Clinical trial NCT02369458
Conditions: Squamous Cell Carcinoma of the Head and Neck Squamous Cell Carcinoma, Head and Neck
Sponsor: Washington University School of Medicine
Start date: 2015-04-14; Completion date: 2024-11-01
Enrollment: 48 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
No agent is known to have efficacy in patients with incurable HNSCC that progressed with prior platin, 5-FU, cetuximab and taxane. Herein lies the unmet need to be addressed by this trial. Based on the preclinical and clinical data presented, the investigators propose that mitomycin C will have anti-tumor activity in these patients.

Detailed description:

Arms: arm 1: * Mitomycin C given on Day 1 every 5 weeks (each cycle is 5 weeks).
* Pegfilgrastim will be given on Day 2 of each cycle (subcutaneous injection) arm 2: * Mitomycin C given on Day 1 every 5 weeks (each cycle is 5 weeks).
* Pegfilgrastim will be given on Day 2 of each cycle (subcutaneous injection)
Interventions: intervention 1: Mitomycin-C intervention 2: Pegfilgrastim
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_001.pdf: 
 
 
 
 
Phase II Trial of Mitomycin C in Patients with Incurable p16 Positive Oropharyngeal and 
p16 Negative Head and Neck Squamous Cell Carcinoma (HNSCC) Resistant to Standard 
Therapies 
 
Washington University School of Medicine 
Division of Oncology 
660 South Euclid Avenue, Campus Box 8056 
St. Louis, MO  63110 
 
Protocol #: 201503060 
Version Date: 03/09/2023 
 
Principal Investigator: 
Peter Oppelt, M.D. 
Phone:  (636) 916-9922 
E-mail: poppelt@wustl.edu 
 
Sub-Investigators 
 
 
Modality 
 
Fei Wan, PhD  
 
 
Biostatistics 
Douglas Adkins, M.D. 
 
Medical Oncology 
 
 
Study Drugs:  
Mitomycin C 
 
IND#:  
 
125811 EXEMPT 
clinicaltrials.gov #: NCT02369458 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL 
The information contained in this document is regarded as confidential and, except to the extent necessary to 
obtain informed consent, may not be disclosed to another party unless law or regulations require such 
disclosure.  Persons to whom the information is disclosed must be informed that the information is 
confidential and may not be further disclosed by them 
 
 


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Phase II Trial of Mitomycin C in Patients with Incurable p16 Positive Oropharyngeal and 
p16 Negative Head and Neck Squamous Cell Carcinoma (HNSCC) Resistant to Standard 
Therapies 
 
Protocol Revision History 
 
Initial Approval Version 
 
 
 
 
 
 
02/04/2015 
Amendment #1 Version 
 
 
 
 
 
 
05/06/2015 
Amendment #2 Version 
 
 
 
 
 
 
05/29/2015 
Amendment # 3 Version 
 
 
 
 
 
 
11/11/2015 
Amendment #4 Version 
 
 
 
 
 
 
03/22/2017 
Amendment #5 Version (PRMC only) 
 
 
 
 
11/08/2017 
Amendment #5 Version 
 
 
 
 
 
 
11/10/2017 
Amendment #6 Version 
 
 
 
 
 
 
01/15/2020 
Amendment #7 Version 
 
 
 
 
 
 
10/28/2020 
Amendment #8 Version 
 
 
 
 
 
 
03/09/2023 


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Phase II Trial of Mitomycin C in Patients with Incurable p16 Positive Oropharyngeal and 
p16 Negative Head and Neck Squamous Cell Carcinoma (HNSCC) Resistant to Standard 
Therapies 
 
 
SCHEMA 
 
 
 
 
Baseline Evaluation: 
Stratify for p16+ 
OPSCC and p16-
HNSCC
Mitomycin C q5 weeks
(scans after every 2 
cycles)
Treatment until progression


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Glossary of Abbreviations 
 
AE 
Adverse event 
ALT (SGPT) 
Alanine transaminase (serum glutamate pyruvic transaminase) 
ANC 
Absolute neutrophil count 
AST (SGOT) 
Aspartate transaminase (serum glutamic oxaloacetic transaminase) 
B-HCG 
Beta human chorionic gonadotropin  
CBC 
Complete blood count 
CR 
Complete response 
CrCl 
Creatinine clearance 
CRF 
Case report form 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
DNA 
deoxyribonucleic acid 
DSM 
Data and Safety Monitoring  
ECOG 
Eastern Cooperative Oncology Group 
EORTC 
European Organization for Research and Treatment of Cancer 
FDA 
Food and Drug Administration 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
HNSCC 
Head and neck squamous cell carcinoma 
HPV 
Human papillomavirus 
HRPO 
Human Research Protection Office (IRB) 
IHC 
Immunohistochemistry 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IULN 
Institutional upper limit of normal 
IV 
Intravenous (i.v.) 
MRI 
Magnetic resonance imaging 
NCI 
National Cancer Institute 
NIH 
National Institutes of Health 
OHRP 
Office of Human Research Protections  
OPSCC 
Oropharyngeal squamous cell carcinoma 
OS 
Overall survival 
PD 
Progressive disease 
PET 
Positron emission tomography 
PFS 
Progression-free survival 
PHI 
Protected health information 
PI 
Principal investigator 
PR 
Partial response 


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QASMC 
Quality Assurance and Safety Monitoring Committee 
QOL 
Quality of life 
RECIST 
Response Evaluation Criteria in Solid Tumors (Committee) 
RNA 
Ribonucleic acid 
RR 
Response rate 
SAE 
Serious adverse event 
SCC 
Siteman Cancer Center 
SD 
Stable disease 
SQ 
Subcutaneous 
TRR 
Tumor response rate 
UPN 
Unique patient number 
WUSM 
Washington University School of Medicine 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table of Contents 
SCHEMA ........................................................................................................................................ 3 
1.0 
BACKGROUND AND RATIONALE ................................................................................ 8 
1.1 
Head and Neck Squamous Cell Carcinoma ..................................................................... 8 
1.2 
Incurable HNSCC ............................................................................................................ 8 
1.3 
Mitomycin C .................................................................................................................... 9 
1.4 
Study Rationale .............................................................................................................. 11 
1.5 
Correlative Studies Background..................................................................................... 12 
2.0 
OBJECTIVES .................................................................................................................... 12 
2.1 
Primary Objective .......................................................................................................... 12 
2.2 
Secondary Objectives ..................................................................................................... 12 
2.3 
Exploratory Objective .................................................................................................... 12 
3.0 
PATIENT SELECTION .................................................................................................... 12 
3.1 
Inclusion Criteria ............................................................................................................ 12 
3.2 
Exclusion Criteria ........................................................................................................... 13 
3.3 
Inclusion of Women and Minorities ............................................................................... 14 
4.0 
REGISTRATION PROCEDURES ................................................................................... 14 
4.1 
Confirmation of Patient Eligibility ................................................................................. 14 
4.2 
Patient Registration in the Siteman Cancer Center OnCore Database ........................... 15 
4.3 
Assignment of UPN ....................................................................................................... 15 
5.0 
TREATMENT PLAN ........................................................................................................ 15 
5.1 
Premedication Administration ........................................................................................ 15 
5.2 
Agent Administration ..................................................................................................... 15 
5.3 
Evaluability .................................................................................................................... 15 
5.4 
General Concomitant Medication and Supportive Care Guidelines .............................. 16 
5.5 
Women of Childbearing Potential .................................................................................. 16 
5.6 
Duration of Therapy ....................................................................................................... 16 
5.7 
Duration of Follow-up .................................................................................................... 17 
6.0 
DOSE DELAYS/DOSE MODIFICATIONS .................................................................... 17 
6.1 
Dose Modifications for Mitomycin C ............................................................................ 17 
7.0 
REGULATORY AND REPORTING REQUIREMENTS ............................................... 17 
7.1 
Sponsor-Investigator Reporting Requirements .............................................................. 18 
7.2 
Exceptions to Expedited Reporting ................................................................................ 18 
8.0 
PHARMACEUTICAL INFORMATION .......................................................................... 19 
8.1 
Mitomycin C .................................................................................................................. 19 
9.0 
CORRELATIVE STUDIES .............................................................................................. 20 
9.1 
Archived Tumor Tissue .................................................................................................. 20 
9.2 
Blood for Future Research ............................................................................................. 20 
9.3 
Quality of Life Assessments .......................................................................................... 21 
10.0 STUDY CALENDAR ....................................................................................................... 22 
11.0 DATA AND SAFETY MONITORING ............................................................................ 23 
12.0 DATA SUBMISSION SCHEDULE ................................................................................. 23 
12.1 Adverse Event Collection in the Case Report Forms ..................................................... 24 
13.0 MEASUREMENT OF EFFECT........................................................................................ 24 
13.1 Antitumor Effect – Solid Tumors ................................................................................... 24 
13.2 Disease Parameters ......................................................................................................... 25 


