Conditions: Gastrointestinal Cancer
Keywords: Gastrointestinal cancer Hyperthermic Intraperitoneal Chemoperfusion HIPEC Gastric carcinomatosis Gastroesophageal cancer Mitomycin C Mitomycin Cisplatin Platinol-AQ Platinol CDDP Sodium Thiosulfate Tinver
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 21
Healthy volunteers: no

Brief summary:
The goal of this clinical research study is to learn if hyperthermic intraperitoneal chemotherapy (HIPEC) will help to control the disease in patients with Stage 4 stomach or gastroesophageal cancer. The safety of this treatment will also be studied.

Detailed description:
HIPEC Treatment:

If you are found to be eligible to take part in this study, on the day of HIPEC treatment, you will receive heated mitomycin-C and cisplatin as a liquid that is injected through 3 to 4 small incisions in your abdomen for about 1 hour. This will be done as a surgical procedure, and you will be under general anesthesia. The chemotherapy will then be flushed out of your abdomen and collected, and the treatment area inside your abdomen will be washed. Also during the HIPEC procedure, fluid will be collected and checked for cancer cells. As is standard of care, any lesions that are found during treatment may also be biopsied at this time, if the study doctor thinks it is necessary. You may receive up to 5 HIPEC treatments on this study.

You will also receive sodium thiosulfate by vein over about 20 minutes to protect the kidneys.

You will remain in the hospital for 3-7 days after treatment.

While you are in the hospital after surgery:

* Blood (about 2-3 tablespoons) may be drawn for routine tests, if the study doctor thinks it is necessary.

Study Visits:

One (1) time between Weeks 2-6:

* You will have a physical exam.
* Blood (about 2-3 tablespoons) will be drawn for routine tests.

Gastrectomy Surgery:

If your doctor thinks it is needed, you will have a standard of care surgery. You will receive a separate consent form which explains the surgery and its risks.

On or before 8 weeks after your surgery:

* You will have a physical exam.
* Blood (about 2-3 tablespoons) will be drawn for routine tests.

Follow-Up Visits:

You will have routine clinic visits every 6 months from the date of your last surgery. You will be asked about any other cancer treatments you may be receiving. If you stopped the study early, the study doctor may ask you to return to the office for extra CT scans, PET scan, or MRIs during the follow-up period.

You will have a CT scan, PET scan, or MRI of your chest, abdomen, and pelvis every 6 months for 5 years after surgery to check the status of the disease.

Length of Study Participation:

You will be on study for about 5 years after your last surgery. You will be taken off study early if the disease gets worse, if intolerable side effects occur, or if you are unable to follow study directions.

Your participation on the study will be over after the follow-up visits.

This is an investigational study. The chemotherapy and surgery are standard treatment for stomach and gastroesophageal cancer. It is investigational to give the chemotherapy by HIPEC.

Up to 30 participants will take part in this study. All will be enrolled at MD Anderson.

Arms:
arm 1: Laparoscopic HIPEC consists of Mitomycin C 30 mg and Cisplatin 200 mg for 60 minutes, performed 2-8 weeks after completion of systemic chemotherapy. Loading dose Sodium Thiosulfate 7.5 gm/M2 infused prior to addition of Cisplatin to the peritoneal perfusion circuit. Then a maintenance infusion of Sodium Thiosulfate 25.56 gm/M2 delivered by infusion pump over 12 hours.

Interventions: intervention 1: Mitomycin C intervention 2: Cisplatin intervention 3: Sodium Thiosulfate
Intervention descriptions: intervention 1: Mitomycin C 30 mg delivered laparoscopically for 60 minutes. intervention 2: Cisplatin 200 mg delivered laparoscopically 60 minutes, 2-8 weeks after completion of systemic chemotherapy. intervention 3: Loading dose of 7.5 gm/M2 of Sodium Thiosulfate infused prior to addition of Cisplatin to the peritoneal perfusion circuit. Then a maintenance infusion of Sodium Thiosulfate 25.56 gm/M2 delivered by continuous infusion pump over 12 hours.

