and none of the 
6 patients on the MTD (or RP2D) is HIV+ cervical cancer patient. Thus, the maximum number 
of patients for this trial is 36+12+28=76. Patients who do not complete at least 80% the first 
cycle of therapy and do not suffer a DLT which leads to the termination of the treatment during 
the observation period (5 weeks excluding treatment delay period) will not be evaluable and will 
be replaced. Review of patient toxicity and DLT monitoring will be conducted on a weekly basis 
by the PI and Phase I clinical team. 
 
We expect that the accrual rate will be approximately 1 per 5 weeks. The follow-up period of the 
primary endpoint, DLT, is approximately 5 weeks after the starting of the treatment (excluding 
the treatment delay time as described in section 5.5). During the 3+3 dose escalation stage, we 
will allow the first 2 patients to be enrolled without stopping. During the expansion cohort, the 
patients will be accrued continuously. On the other hand, the treatment may be delayed during 
the DLT follow up period as described in section 5.5. Therefore, for a portion of the patients, the 
overall follow up time may be longer than 5 weeks. Thus, the accrual rate of 1 per 5 weeks is an 
estimate considering the facts stated above. 
 
PLANNED ENROLLMENT REPORT 
 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
Female 
Female 
American Indian/ Alaska 
Native 
0 
0 
0 
Ethnic Categories 

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Asian 
1 
0 
1 
Native Hawaiian or 
Other Pacific Islander 
0 
0 
0 
Black or African 
American 
3 
0 
3 
White 
72 
0 
72 
More Than One Race 
0 
0 
0 
Total 
76 
0 
76 
PHS 398 / PHS 2590 (Rev. 08/12 Approved Through 8/31/2015) 
OMB No. 0925-0001/0002 
 
 
 
13.3 Data Analysis 
 
13.3.1 Analysis Sets 
 
 
Evaluable patients: patients who meet all of the protocol inclusion/exclusion criteria 
and begin treatment with the protocol regimen. 
 
 
Evaluable patients for DLT: evaluable patients who received at least 80% of the 
treatment intended during the DLT follow up period as defined in section 5.5 and patients who 
received any amount of treatment and experienced a protocol defined DLT which leads to the 
termination of the treatment are evaluable for DLT. 
 
Safety set: data from all evaluable patients who receive initial treatment of the study 
treatment will be used in the analysis of safety. 
 
Efficacy set: data from all evaluable patients who receive initial treatment of the 
study treatment will be used in the analysis of efficacy endpoints. 
 
PK and correlative biomarker set: the data from all study-eligible patients (i.e. those 
meeting all of the protocol inclusion/exclusion criteria) who begin the study treatment and have 
adequate blood and tissue samples taken will be used in the analyses to address the PK and 
correlative biomarker aims. 
 
13.3.2 Analysis of baseline demographic variables 
Baseline descriptive statistics on all evaluable patients will be provided for demographic variables 

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(age, BMI, race/ethnicity), ECOG performance status, disease stage and status at the time of 
enrollment (stable disease, progressive disease), and treatment regimens previously used. 
 
13.3.3 Analysis of Safety Endpoints 
 
The NCI common terminology criteria for adverse events (CTCAE 5.0) will be used to evaluate 
toxicity; we will consider a toxicity to be an adverse event that is possibly, probably or definitely 
related to treatment. The rate of DLT at RP2D will be calculated and the exact 95% CI will be 
provided. The maximum grade of toxicity for each category of interest will be recorded for each 
patient and the summary results will be tabulated by category and grade. We will describe all 
DLTs and other serious (≥ Grade 3) adverse events on a patient-by-patient basis; descriptions will 
include dose level and any relevant baseline data. Statistics on the number of cycles received by 
patients and any dose reductions will also be tabulated. 
 
13.3.4 Analysis of Efficacy Endpoints 
We will determine the post-therapy, 3-month 18F-FDG-PET/CT metabolic complete response rate 
of oral triapine in combination with cisplatin chemoradiation. The mCR rate and the ORR at RP2D 
will be calculated with corresponding 95% exact confidence interval (CI). The IV triapine version 
of this regimen has demonstrated a high response rate of >90% in patients with stage IB2, II, IIIA, 
IIIB, and IVA cervical carcinoma 6, 7. Thus, we could consider the oral treatment not worthy of 
further study if the response rate is <70%.  Assuming an inferior margin of 5%, we will conclude 
that the mCR rate for the study regimen is non-inferior to 70% in this population if we observe at 
least 23 mCR events in the 28 patients. This is based on a non-inferiority test with type I error of 
5%.  OS and PFS will be analyzed using the Kaplan-Meier’s method. Median survival time will 
be reported with corresponding 95% CIs. 
The proportion of patients experiencing mCR and experiencing objective response will be 
estimated in both the HIV+ and non-HIV+ cohorts, along with exact 95% binomial confidence 
intervals.  This is an exploratory objective and the trial is not powered for formal statistical tests 
comparing the cohorts.  
 