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13.3 Methods for Evaluation of Measurable Disease ............................................................ 26 
13.4 Response Criteria ........................................................................................................... 28 
14.0 STATISTICAL CONSIDERATIONS............................................................................... 30 
14.1 Hypothesis ...................................................................................................................... 30 
14.2 Study Endpoints ............................................................................................................. 31 
14.3 Statistical Design ............................................................................................................ 31 
14.4 Analysis Plan for Time to Event and Adverse Events Endpoints .................................. 31 
14.5 Analysis Plan for Quality of Life Endpoints .................................................................. 31 
15.0 REFERENCES .................................................................................................................. 33 
APPENDIX A: ECOG Performance Status Scale ........................................................................ 35 
APPENDIX B: EORTC QLQ-C30 ............................................................................................... 36 
APPENDIX C: COGNITIVE FAILURES QUESTIONNAIRE .................................................. 38 
APPENDIX D: Definitions for Adverse Event Reporting ........................................................... 40 
APPENDIX E: Reporting Timelines .............................................................................................. 0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1.0 
BACKGROUND AND RATIONALE 
 
1.1 
Head and Neck Squamous Cell Carcinoma 
 
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer. Fifty 
thousand new cases are diagnosed each year. Most patients present with locally advanced 
disease stage (III, IVa, and IVb) and are treated with multimodality therapy. Human 
papilloma virus (HPV; p16+)-related oropharyngeal squamous cell carcinoma (OPSCC) 
represents 15% of all new cases of HNSCC. Such patients have an excellent prognosis with 
recurrence rates of only 10-20%. However, patients with HPV-unrelated (p16-)/smoking-
induced HNSCC have a substantially poorer prognosis, and 50% or more of these patients 
will experience death due to disease recurrence. Patients with incurable HNSCC have a 
poor prognosis and limited therapy options, resulting in major unmet need. 
 
1.2 
Incurable HNSCC 
 
1.2.1 First Line Therapy 
 
Patients with recurrent, incurable HNSCC have a median overall survival (OS) of 
10.1 months, median progression-free survival (PFS) of 5.6 months, and an overall 
tumor response rate (RR) of 36% when treated with the current standard first line 
chemotherapy regimen of cis/carboplatin, 5-FU, and cetuximab.1,2 This was 
established in a landmark study called the EXTREME trial, during which 
Vermorken et al randomly assigned patients with untreated incurable HNSCC to 
receive a regimen of PF (platin [cisplatin 100 mg/m2 or carboplatin AUC 5] on Day 
1 plus 5-FU 1000 mg/m2/day for 4 days) on a 3-week cycle either alone or with 
concurrent cetuximab for a maximum of 6 cycles.1  The trial showed a significant 
improvement in all major efficacy parameters including OS (7.4 vs 10.1 mos), PFS 
(3.3 vs 5.6 mos), and RR (20% vs 36%) with the addition of cetuximab to 
chemotherapy. In addition to promoting the institution of the new standard of care 
therapy for incurable HNSCC, the EXTREME trial led to a new Food and Drug 
Administration (FDA) approved indication for cetuximab. 
 
1.2.2 Second Line Therapy 
 
Paclitaxel has substantial single agent activity as first line treatment of incurable 
HNSCC with tumor RR of 40%.3,4 However, the efficacy of paclitaxel alone in 
patients with incurable HNSCC that progressed with platin, 5-FU, and cetuximab 
is unknown. 
 
Docetaxel also has substantial single agent activity as first line treatment in 
incurable HNSCC with RR of 42%.4 However, the efficacy of docetaxel in patients 
with incurable HNSCC that progressed with platin, 5-FU, and cetuximab is 
unknown. 
 
Methotrexate has been used in the treatment of incurable HNSCC; however, the 


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efficacy of this agent in patients with HNSCC that progressed with platin, 5-FU, 
and cetuximab is also unknown. 
 
1.2.3 PD-L1 in HNSCC 
 
Expression of PD-L1 is frequent (80%) in HNSCC.5 Clinical trials showed an OS 
benefit with nivolumab, a PD-1 inhibitor, in platin-resistant RM-HNSCC.6 
Regulatory agencies approved nivolumab and pembrolizumab in 2016 for this 
indication. However, the benefit of PD-1 inhibitors was also modest. The tumor 
response rate of these agents was 13-18%,5,6 the median PFS was 2.0 months and 
the median OS was only 7.5 months.6 These data point to the observation that only 
a small subset of patients with RM-HNSCC benefit from PD-1 inhibitors. 
 
1.3 
Mitomycin C 
 
1.3.1 In HNSCC 
                         
Although mitomycin C is not currently considered a standard option in the 
treatment of incurable HNSCC, there is a body of data supporting its efficacy in 
preclinical experiments7 and in combination with radiation as a radiosensitizer for 
curable disease and in combination with other chemotherapy in incurable disease.8  
 
Preclinical experiments demonstrated repression of E6 expression and induction of 
apoptosis in HPV SCC cell lines exposed to mitomycin C.7  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cellular responses of HPV-positive 
cancer cells to genotoxic anti-
cancer agents: repression of 
E6/E7-oncogene expression and 
induction of apoptosis
*Butz K, et al. Int J Cancer 68, 1996
*Butz K,et al. Int J Cancer 68, 1996
Repression of E6 Expression by Cisplatin*
 
*Butz K, et al. Int J Cancer 68,1996
Induction of p21 and p53 with Chemotherapy
 
Induction of BAX Expression with Chemotherapy*
*Butz K, et al. Int J Cancer 68,1996


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In patients with curable HNSCC, several studies have added mitomycin C to 
radiation as a radiosensitizer;9 however, the independent effect of mitomycin C on 
efficacy is not clear. In patients with incurable HNSCC, studies have combined 
mitomycin C with other chemotherapy; however, the independent effect of 
mitomycin C is not clear.8 
 
1.3.2 Patients with Incurable HNSCC Treated with Single Agent 
Mitomycin C 
 
We have treated two patients with incurable HNSCC with mitomycin C. Each 
patient’s cancer had progressed on prior platin, 5-FU, cetuximab, and taxane. 
Mitomycin C was administered at either 20 mg/m2 (Case 1) or 10 mg/m2 (Case 2) 
q6 wks. Both patients’ cancer responded to mitomycin C. Case 1 is shown below: 
                Pre-Treatment                                   Post-Cycle 2 
 
 
              
                  Pre-Treatment                                             Post Cycle-2 
 
 
 
Case 1 was given 20 mg/m2 of mitomycin C q6 weeks; however, this patient 
experienced prolonged grade 4 thrombocytopenia after Cycle 2 during which the 


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patient’s cancer progressed. Therefore, a lower dose of mitomycin C (10 mg/m2) 
was used for Case 2. This patient did not experience grade 3 or 4 hematologic 
toxicity with Cycle 1. Although Case 2 has not undergone full radiologic 
assessment of tumor response assessment yet, the large fungating neck mass has 
dramatically decreased in size based on direct visual examination. 
  