Protocol document:
Prot_SAP_000.pdf: 
2013-0989 
August 19, 2015 
Page 1 
 
 
PROTOCOL 
 
SHORT TITLE: Laparoscopic HIPEC for metastatic gastric cancer 
 
FULL TITLE: A Phase II study of laparoscopic hyperthermic intraperitoneal chemoperfusion 
(HIPEC) for gastric carcinomatosis or positive cytology  
 
PROTOCOL TYPE: Standard Clinical 
 
PROTOCOL PHASE: II 
 
Principal Investigator:  Brian Badgwell, MD, MS 
 
Co-Investigators:  
Mariela Blum, MD 
 
 
 
Jaffer Ajani, MD 
Paul Mansfield, MD 
Keith Fournier, MD 
Xuemei Wang, MS 
Graciela M. Nogueras González, MPH 
Jeannelyn S. Estrella, MD 
 
 
 
 
 


2013-0989 
August 19, 2015 
Page 2 
 
Table of Contents 
 
Title Page………………………………………………………………………..1 
Table of Contents……………………………………………………………...2 
Abbreviations…………………………………………………………………...3 
1.0 Objectives…………………………………………………………………...4 
2.0 Background…………………………………………………………………4 
3.0 Eligibility Criteria…………………………………………………………...6 
4.0 Design & Methods………………………………………………………….7 
Conceptual Model………………………………………………………..8 
Study Calendar……………………………………………………….......9 
Procedures & Treatment Plan………………………………………...10 
Pretreatment Evaluation……………………………………………….11 
Preoperative Evaluation………………………………………………..11 
Postoperative Evaluation………………………………………………11 
 
Correlative Studies……………………………………………………...12 
5.0 Adverse Events Reporting Requirements…………………………….13 
 
Adverse Events………………………………………………………….13 
 
Recording of Adverse Events…………………………………………..14 
 
Method of Detecting AE/SAE…………………………………………..14 
6.0 Statistical Considerations………………………………………………..14 
7.0 Toxicity Monitoring………………………………………………………...15 
8.0 Audits and Inspections…………………………………………………...18 
9.0 Training of Staff…………………………………………………………….18 
10.0 Changes to the Protocol…………………………………………………18 
11.0 Ethics………………………………………………………………………..18 
12.0 Emergency Procedures…………………………………………………..19 
13.0 Data Safety Monitoring Plan……………………………………………..19 
14.0 Data Quality Assurance and Documentation….................................20 
15.0 Retention of Records……………………………………………………...21 
16.0 References…………………………………………………………………..22 
 


2013-0989 
August 19, 2015 
Page 3 
 
ABBREVIATIONS 
AE 
Adverse Event 
ALT 
Alanine Transaminase 
ANC 
Absolute Neutrophil Count 
AST 
Aspartate aminotransferase 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
Cis 
Cisplatin 
CRF 
Case Report Form 
CT 
Computed Tomography 
CXR 
Chest X-Ray 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
H & P 
History and Physical 
HIPEC 
Hyperthermic Intraperitoneal Chemotherapy 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IV 
Intravenous  
LDH 
Lactate dehydrogenase 
LFT 
Liver Function Test 
NCI 
National Cancer Institute  
NYHA 
New York Heart Association 
OAE 
Other Significant Adverse Event 
PET 
Positron Emission Tomography 
RBC 
Red Blood Cells 
SAE 
Serious Adverse Event 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SGPT 
Serum Glutamic Pyruvic Transaminase  
SOP 
Standard Operating Procedure 
STEAE 
Serious Treatment Emergent Adverse Event 
UA 
Urine Analysis 
WBC 
White Blood Count 
WHO 
World Health Organization 
 
 
 
 
 
 
 


2013-0989 
August 19, 2015 
Page 4 
 
1.0 OBJECTIVES 
Primary: To assess overall survival from the date of diagnosis in subjects with stage IV gastric and 
gastroesophageal cancer and positive cytology or imaging occult carcinomatosis after laparoscopic 
hyperthermic intraperitoneal chemotherapy administration.  
Secondary:  
1) To assess the safety of laparoscopic hyperthermic intraperitoneal chemotherapy administration 
for subjects with gastric and gastroesophageal cancer and positive cytology or imaging occult 
carcinomatosis. 
2) To assess the gastric resection rate in subjects with stage IV gastric and gastroesophageal 
cancer representing positive cytology or imaging occult carcinomatosis after laparoscopic 
hyperthermic intraperitoneal chemotherapy administration.  
 