13.3.5 Analysis of PK Data  
The oral bioavailability of triapine will be determined with sufficient precision that the 95% CI of 
the mean population bioavailability falls within 80-125% of that mean. Based on reported 
preliminary data and assuming a normal distribution at log base 10 level, a true bioavailability rate 
of 0.67, and a standard deviation of 0.175 at log base 10 level, with 28 patients on RP2D, we will 
be able to establish the bioavailability with the 95% confidence interval of the population mean 
falling within 0.53-0.83. 
 
Standard PK parameters will be determined and will include Cmax, Tmax, Cl, Vss, and half-life. 
These parameters will be descriptively reported. 
The association of methemoglobin proportion (%) and  PK parameters  will be evaluated by 
Spearman correlation coefficients. 

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REFERENCES 
 
Please provide the citations for all publications referenced in the text. 
1. 
Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA: a cancer journal for 
clinicians 2014; 64(1): 9-29. 
2. 
Wang N, Guan QL, Wang K, et al. Radiochemotherapy versus radiotherapy in locally 
advanced cervical cancer: a meta-analysis. Archives of gynecology and obstetrics 2011; 283(1): 
103-8. 
3. 
Delgado G, Bundy B, Zaino R, Sevin BU, Creasman WT, Major F. Prospective 
surgical-pathological study of disease-free interval in patients with stage IB squamous cell 
carcinoma of the cervix: a Gynecologic Oncology Group study. Gynecologic oncology 1990; 
38(3): 352-7. 
4. 
Kunos CA. Therapeutic Mechanisms of Treatment in Cervical and Vaginal Cancer. 
Oncology & hematology review 2012; 8(1): 55-60. 
5. 
Kunos CA, Radivoyevitch T, Kresak A, et al. Elevated ribonucleotide reductase 
levels associate with suppressed radiochemotherapy response in human cervical cancers. 
International journal of gynecological cancer : official journal of the International 
Gynecological Cancer Society 2012; 22(9): 1463-9. 
6. 
Kunos CA, Radivoyevitch T, Waggoner S, et al. Radiochemotherapy plus 3- 
aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, NSC #663249) in advanced-stage 
cervical and vaginal cancers. Gynecologic oncology 2013; 130(1): 75-80. 
7. 
Kunos CA, Waggoner S, von Gruenigen V, et al. Phase I Trial of Pelvic Radiation, 
Weekly Cisplatin, and 3-Aminopyridine-2-Carboxaldehyde Thiosemicarbazone (3-AP, NSC # 
663249) for Locally Advanced Cervical Cancer. Clin Cancer Res 2010; 16(4): 1298-306. 
8. 
Kunos CA, Waggoner S, von Gruenigen V, et al. Phase I trial of pelvic radiation, 
weekly cisplatin, and 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, NSC 
#663249) for locally advanced cervical cancer. Clinical cancer research : an official journal of 
the American Association for Cancer Research 2010; 16(4): 1298-306. 
9. 
Hreshchyshyn MM. Gynecologic Oncology Group Reports I and II. Gynecologic 
oncology 1975; 3(3): 251-7. 
10. 
Kunos CA, Chiu SM, Pink J, Kinsella TJ. Modulating radiation resistance by 
inhibiting ribonucleotide reductase in cancers with virally or mutationally silenced p53 protein. 
Radiat Res 2009; 172(6): 666-76. 
11. 
Kunos CA, Radivoyevitch T, Pink J, et al. Ribonucleotide reductase inhibition 
enhances chemoradiosensitivity of human cervical cancers. Radiat Res 2010; 174(5): 574-81. 
12. 
Chao J, Synold TW, Morgan RJ, Jr., et al. A phase I and pharmacokinetic study 
of oral 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, NSC #663249) in the 
treatment of advanced-stage solid cancers: a California Cancer Consortium Study. Cancer 
chemotherapy and pharmacology 2012; 69(3): 835-43. 
13. 
Schwarz JK, Siegel BA, Dehdashti F, Grigsby PW. Metabolic response on post- 
therapy FDG-PET predicts patterns of failure after radiotherapy for cervical cancer. International 
journal of radiation oncology, biology, physics 2012; 83(1): 185-90. 
14. 
Beriwal S, Kannan N, Sukumvanich P, et al. Complete metabolic response after 
definitive radiation therapy for cervical cancer: patterns and factors predicting for recurrence. 
Gynecologic oncology 2012; 127(2): 303-6. 
15. 
Schwarz JK, Lin LL, Siegel BA, Miller TR, Grigsby PW. 18-F-fluorodeoxyglucose- 