1.3.3 In Anal SCC   
 
Anal SCC is also caused by HPV infection. Most patients are treated with definitive 
chemoradiation, the current standard regimen being mitomycin C, 5-FU, and 
radiation.10 Randomized trials have established the critical importance of 
mitomycin C in the CRT regimen. RTOG 87-04/ ECOG 1289 demonstrated that 
mitomycin C/5-FU/RT was superior to 5-FU/RT alone.11 RTOG 98-11 
demonstrated that mitomycin C/5-FU/RT was superior to cisplatin/5-FU/RT.12,13 
These studies highlight the effectiveness of mitomycin C in the treatment of HPV 
induced anal SCC, and provide rationale for investigating this agent in other HPV 
induced mucosal SCC such as those of the oropharynx. 
  
1.3.4 In Cervical SCC 
 
Cervical SCC is initiated by high risk HPV serotypes. Several studies have included 
mitomycin C in the treatment of incurable cervical SCC; however, the independent 
effects of mitomycin C in these studies is unclear.8 
 
1.4 
Study Rationale 
 
In incurable HNSCC, no standard second line therapy exists following disease progression 
on platin/5-FU/cetuximab, although most would deliver a taxane, even though no 
prospective data exists to support the benefit of this approach.  
 
No agent is known to have efficacy in patients with incurable HNSCC that progressed with 
prior platin, 5-FU, cetuximab and taxane. Herein lies the unmet need to be addressed by 
this trial. Based on the preclinical and clinical data presented, we propose that mitomycin 
C will have anti-tumor activity in these patients. Since the biology of p16 positive OPSCC 
and p16 negative HNSCC are distinctly different, we will stratify patients into two groups 
based on p16 status.  A two stage Simon schema will be used for each group (p16+ OPSCC 
and p16- HNSCC). The primary endpoint is tumor response rate as assessed by RECIST 
1.1 criteria. 
 
Amendment #7: As of October 2020, accrual to the p16+ cohort continues based on activity 
observed in Simon Stage 1; the p16- cohort was closed after Simon Stage 1 due to 
inactivity. However, accrual to the trial has been slower than expected. Since the trial 
opened, a key impediment to accrual was the interim FDA approval of immunotherapy for 
HNSCC, adding an additional line of standard treatment prior to patients going on to this 
trial. In an effort to increase the pace of accrual to this trial, we propose changing the 
current inclusion requirement of disease progression on prior platinum, cetuximab, taxane 


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and 5-FU to disease progression on prior platinum and immunotherapy. The rationale for 
this amendment is that platinum and immunotherapy are the only agents that improved OS 
when given as monotherapy; whereas, monotherapy with either cetuximab, taxane, and 5-
FU do not yield an OS benefit and have a low response rate (<5%) in this setting.   
 
1.5 
Correlative Studies Background 
 
Tumor 
biopsies 
and 
blood 
will 
be 
obtained, 
if 
possible, 
for 
planned 
immunohistochemistries of smad4, BRCA1, and Rad51, which are known to be reduced in 
HNSCC and whose loss confers sensitivity to mitomycin C. Other studies may be 
performed as indicated.  
 
2.0 
OBJECTIVES 
 
2.1 
Primary Objective 
 
To determine the tumor response rate of patients with incurable HNSCC that progressed 
following platin, 5-FU, cetuximab and taxane who are treated with mitomycin C, stratified 
for p16+ OPSCC and p16- HNSCC.  Post October 2020: To determine the tumor response 
rate of patients with incurable p16+ OPSCC HNSCC that progressed following platin, and 
immunotherapy who are treated with mitomycin C. 
 
2.2 
Secondary Objectives 
 
1. To determine progression-free survival (PFS) of these patients, stratified for p16+ 
OPSCC and p16- HNSCC. 
2. To evaluate the instances of grades 3 and 4 adverse events (using CTCAE version 3.0) 
on this trial. 
3. To determine the overall survival (OS) of these patients, stratified for p16+ OPSCC 
and p16- HNSCC.  
 
2.3 
Exploratory Objectives 
 
1. To evaluate tumor tissue and blood for immunohistochemical analyses relating to 
response to mitomycin C. 
2. To characterize the quality of life of patients on this trial. 
 
 
3.0 
PATIENT SELECTION 
 
3.1 
Inclusion Criteria 
 
1. Histologically or cytologically confirmed incurable HNSCC of the oral cavity, 
oropharynx, larynx, hypopharynx, and/or Level 1-3 neck node with non-cutaneous 
SCC and unknown primary.  “Incurable” is defined as metastatic disease or a local or 


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regional recurrence in a previously irradiated site that is unresectable (or patient 
declines resection).  
 
2. Progression following platin and immunotherapy given for incurable disease. 
 
3. Measurable disease defined as lesions that can be accurately measured in at least one 
dimension (longest diameter to be recorded) as ≥ 10 mm with CT scan, as ≥ 20 mm by 
chest x-ray, or ≥ 10 mm with calipers by clinical exam per RECIST 1.1. 
 
4. Tissue available (either initial diagnostic or recurrent tissue specimen) for p16 testing 
(if p16 status is already known, this criterion may be waived).   
 
5. At least 18 years of age. 
 
6. ECOG performance status ≤ 3 (see Appendix A). 
 
7. Adequate hematologic, renal, and hepatic function as defined below: 
a. Absolute neutrophil count ≥ 1,000/mcl 
b. Platelets ≥ 75,000/mcl 
c. Total bilirubin ≤ 1.5 mg/dL 
d. AST(SGOT)/ALT(SGPT) ≤ 2.5 x ULN, alkaline phosphatase ≤ 2.5 x ULN, unless 
bone metastasis is present in the absence of liver metastasis 
e. Creatinine below ULN (males 0.7-1.30 mg/dl; females 0.6-1.10 mg/dl) OR 
creatinine clearance ≥ 60 mL/min/1.73 m2 for patients with creatinine levels above 
institutional normal 
 
8. Women of childbearing potential and men must agree to use adequate contraception 
(hormonal or barrier method of birth control, abstinence) prior to study entry, for the 
duration of study participation, and for 1 month after completing treatment.  Should a 
woman become pregnant or suspect she is pregnant while participating in this study, 
she must inform her treating physician immediately. 
 
9. Patients who have known HIV positivity must be on a 3-drug antiviral regimen that 
does not include zidovudine, and must have a CD4 count >100/mm3 and virus load 
<5000 copies/ml, and are placed on a regimen to prevent PCP reactivation during 
treatment.  
 
10. Ability to understand and willingness to sign an IRB approved written informed 
consent document (or that of legally authorized representative, if applicable). 
 
3.2 
Exclusion Criteria 
 
1. Other active malignancy with the exception of basal cell or squamous cell carcinoma 
of the skin which were treated with local resection only, carcinoma in situ of the cervix, 
or synchronous H&N primaries. 
 


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2. Currently receiving any other investigational agents. 
 
3. Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance with 
study requirements. 
 
4. Pregnant and/or breastfeeding.  Patient must have a negative pregnancy test within 7 
days of start of study treatment. 
 
5. Known active central nervous system (CNS) metastases. Subjects with previously 
treated brain metastases may participate provided they are stable (without evidence of 
progression by imaging for at least four weeks prior to the first dose of trial treatment 
and any neurologic symptoms have returned to baseline), have no evidence of new or 
enlarging brain metastases, and are not using steroids for at least 28 days prior to 
treatment.  
 
6. A history of allergic reactions attributed to compounds of similar chemical or biologic 
composition to mitomycin C or other agents used in the study. 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women and members of all races and ethnic groups are eligible for this trial. 
 
 
4.0 
REGISTRATION PROCEDURES 
 
Patients must not start any protocol intervention prior to registration through the Siteman 
Cancer Center. 
 
The following steps must be taken before registering patients to this study: 
 
1. Confirmation of patient eligibility 
2. Registration of patient in the Siteman Cancer Center OnCore database 
3. Assignment of unique patient number (UPN) 
 
4.1 
Confirmation of Patient Eligibility 
 
Confirm patient eligibility by collecting the information listed below: 
 
1. Registering MD’s name 
2. Patient’s race, sex, and DOB 
3. Three letters (or two letters and a dash) for the patient’s initials 
4. Copy of signed consent form 
5. Completed eligibility checklist, signed and dated by a member of the study team 
6. Copy of appropriate source documentation confirming patient eligibility 


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4.2 
Patient Registration in the Siteman Cancer Center OnCore Database 
 
All patients must be registered through the Siteman Cancer Center OnCore database. 
 
4.3 
Assignment of UPN 
 
Each patient will be identified with a unique patient number (UPN) for this study.  All data 
will be recorded with this identification number on the appropriate CRFs. 
 
 
5.0 
TREATMENT PLAN 
 
This is a phase II trial of mitomycin C, given in 5 week cycles. Tumor response assessment using 
RECIST criteria will occur after every two cycles of chemotherapy. Treatment will be 
discontinued for disease progression, unacceptable AE, or patient or physician decision. 
 
Tissue will be requested for p16 analysis IHC stain.  This may be either an initial diagnostic or 
recurrent tissue specimen.  p16+ is defined as ≥ 70% of tumor cells staining for p16; p16- is defined 
as < 70% tumor cells staining for p16. 
 
5.1 
Premedication Administration 
 
Standard anti-emetics will be given before mitomycin C. 
 
5.2 
Agent Administration 
 
The regimen consists of:  
 
1. Mitomycin C 10 mg/m2 IV will be given on Day 1 Q5 weeks. 
2. Pegfilgrastim 6 mg SQ will be given on Day 2 of each cycle. 
 
Pegfilgrastim will be administered as per routine care, and may be given during an office 
visit on Day 2 using a prefilled syringe or using the on-body injector, which will be applied 
to the back of the patient’s upper arm or to the patient’s abdomen in the clinic on Day 1 
and will administer the injection approximately 27 hours after application. 
 
5.3 
Evaluability 
 
All patients who receive any study treatment are evaluable for toxicity.  Patients are 
evaluated from first receiving study treatment until a 28-day follow up after the conclusion 
of treatment or death. 
 
All patients are evaluable for disease response unless they come off study prior to 
completion of cycle 2 due to adverse event(s), patient withdrawal, or early death and have 
not had an assessment of tumor response. 
 


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5.4 
General Concomitant Medication and Supportive Care Guidelines 
 
Supportive care, including but not limited to anti-emetic medications, may be administered 
at the discretion of the Investigator.  Concurrent treatment with bisphosphonates and 
denosumab is allowed.  Erythropoietin and G-CSF may be administered at the discretion 
of the investigator, consistent with institutional guidelines.  Palliative radiation therapy is 
acceptable for bone metastases provided the bone lesion is not a target lesion.  
 
5.5 
Women of Childbearing Potential 
 
Women of childbearing potential (defined as women with regular menses, women with 
amenorrhea, women with irregular cycles, women using a contraceptive method that 
precludes withdrawal bleeding, and women who have had a tubal ligation) are required to 
have a negative pregnancy test within 7 days prior to the first dose of mitomycin C.   
 
Female and male patients (along with their female partners) are required to use two forms 
of acceptable contraception, including one barrier method, during participation in the study 
and for 1 month following the last dose of study treatment.  
 
If a patient is suspected to be pregnant, all study drugs should be immediately discontinued.  
In addition a positive urine test must be confirmed by a serum pregnancy test.  If it is 
confirmed that the patient is not pregnant, the patient may resume dosing. 
 
If a female patient or female partner of a male patient becomes pregnant during therapy or 
within 1 month after the last dose of study treatment, the investigator must be notified in 
order to facilitate outcome follow-up. 
 
5.6 
Duration of Therapy 
 
If at any time the constraints of this protocol are considered to be detrimental to the 
patient’s health and/or the patient no longer wishes to continue protocol therapy, the 
protocol therapy should be discontinued and the reason(s) for discontinuation documented 
in the case report forms. 
 
In the absence of treatment delays due to adverse events, treatment may continue 
indefinitely until one of the following criteria applies: 
 
• Documented and confirmed disease progression 
• Death 
• Adverse event(s) that, in the judgment of the investigator, may cause severe or 
permanent harm or which rule out continuation of study drug 
• General or specific changes in the patient’s condition render the patient 
unacceptable for further treatment in the judgment of the investigator 
• Suspected pregnancy 
• Serious noncompliance with the study protocol 
• Lost to follow-up 


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• Patient withdraws consent 
• Investigator removes the patient from study 
• The Siteman Cancer Center decides to close the study 
 
Patients who prematurely discontinue treatment for any reason will be followed as 
indicated in the study calendar. 
 
5.7 
Duration of Follow-up 
 
Patients will be followed for progression and survival every 3 months indefinitely until 
death.  Patients removed from study for unacceptable adverse events will be followed until 
resolution or stabilization of the adverse event. 
 
 
6.0 
DOSE DELAYS/DOSE MODIFICATIONS 
 
6.1 
Dose Modifications for Mitomycin C 
   
Nadir After Prior Dose 
Percentage of 
Prior Dose 
To Be Given 
Neutrophils/mm3 Platelets/mm3 
 
 
 
>1000 
>50,000 
100% 
>500 
20,000–50,000 
75% 
<500 
<20,000 
50% 
 
Dosing will not be re-escalated after reduction, and there is no limit to the number of dose 
reductions a patient may have during the course of his/her participation on trial.  There is 
no minimum dose.  Patients may be dose-reduced until dosing cannot physically be further 
reduced or until progression. 
  
No repeat dosage should be given until absolute neutrophil count has returned to 1000/mm3 
and a platelet count to 75,000/mm3.  Dosing between cycles may be delayed for up to 5 
weeks.  If a patient requires a delay of more than 5 weeks s/he must come off study. 
 
Mitomycin C will not be re-dosed following the diagnosis of Hemolytic Uremic Syndrome 
(HUS). 
 
 
 
7.0 
REGULATORY AND REPORTING REQUIREMENTS 
 
The entities providing oversight of safety and compliance with the protocol require reporting as 
outline below. Please refer to Appendix D for definitions and Appendix E for a grid of reporting 
timelines.  


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Adverse events will be tracked from start of study treatment through 28 days following the last 
day of study treatment. All adverse events must be recorded on the toxicity tracking case report 
form (CRF). 
 
 
Refer to the data submission schedule in Section 12 for instructions on the collection of AEs in the 
EDC.  
 
Reporting requirements for Washington University study team may be found in Section 7.1. 
 
 
7.1 
Sponsor-Investigator Reporting Requirements 
 
   
7.1.1 Reporting to the Human Research Protection Office (HRPO) at 
Washington University 
 
Reporting will be conducted in accordance with Washington University IRB 
policies. 
 
Pre-approval of all protocol exceptions must be obtained prior to implementing the 
changes. 
 