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Page 79 of 84 
 
positron emission tomography evaluation of early metabolic response during radiation therapy 
for cervical cancer. International journal of radiation oncology, biology, physics 2008; 72(5): 
1502-7. 
16. 
Cheung YK, Chappell R. Sequential designs for phase I clinical trials with late-onset 
toxicities. Biometrics 2000; 56(4): 1177-82. 
17. 
Normolle D, Lawrence T. Designing dose-escalation trials with late-onset toxicities 
using the time-to-event continual reassessment method. Journal of clinical oncology : official 
journal of the American Society of Clinical Oncology 2006; 24(27): 4426-33. 
18. 
Bakkenist CJ, Czambel RK, Clump DA, Greenberger JS, Beumer JH, Schmitz JC. 
Radiation therapy induces the DNA damage response in peripheral blood. Oncotarget 2013. 
19. 
Kunos CA, Winter K, Dicker AP, et al. Ribonucleotide reductase expression in 
cervical cancer: a radiation therapy oncology group translational science analysis. International 
journal of gynecological cancer : official journal of the International Gynecological Cancer 
Society 2013; 23(4): 615-21. 

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APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
 
ECOG Performance Status Scale 
Grade 
Descriptions 
0 
Normal activity.  Fully active, able to carry on all pre-disease performance 
without restriction. 
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). 
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. 
3 
In bed >50% of the time.  Capable of only limited self-care, confined to bed or 
chair more than 50% of waking hours. 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care. Totally 
confined to bed or chair. 
5 
Dead. 
 
 
 

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APPENDIX B 
PHARMACOKINETIC SHEET DAY 1-2 
 
 
 
Study Sample Collection Log
Date:
BSA:
(m2)
Pharmacokinetic (PK) Sample Collection
Protocol Sample and Time 
Point
Projected Sample Due 
Time
(24 hr clock)
Actual Time
(24 hr clock)
Day 1
pre sample
TRI infusion start
30 min post TRI start
60 min post TRI start
90 min post TRI start
110 min post TRI start
(~10 min prior to EOI)
TRI infusion end
30 min post end TRI
1 h post end TRI
2 h post end TRI
4 h post end TRI
6 h post end TRI
Day 2
~24 h post start TRI infusion
=pre PO dose (D2 AM)
TRI PO dose time
(D2 AM)
Triapine (TRI) oral (PO) dose                  TRI Dose (mg) _____________
Also obtain Methemoglobin sample, 
(See 9.3.2) (2cc)
NCI 9892 (Triapine (TRI) in Plasma): Phase I of Oral Triapine with Concurrent Chemoradiation for Locally Advanced Cervical Cancer (LACC) and Vaginal Cancer
Subject Initials:
(First_Middle_Last)  
Subject ID:  
Site Name:
At each time point, ~4 mL of peripheral blood will be collected in a purple-topped (EDTA), mix by inversion, and place sample immediately on ice after collection; samples 
must be processed within 30 minutes. After sample processing, store plasma samples at -70°C or below until shipment. See Section 9 of the protocol for more specific 
processing instructions and shipping instructions. At the time of sample transfer, the dosing information must be transferred also  (through this completed form).
Note the start and stop times of infusions and dose times in this form. Whenever the timing of drawing samples is dependent on the recent start or end of an infusion, a green 
arrow indicates which time-point starts the clock on subsequent blood draws.
Comments
Also obtain Methemoglobin sample, 
(See 9.3.2) (2cc)
Triapine (TRI)
Triapine (TRI) infusion (nominal 2 h)  TRI Dose (mg): ___50 _______________  
Also obtain Methemoglobin sample, 
(See 9.3.2) (2cc)

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APPENDIX C 
PHARMACOKINETIC SHEET DAY 8-9 
 