7.1.2 Reporting to the Quality Assurance and Safety Monitoring 
Committee (QASMC) at Washington University 
 
The Sponsor-Investigator is required to notify the QASMC of any unanticipated 
problems involving risks to participants or others occurring at WU or any BJH or 
SLCH institution that has been reported to and acknowledged by HRPO.  
(Unanticipated problems reported to HRPO and withdrawn during the review 
process need not be reported to QASMC.) 
 
QASMC must be notified within 10 days of receipt of IRB acknowledgment via 
email to qasmc@wustl.edu. Submission to QASMC must include the myIRB form 
and any supporting documentation sent with the form. 
 
7.2 
Exceptions to Expedited Reporting 
 
Events that do not require expedited reporting as described in Section 7.1 include: 
• planned hospitalizations 
• hospitalizations < 24 hours 
• respite care 
• events related to disease progression 
 
 
Events that do not require expedited reporting must still be captured in the EDC. 


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8.0 
PHARMACEUTICAL INFORMATION 
 
8.1 
Mitomycin C 
 
8.1.1 Mitomycin C Description 
 
Mitomycin (also known as mitomycin-C) is an antibiotic isolated from the broth of 
Streptomyces caespitosus which has been shown to have antitumor activity. The 
compound is heat stable, has a high melting point, and is freely soluble in organic 
solvents. 
 
Mitomycin is a blue-violet crystalline powder with the molecular formula of 
C15H18N4O5, and a molecular weight of 334.33. Its chemical name is 7-amino-9α-
methoxymitosane and it has the following structural formula. 
 
8.1.2 Clinical Pharmacology 
 
Mitomycin selectively inhibits the synthesis of deoxyribonucleic acid (DNA).  The 
guanine and cytosine content correlates with the degree of mitomycin-induced 
cross-linking.  At high concentrations of the drug, cellular RNA and protein 
synthesis are also suppressed. 
 
In humans, mitomycin is rapidly cleared from the serum after intravenous 
administration.  Time required to reduce the serum concentration by 50% after a 30 
mg bolus injection is 17 minutes.  Clearance is effected primarily by metabolism in 
the liver, but metabolism occurs in other tissues as well.  The rate of clearance is 
inversely proportional to the maximal serum concentration because, it is thought, 
of saturation of the degradation pathways. 
 
Approximately 10% of a dose of mitomycin is excreted unchanged in the urine. 
 
8.1.3 Supplier 
 
Mitomycin for Injection is available commercially. 
 
8.1.4 Dosage Form and Preparation 
 
Mitomycin for Injection is a sterile dry mixture of mitomycin and mannitol, which 
when reconstituted with Sterile Water for Injection provides a solution for 
intravenous administration. Each vial contains either mitomycin 5 mg and mannitol 
10 mg, or mitomycin 20 mg and mannitol 40 mg, or mitomycin 40 mg and mannitol 
80 mg. Each mL of reconstituted solution will contain 0.5 mg mitomycin and have 
a pH between 6.0 and 8.0. 
 
8.1.5 Storage and Stability 


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Mitomycin C should be stored at controlled room temperature at 15°C-30°C and 
protected from light.  Reconstituted mitomycin C should be used within 24 hours. 
 
8.1.6 Administration 
 
Mitomycin C will be given IV at a dose of 10 mg/m2 on Day 1 Q5 weeks. 
 
 
9.0 
CORRELATIVE STUDIES 
 
9.1 
Archived Tumor Tissue 
 
9.1.1 Collection of Specimen(s) 
 
Previously collected formalin-fixed paraffin embedded tissue (15 slides per case) 
will be requested for immunohistochemical analyses.  This may be archival tissue 
from a previous pre-treatment diagnostic biopsy, tissue collected under HRPO# 
201102323 (“Analysis of Histological, Genomic, Molecular, and Clinical Factors 
in Head and Neck Cancer: The Tissue Acquisition Protocol (TAP)”) to which 
participants in this study will be encouraged to enroll, or tissue collected under the 
auspices of this protocol should archival or previously banked tissue be unavailable.  
If biopsies are performed as part of this protocol, collection will be performed as 
follows.  Tissue samples will be obtained by simple excision (1-2 cm3 portion of 
tissue) or 4 mm or greater dermatology biopsy punch.  Specimens should be fixed 
in 10% buffered formalin. 
 
Tissue for p16 testing is required. Tissue collection is highly encouraged for 
correlative testing, but is not required for trial participation. 
 
9.1.2 Handling of Specimen(s) 
 
Archived tissue should be delivered to the study team at Campus Box 8056. 
 
9.2 
Blood for Future Research 
 
For patients not enrolled in HRPO# 201102323, 20 mL of anticoagulated blood will be 
collected in three EDTA purple top tubes prior to initiation of treatment and again at 
progression/recurrence.  Samples will be spun and processed for peripheral white blood 
cells.  Residual red blood cells will be removed by hypotonic lysis.  Nucleated cells will 
be washed in phosphate buffered saline, divided into approximately 20 x 106 cells/aliquot, 
spun down, and the supernatant removed.  Cell pellets will be labeled with a unique 
specimen ID number, snap frozen in liquid nitrogen, and stored under liquid nitrogen vapor 
in an inventoried storage unit at the Siteman Cancer Center Tissue Procurement Core 
Facility. 
  


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9.3 
Quality of Life Assessments 
 
QOL assessments will be performed at screening, every 5 weeks, and at the end of 
treatment visit. 
 
QOL assessment tools will include EORTC QLQ-C30 (Appendix B) and Cognitive 
Failures Questions (CFQ) (Appendix C).  
 
 


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10.0 
STUDY CALENDAR 
 
Screening evaluations are to be conducted within 28 days prior to start of protocol therapy. 
 
 
Screening 
Treatment1 
EOT2 
Follow-
Up3 
W1D1 W1D2 
W3 
Informed consent 
X 
 
 
 
 
 
H&P, ECOG PS, weight 
X 
X 
 
X 
X 
 
CBC 
X 
X 
 
X 
X 
 
CMP 
X 
X 
 
 
X 
 
BMP 
 
 
 
X 
 
 
Β-hCG4 
X 
 
 
 
 
 
CT or MRI of neck and 
chest (abdomen/pelvis 
only if disease in area) 
X 
X5 
 
 
 
X 
X6 
Mitomycin-C 
 
X 
 
 
 
 
Neulasta 
 
 
X8 
 
 
 
QOLs 
X 
X 
 
 
X 
 
Research blood draw 
See Section 9.2  
Archival tumor tissue 
for correlatives 
X9 
 
 
 
 
 
Archival tumor tissue 
for p16 testing10 
X 
 
 
 
 
 
AE assessment 
 
X------------------------------------------------X7 
1. Indefinite number of cycles – q 5 weeks 
2. Defined as date patient comes off study (due to progression, adverse event, patient/physician decision, etc) 
3. Every 3 months (+/- 1 month) 
4. Women of childbearing potential only; must be within 7 days of first dose of study treatment 
5. Scans to be repeated after every 2 cycles 
6. Only if off study for reason other than progression, scan until progression  
7. Date of first treatment until 28 days post treatment 
8. May be given in clinic using a pre-filled syringe or at home using the on-body injector 
9. Optional 
10. Or separate confirmation of p16 status 
 
 
 


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11.0 
DATA AND SAFETY MONITORING 
 
In compliance with the Washington University Institutional Data and Safety Monitoring Plan, the 
Principal Investigator will provide a Data and Safety Monitoring (DSM) report to the Washington 
University Quality Assurance and Safety Monitoring Committee (QASMC) semi-annually 
beginning six months after accrual has opened (if at least one patient has been enrolled) or one 
year after accrual has opened (if no patients have been enrolled at the six-month mark). 
 
For phase I dose escalation studies, the Principal Investigator will review all patient data at least 
monthly (or before each dose-escalation if occurring sooner than monthly), and provide a semi-
annual report to the Quality Assurance and Safety Monitoring Committee (QASMC). For phase II 
or dose expansion cohorts of a phase I study, the Principal Investigator will review all patient data 
at least every six months, and provide a semi-annual report to the QASMC.  This report will 
include: 
 
• HRPO protocol number, protocol title, Principal Investigator name, data coordinator 
name, regulatory coordinator name, and statistician 
• Date of initial HRPO approval, date of most recent consent HRPO approval/revision, 
date of HRPO expiration, date of most recent QA audit, study status, and phase of study 
• History of study including summary of substantive amendments; summary of accrual 
suspensions including start/stop dates and reason; and summary of protocol exceptions, 
error, or breach of confidentiality including start/stop dates and reason 
• Study-wide target accrual and study-wide actual accrual 
• Protocol activation date  
• Average rate of accrual observed in year 1, year 2, and subsequent years 
• Expected accrual end date and accrual by cohort 
• Objectives of protocol with supporting data and list the number of participants who 
have met each objective 
• Measures of efficacy (phase I studies only if efficacy is objective of the protocol) 
• Early stopping rules with supporting data and list the number of participants who have 
met the early stopping rules 
• Power analysis and/or interim analysis (if described in the protocol) 
• Summary of toxicities separated by cohorts with the number of dose-limiting toxicities 
indicated 
• Abstract submissions/publications 
• Summary of any recent literature that may affect the safety or ethics of the study 
 
The study principal investigator and Research Patient Coordinator will monitor for serious 
toxicities on an ongoing basis. Once the principal investigator or Research Patient Coordinator 
becomes aware of an adverse event, the AE will be reported to the HRPO and QASMC according 
to institutional guidelines. 
 
12.0 
DATA SUBMISSION SCHEDULE 
 
Case report forms with appropriate source documentation will be completed according to the 
schedule listed in this section. 


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Case Report Form 
Submission Schedule 
Original Consent Form 
Prior to registration 
On-Study Form 
Prior to starting treatment 
Treatment Form 
Every cycle 
Toxicity Form 
Continuous 
Treatment Summary Form 
Completion of treatment 
Follow Up Form 
Every 3 months 
Tumor Measurement Form 
Baseline 
End of every even-numbered cycle 
End of treatment 
QOL Form 
Baseline 
Every cycle 
End of treatment 
Correlative Studies Form 
Baseline 
SAE Form 
See Section 7.0 for reporting 
requirements 
Progression Form 
Time of progression 
Death Form 
Time of death 
 
 
12.1 
Adverse Event Collection in the Case Report Forms 
 
All adverse events that occur beginning with start of treatment must be captured in the 
Toxicity Form.   
 
Participant death due to disease progression should be reported on the Toxicity Form as 
grade 5 disease progression.  If death is due to an AE (e.g. cardiac disorders: cardiac 
arrest), report as a grade 5 event under that AE.  Participant death must also be recorded 
on the Death Form. 
 
13.0 
MEASUREMENT OF EFFECT 
 
13.1 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be re-evaluated for response at the end of 
every even-numbered cycle (every 10 weeks).  In addition to a baseline scan, confirmatory 
scans should also be obtained not less than 4 weeks following initial documentation of 
objective response. 
 
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 


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(unidimensional measurement) of the tumor lesions and the shortest diameter in the case 
of malignant lymph nodes are used in the RECIST criteria. 
 
13.2 
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 by chest 
x-ray, as >10 mm with CT scan, or >10 mm with calipers by clinical exam.  All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters). 
 
Malignant lymph nodes:  To be considered pathologically enlarged and measurable, a 
lymph node must be >15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm).  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 or pathological lymph nodes with ≥10 to <15 mm 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 


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presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up.  
 
13.3 
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. 
 
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 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 or less.  If CT scans have 
slice thickness greater than 5 mm, 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.  


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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 
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:  
 
• Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. 
• 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 


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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. 
• 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. 
  
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. 
 
13.4 
Response Criteria 
 
13.4.1 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. 
 
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.  (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. 
 
13.4.2 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 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. 


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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 Investigator). 
 
13.4.3 Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started).  The 
patient's best response assignment will depend on the achievement of both 
measurement and confirmation criteria. 
    
For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response 
when Confirmation is 
Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non-PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-PD/not 
evaluated 
No 
SD 
Documented at least once 
>4 wks. from baseline** 
PD 
Any 
Yes or 
No 
PD 
no prior SD, PR or CR 
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. 
** 
Only for non-randomized trials with response as primary endpoint. 
*** 
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. 
 
 
 
 


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                                      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 
 
 
13.4.4 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.  
 
13.4.5 Progression-Free Survival 
 
PFS is defined as the duration of time from start of treatment to time of first 
radiologic confirmation of progression or death, whichever occurs first. 
 
13.4.6 Response Review 
 
For trials where the response rate is the primary endpoint, it is strongly 
recommended that all responses be reviewed by an expert(s) independent of the 
study at the study’s completion.  Simultaneous review of the patients’ files and 
radiological images is the best approach.  
 
 
14.0 
STATISTICAL CONSIDERATIONS 
 
14.1 
Hypothesis 
 
A novel regimen of mitomycin C will result in tumor responses in patients with incurable 
p16+ OPSCC and p16- HNSCC. 
 


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14.2 
Study Endpoints 
 
The primary endpoint is tumor response rate in p16+ OPSCC and p16- HNSCC. Secondary 
endpoints are progression free survival (PFS), occurrence of grade 3-4 adverse events by 
CTCAE 3.0, and overall survival (OS). Exploratory endpoints of quality of life measured 
by the EORTC-QLQ-30 and Cognitive Failures Questions (CFQ). 
 
14.3 
Statistical Design 
 
Tumor response rate (TRR) will be evaluated separately in p16- HNSCC patients and in 
p16+ OPSCC patients using two optimal two-stage Simon designs. In both cases, the 
expected TRR is 10%.  A TRR of 30% is considered a clinically significant increase. In 
each study arm a maximum of 35 patients will be enrolled, 12 in the first stage. If at least 
2 tumor responses are observed in the first stage, an additional 23 patients will be enrolled 
in the second stage. The trial will conclude that there is evidence of increased efficacy if at 
least 6 tumor responses are observed among the 35 patients in both stages. The probability 
of termination after the first stage is .66 if the true TRR is 10%.  Power is .90 at a .10 
significance level. 
 
We did not see at least 2 tumor responses in the p16- HNSCC group, so there will not be a 
second stage of enrollment for that patient population. 
 
14.4 
Analysis Plan for Time to Event and Adverse Events Endpoints 
 
All grade AEs, all serious (Grades 3-4) AEs, and all Grade 5 (treatment-related deaths) 
AEs will be analyzed using descriptive statistics and compared to historical controls using 
one-sample tests for difference of proportions. 
 
PFS and OS will be described in each study group using Kaplan-Meier or Cox proportional 
hazards models to estimate medians and hazard ratios with 95% confidence intervals. 
 
14.5 
Analysis Plan for Quality of Life Endpoints 
 
The exploratory quality of life endpoints will include the EORTC-QLQ-C30, which has a 
total score, one general QOL and one “within the last week” subscale, as well as a single 
general health item and a single overall QOL item. The CFQ has 3 subscales describing 
perception, memory and motor function.  
 
Mean or median quality of life will be documented in the two study groups. Patient-specific 
and clinical significance of observed differences will be a matter for discussion at the end 
of the study; the study does not intend to determine a minimal important difference. The 
study does use current empirical guidelines for the EORTC-QLQ-30 global score with the 
understanding that both the magnitude and variance of scores vary considerably from 
patient to patient, from one time point to another and by such factors as disease condition, 
age and comorbidity.  For the CFQ, a change of 1 standard deviation will be considered a 
perceptible difference.  