 
 
 
Study Sample Collection Log
Date:
BSA:
(m2)
Pharmacokinetic (PK) Sample Collection
Protocol Sample and Time 
Point
Projected Sample Due 
Time
(24 hr clock)
Actual Time
(24 hr clock)
Day 8
pre sample
TRI PO dose time
(D8 AM)
30 min post TRI
60 min post TRI
90 min post TRI
110 min post TRI
2 h 30 min post TRI
3 h post TRI
4 h post TRI
6 h post TRI
8 h post TRI
Day 9
~24 h post D8 dose
=pre PO dose (D9 AM)
TRI PO dose time
(D9 AM)
NCI 9892 (Triapine (TRI) in Plasma): Phase I of Oral Triapine with Concurrent Chemoradiation for Locally Advanced Cervical Cancer (LACC) and Vaginal Cancer
Subject Initials:
(First_Middle_Last)  
Subject ID:  
Site Name:
At each time point, ~4 mL of peripheral blood will be collected in a purple-topped (EDTA), mix by inversion, and place sample immediately on ice after collection; samples 
must be processed within 30 minutes. After sample processing, store plasma samples at -70°C or below until shipment. See Section 9 of the protocol for more specific 
processing instructions and shipping instructions. At the time of sample transfer, the dosing information must be transferred also  (through this completed form).
Note the start and stop times of infusions in this form. Whenever the timing of drawing samples is dependent on the recent start or end of an infusion, a green arrow indicates 
which time-point starts the clock on subsequent blood draws.
Triapine (TRI)
Comments
Triapine (TRI) oral (PO) dose               TRI Dose (mg): __________________  
Also obtain Methemoglobin sample, 
(See 9.3.2) (2cc)
Also obtain Methemoglobin sample, 
(See 9.3.2) (2cc)
Triapine (TRI) oral (PO) dose                  TRI Dose (mg) _____________
Also obtain Methemoglobin sample, 
(See 9.3.2) (2cc)

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APPENDIX D PATIENT MEDICATION DIARY – TRIAPINE 
 
 
 
Today’s Date: ________________________ 
Agent: __Triapine______________________ 
Patient’s name:________________________ 
Patient Study ID:_______________________ 
 
Instructions to the patient: 
1.) You will take ___ capsules on each of the indicated days. 
2.) You should take within 90 minutes after completion of pelvic radiation therapy. 
3.) Take on an empty stomach (except water).  No food for 2hours prior to dosing, 
and for 1 hour after ingesting the oral dose. 
4.) Triapine will not be administered on days that radiation is not given, or on the 
days that radiation is missed or held. 
5.) Record the date, the number of capsules you took, and when you took them. 
6.) If you have any comments or notice any side effects, please record them in the 
comments column. 
7.) Please return the form to the study team at the Week 6 visit. 
 
Day 
Date 
Time 
# of 
capsules 
taken 
Comments 
Week 1 
1 
IV Triapine in clinic 
 
2 
 
 
 
 
3 
 
 
 
 
4 
 
 
 
 
5 
 
 
 
 
6 
 
 
7 
 
Week 2 
8 
 
 
 
 
9 
 
 
 
 
10 
 
 
 
 
11 
 
 
 
 
12 
 
 
 
 
13 
 
 
14 
 
Week 3 
15 
 
 
 
 
16 
 
 
 
 
17 
 
 
 
 
18 
 
 
 
 
19 
 
 
 
 
20 
 
 
21 
 
CTEP-assigned Protocol# 9892 
 
Local Protocol # ______________ 

NCI Protocol #:  9892 
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Day 
Date 
Time 
# of 
capsules 
taken 
Comments 
Week 4 
22 
 
 
 
 
23 
 
 
 
 
24 
 
 
 
 
25 
 
 
 
 
26 
 
 
 
 
27 
 
 
28 
 
Week 5 
29 
 
 
 
 
30 
 
 
 
 
31 
 
 
 
 
32 
 
 
 
 
33 
 
 
 
 
34 
 
 
35 
 
Physician’s office will complete this section: 
1.) Date patient started protocol treatment:________________________ 
2.) Date patient was removed from study:_________________________ 
3.) Patient’s planned total daily dose: ____________________________ 
4.) Total number of pills taken: __________________________________ 
 
Physician/Nurse/Data Manager’s 
signature:__________________________________________ 
 
 
 
Patient’s signature: 
__________________________________________________________________