Protocol Version: 03/09/23 
 
Page 32 of 43 
 
 
Tables and histograms will be used to explore change in the subscales and summary scales 
in each study group. Scale and subscale scores may be used as independent variables in 
models of TRR, OS or PFS using chi-square, Kaplan-Meier and Cox proportional hazards 
methods. Spearman’s rank correlation or, where there are a large number of tied scores, 
Kendall’s tau-b will be used to explore correlation (redundancy) between QOL (sub)scales 
prior to modeling.  
 
 
 


Protocol Version: 03/09/23 
 
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15.0 
REFERENCES 
 
1. Vermorken JB, Mesia R, Rivera F, et al. Platinum-based chemotherapy plus cetuximab in 
head and neck cancer. N Engl J Med. 2008 Sep 11;349(11):1116-27. 
 
2. Colevas AD. Chemotherapy options for patients with metastatic or recurrent squamous 
cell carcinoma of the head and neck. J Clin Oncol. 2006 Jun 10;24(17):2644-52. 
 
3. Forastiere AA, Shank D, Neuberg D, et al. Final report of a phase II evaluation of 
paclitaxel in patients with advanced squamous cell carcinoma of the head and neck: an 
Eastern Cooperative Oncology Group trial (PA390). Cancer. 1998 Jun 1;82(11):2270-74.  
 
4. Dreyfuss AI, Clark JR, Norris CM, et al. Docetaxel: an active drug for squamous cell 
carcinoma of the head and neck. J Clin Oncol. 1996 May;14(5):1672-78. 
 
5. Seiwert TY, Burtness B, Mehra R, et al. Safety and clinical activity of pembrolizumab for 
treatment of recurrent or metastatic squamous cell carcinoma of the head and neck 
(KEYNOTE-012): an open-label, multicentre, phase 1b trial. Lancet Oncol. 
2016;17(7):956-965. 
 
6. Ferris RL, Blumenschein G, Fayette J, et al. Nivolumab for Recurrent Squamous-Cell 
Carcinoma of the Head and Neck. N Engl J Med. 2016;375(19):1856-1867. 
 
7. Butz K, Geisen C, Ullmann A, et al. Cellular responses of HPV-positive cancer cells to 
genotoxic anti-cancer agents: repression of E6/E7-oncogene expression and induction of 
apoptosis. Int J Cancer. 1996;68(4):506-13. 
 
8. Bradner WT. Mitomycin C: a clinical update. Cancer Treatment Reviews. 2001;27:35-50. 
 
9. Haffty BG, Son YH, Sasaki CT, et al. Mitomycin C as an adjunct to postoperative 
radiation therapy in squamous cell carcinoma of the head and neck: results from two 
randomized clinical trials. Int J Radiat Oncol Biol Phys. 1993;27(2):241-50. 
 
10. Spithoff K, Cummings B, Jonker D, et al. Chemoradiotherapy for squamous cell cancer 
of the anal canal: a systematic review. Clin Oncol. 2014;26(8):473-87. 
 
11. Flam M, John M, Pajak TF, et al. Role of mitomycin in combination with fluorouracil 
and radiotherapy, and of salvage chemoradiation in the definitive nonsurgical treatment 
of epidermoid carcinoma of the anal canal: results of a phase III randomized intergroup 
study. J Clin Oncol. 1996;14(9):2527-39. 
 
12. Ajani JA, Winter KA, Gunderson LL, et al. Fluorouracil, mitomycin and radiotherapy vs 
fluorouracil, cisplatin and radiotherapy for carcinoma of the anal canal: a randomized 
controlled trial. JAMA. 2008;299(16):1914-21. 
 


Protocol Version: 03/09/23 
 
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13. Gunderson LL, Winter KA, Ajani JA, et al. Long-term update of US GI intergroup 
RTOG 98-11 phase III trial for anal carcinoma: survival, relapse, and colostomy failure 
with concurrent chemoradiation involving fluorouracil/mitomycin versus 
fluorouracil/cisplatin. J Clin Oncol. 2012;30(35):4344-51. 
 
 
 


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APPENDIX A: ECOG Performance Status Scale 
 
 
Grade 
 
 
Description 
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. 
 
 
 
 


Protocol Version: 03/09/23 
 
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APPENDIX B: EORTC QLQ-C30 
 
We are interested in some things about you and your health. Please answer all of the questions 
yourself by circling the number that best applies to you. There are no "right" or "wrong" 
answers. The information that you provide will remain strictly confidential. 
 
 
Not 
at 
All 
A 
Little 
Quite a 
bit 
Very 
Much 
1. Do you have any trouble doing strenuous activities, 
like carrying a heavy shopping bag or a suitcase? 
1 
2 
3 
4 
2. Do you have any trouble taking a long walk? 
1 
2 
3 
4 
3. Do you have any trouble taking a short walk outside of 
the house? 
1 
2 
3 
4 
4. Do you need to stay in bed or a chair during the day? 
1 
2 
3 
4 
5. Do you need help with eating, dressing, washing 
yourself or using the toilet? 
1 
2 
3 
4 
During the past week: 
Not 
at 
All 
A 
Little 
Quite a 
Bit 
Very 
Much 
6. Were you limited in doing either your work or other 
daily activities? 
1 
2 
3 
4 
7. Were you limited in pursuing your hobbies or other 
leisure time activities? 
1 
2 
3 
4 
8. Were you short of breath? 
1 
2 
3 
4 
9. Have you had pain? 
1 
2 
3 
4 
10. Did you need to rest? 
1 
2 
3 
4 
11. Have you had trouble sleeping? 
1 
2 
3 
4 
12. Have you felt weak? 
1 
2 
3 
4 
13. Have you lacked appetite? 
1 
2 
3 
4 
14. Have you felt nauseated? 
1 
2 
3 
4 
15. Have you vomited? 
1 
2 
3 
4 
16. Have you been constipated? 
1 
2 
3 
4 
During the past week: 
Not 
at 
All 
A 
Little 
Quite a 
Bit 
Very 
Much 
17. Have you had diarrhea? 
 
 
 
 
18. Were you tired? 
 
 
 
 
19. Did pain interfere with your daily activities? 
 
 
 
 
20. Have you had difficulty in concentrating on things, 
like reading a newspaper or watching television? 
 
 
 
 
21. Did you feel tense? 
 
 
 
 
22. Did you worry? 
 
 
 
 
23. Did you feel irritable? 
 
 
 
 
24. Did you feel depressed? 
 
 
 
 


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25. Have you had difficulty remembering things? 
 
 
 
 
26. Has your physical condition or medical treatment 
interfered with your family life? 
 
 
 
 
27. Has your physical condition or medical treatment 
interfered with your social activities? 
 
 
 
 
28. Has your physical condition or medical treatment 
caused you financial difficulties? 
 
 
 
 
For the following questions please circle the number between 1 and 7 that 
best applies to you 
29. How would you rate your overall health during the past week? 
1 
2 
3 
4 
5 
6 
7 
Very Poor 
 
 
 
 
 
Excellent 
30. How would you rate your overall quality of life during the past week? 
1 
2 
3 
4 
5 
6 
7 
Very Poor 
 
 
 
 
 
Excellent 
 
 
 


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APPENDIX C: COGNITIVE FAILURES QUESTIONNAIRE 
 
The following questions are about minor mistakes which everyone makes from time to time, but 
some of which happen more often than others. We want to know how often these things have 
happened to you in the past 6 months. Please circle the appropriate number. 
 
Very 
Often 
Quite 
Often 
Occasion- 
ally 
Very 
rarely 
Never 
1. Do you read something and find you haven’t 
been thinking about it and must read it again? 
4 
3 
2 
1 
0 
2. Do you find you forget why you went from 
one part of the house to the other? 
4 
3 
2 
1 
0 
3. Do you fail to notice signposts on the road? 
4 
3 
2 
1 
0 
4. Do you find you confuse right and left when 
giving directions? 
4 
3 
2 
1 
0 
5. Do you bump into people? 
4 
3 
2 
1 
0 
6. Do you find you forget whether you’ve 
turned off a light or a fire or locked the door? 
4 
3 
2 
1 
0 
7. Do you fail to listen to people’s names when 
you are meeting them? 
4 
3 
2 
1 
0 
8. Do you say something and realize afterwards 
that it might be taken as insulting? 
4 
3 
2 
1 
0 
9. Do you fail to hear people speaking to you 
when you are doing something else? 
4 
3 
2 
1 
0 
10. Do you lose your temper and regret it? 
4 
3 
2 
1 
0 
11. Do you leave important letters unanswered 
for days? 
4 
3 
2 
1 
0 
12. Do you find you forget which way to turn 
on a road you know well but rarely use? 
4 
3 
2 
1 
0 
13. Do you fail to see what you want in a 
supermarket (although it’s there)? 
4 
3 
2 
1 
0 
14. Do you find yourself suddenly wondering 
whether you’ve used a word correctly? 
4 
3 
2 
1 
0 
15. Do you have trouble making up your mind? 
4 
3 
2 
1 
0 
16. Do you find you forget appointments? 
4 
3 
2 
1 
0 
17. Do you forget where you put something 
like a newspaper or a book? 
4 
3 
2 
1 
0 
18. Do you find you accidentally throw away 
the thing you want and keep what you meant to 
throw away – as in the example of throwing 
away the matchbox and putting the used match 
in your pocket? 
4 
3 
2 
1 
0 
19. Do you daydream when you ought to be 
listening to something? 
4 
3 
2 
1 
0 
20. Do you find you forget people’s names? 
4 
3 
2 
1 
0 


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21. Do you start doing one thing at home and 
get distracted into doing something else 
(unintentionally)? 
 
4 
 
3 
 
2 
 
1 
 
0 
22. Do you find you can’t quite remember 
something although it’s “on the tip of your 
tongue”? 
4 
3 
2 
1 
0 
23. Do you find you forget what you came to 
the shops to buy? 
4 
3 
2 
1 
0 
24. Do you drop things? 
4 
3 
2 
1 
0 
25. Do you find you can’t think of anything to 
say? 
4 
3 
2 
1 
0 
 
 
 


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APPENDIX D: Definitions for Adverse Event Reporting 
 
A. Adverse Events (AEs) 
 
As defined in 21 CFR 312.32: 
 
Definition: any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug-related. 
 
Grading: the descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for all 
toxicity reporting.  A copy of the CTCAE version 5.0 can be downloaded from the 
CTEP website. 
 
Attribution (relatedness), Expectedness, and Seriousness: the definitions for the 
terms listed that should be used are those provided by the Department of Health and 
Human Services’ Office for Human Research Protections (OHRP).  A copy of this 
guidance can be found on OHRP’s website: 
http://www.hhs.gov/ohrp/policy/advevntguid.html 
 
B. Suspected Adverse Reaction (SAR) 
 
As defined in 21 CFR 312.32: 
 
Definition: any adverse event for which there is a reasonable possibility that the drug 
caused the adverse event.  “Reasonable possibility” means there is evidence to 
suggest a causal relationship between the drug and the adverse event.  “Suspected 
adverse reaction” implies a lesser degree of certainty about causality than adverse 
reaction, which means any adverse event caused by a drug. 
 
C. Life-Threatening Adverse Event / Life Threatening Suspected Adverse 
Reaction  
 
As defined in 21 CFR 312.32: 
 
Definition: any adverse drug event or suspected adverse reaction is considered “life-
threatening” if, in the view of the investigator, its occurrence places the patient at 
immediate risk of death. It does not include an adverse event or suspected adverse 
reaction that, had it occurred in a more severe form, might have caused death. 
 
D.  Serious Adverse Event (SAE) or Serious Suspected Adverse Reaction 
 
As defined in 21 CFR 312.32: 
 
Definition:  an adverse event or suspected adverse reaction is considered “serious” 
if, in the view of the investigator, it results in any of the following outcomes: 


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o Death 
o A life-threatening adverse event 
o Inpatient hospitalization or prolongation of existing hospitalization 
o A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
o A congenital anomaly/birth defect 
o Any other important medical event that does not fit the criteria above but, based 
upon appropriate medical judgment, may jeopardize the subject and may 
require medical or surgical intervention to prevent one of the outcomes listed 
above 
 
E. Protocol Exceptions 
 
Definition: A planned change in the conduct of the research for one participant. 
 
F. Deviation 
 
Definition: Any alteration or modification to the IRB-approved research without 
prospective IRB approval.  The term “research” encompasses all IRB-approved 
materials and documents including the detailed protocol, IRB application, consent 
form, recruitment materials, questionnaires/data collection forms, and any other 
information relating to the research study. 
 
A minor or administrative deviation is one that does not have the potential to negatively 
impact the rights, safety, or welfare of participants or others or the scientific validity of 
the study. 
 
A major deviation is one that does have the potential to negatively impact the rights, 
safety, or welfare of participants or others or the scientific validity of the study. 
 


Protocol Version: 10/28/20, Amendment 7 
 
Page 0 of 43 
 
APPENDIX E: Reporting Timelines 
 
Expedited Reporting Timelines 
Event 
HRPO 
QASMC 
Serious AND unexpected suspected 
adverse reaction 
 
 
Unexpected fatal or life-threatening 
suspected adverse reaction 
 
 
Unanticipated problem involving risk to 
participants or others 
Report within 10 working days.  If the event 
results in the death of a participant enrolled 
at WU/BJH/SLCH, report within 1 working 
day. 
Report via email after IRB acknowledgment 
Major deviation 
Report within 10 working days.  If the event 
results in the death of a participant enrolled 
at WU/BJH/SLCH, report within 1 working 
day. 
 
A series of minor deviations that are being 
reported as a continuing noncompliance 
Report within 10 working days.   
 
Protocol exception 
Approval must be obtained prior to 
implementing the change 
 
Clinically important increase in the rate of a 
serious suspected adverse reaction of that 
list in the protocol or IB 
 
 
Complaints 
If the complaint reveals an unanticipated 
problem involving risks to participants or 
others OR noncompliance, report within 10 
working days.  If the event results in the 
death of a participant enrolled at 
WU/BJH/SLCH, report within 1 working day.  
Otherwise, report at the time of continuing 
review. 
 
Breach of confidentiality 
Within 10 working days. 
 


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Expedited Reporting Timelines 
Event 
HRPO 
QASMC 
Incarceration 
If withdrawing the participant poses a safety 
issue, report within 10 working days.   
 
If withdrawing the participant does not 
represent a safety issue and the patient will 
be withdrawn, report at continuing review. 
 
 
Routine Reporting Timelines 
Event 
HRPO 
QASMC 
Adverse event or SAE that does not require 
expedited reporting 
If they do not meet the definition of an 
unanticipated problem involving risks to 
participants or others, report summary 
information at the time of continuing review 
Adverse events will be reported in the 
toxicity table in the DSM report which is 
typically due every 6 months. 
Minor deviation 
Report summary information at the time of 
continuing review. 
 
Complaints 
If the complaint reveals an unanticipated 
problem involving risks to participants or 
others OR noncompliance, report within 10 
working days.  If the event results in the 
death of a participant enrolled at 
WU/BJH/SLCH, report within 1 working day.  
Otherwise, report at the time of continuing 
review. 
 
Incarceration 
If withdrawing the participant poses a safety 
issue, report within 10 working days.   
 
If withdrawing the participant does not 
represent a safety issue and the patient will 
be withdrawn, report at continuing review.