2.0 BACKGROUND 
Peritoneal carcinomatosis and microscopic peritoneal disease represents an aggressive mode of 
spread for gastric cancer which ultimately results in death.  Heated regional peritoneal 
chemotherapy has been demonstrated to be effective in mesothelioma and appendiceal tumors.1, 2  
In addition, intraperitoneal chemotherapy has been found to improve survival in gastric cancer.3-5 
From January 1995 to December 2005, 3747 patients presented to M. D. Anderson Cancer Center 
with gastric or gastroesophageal junction adenocarcinoma.  Of those, 381 were without metastatic 
disease on radiologic imaging and underwent diagnostic laparoscopy for further staging prior to 
consideration for neoadjuvant treatment.  Eighty-three patients had carcinomatosis on laparoscopy 
while 39 had positive cytology in the absence of carcinomatosis.  Carcinomatosis and positive 
cytology are classified as metastatic or Stage IV disease according to the American Joint 
Commission on Cancer Staging Manual (7th edition).6  However, this population of 122 patients had 
stage IV disease that could be described as a local effect from serosal invasion and peritoneal 
spread rather than hematologic or lymphatic spread, and therefore are good candidates for local 
chemotherapy administration.  The population of patients with isolated peritoneal disease are also 
good candidates for a clinical trial as traditional treatment regimens yield dismal survival rates.  
Median OS (overall survival) for patients with positive peritoneal cytology and no visible metastatic 
disease at laparoscopy was 12.8 months while median OS was 10.2 months for patients with 
carcinomatosis at laparoscopy as displayed in Figure 1.7  For the patients with positive peritoneal 
cytology and no visible metastatic disease, use of neoadjuvant therapy (most often induction 5-FU 
and oxaliplatin followed by chemoradiation therapy with 45 Gy) resulted in a 3-year OS rate of 12% 
versus 0% for patients treated as having incurable stage IV disease.  For the patients with 
carcinomatosis at laparoscopy, outcomes were worse with 0% 3-year OS.  For the 122 patients with 
carcinomatosis at laparoscopy or positive cytology, only 8 (6.7%) underwent resection.  The 
proposed trial will focus on the combined population of patients with radiologically occult 
carcinomatosis or positive cytology at laparoscopy. 


2013-0989 
August 19, 2015 
Page 5 
 
Hyperthermic intraperitoneal chemotherapy (HIPEC) is a surgical technique for combining 
hyperthermia and chemotherapeutic agents to the peritoneal surface via a heated perfusion circuit.8  
Support for the concept of combining heat with chemotherapy is provided through in vivo and in 
vitro laboratory studies that have established the selective lethal effects of heat on human and 
murine neoplastic cells.9  Hyperthermia may work through a direct antitumor effect, augmenting the 
cytotoxic effects of chemotherapy, or increasing the depth of penetration of chemotherapy into 
tissues and tumor nodules. 
There are many theoretical benefits to a neoadjuvant laparoscopic approach to HIPEC in gastric 
cancer.  Patients would not be subjected to the risks of gastrectomy unless they demonstrated a 
response to laparoscopic HIPEC.  Performing a laparoscopic HIPEC would also allow for clear 
visualization of the response to treatment as a diagnostic laparoscopy with peritoneal washings 
should be performed at the intitiation of the procedure.  There is also data to suggest that 
performing laparoscopic HIPEC without cytoreduction and gastrectomy is a low risk procedure.  A 
recent systematic review of laparoscopic hyperthermic intraperitoneal chemotherapy suggests this 
is a safe procedure with no mortalities and < 10% morbidity in 183 patients.  Of note, however, is 
that only 5 patients in this series underwent this procedure as part of a neoadjuvant approach prior 
to cancer treatment.10  Therefore, the purpose of this clinical trial is to determine the efficacy and 
safety of laparoscopic hyperthermic intraperitoneal chemotherapy with Mitomycin C and Cisplatin in 
patients with stage IV gastric cancer after treatment with systemic chemotherapy. 
3.0 Eligibility: (List All Criteria) 
Inclusion: 
1)  
Age 18 years and above. There will be no upper age restriction. 
2) 
ECOG performance status ≤ 2. (See Appendix A –ECOG Performance Status Scale).  
3) 
Cytologic or histologic proof of adenocarcinoma of the stomach or gastroesophageal 
junction.  
4) 
Adequate renal, and bone marrow function: 
 
a. 
Leukocytes >= 3,000/uL  
 
b. 
Absolute neutrophil count >= 1,500/uL  
 
c. 
Platelets >= 100,000/Ul  
 
d. 
Serum creatinine <= 1.5 mg/dL 
5) 
Hepatic function: 
 
AST (SGOT)/ALT (SGPT) < 5 X institutional ULN. 
6) 
Distant Metastatic Disease limited to peritoneum and radiologically occult (not visualized on 
preoperative imaging to include CT, U/S, MRI, PET/CT): 


2013-0989 
August 19, 2015 
Page 6 
 
 
a. Positive peritoneal cytology 
 
b. Carcinomatosis on diagnostic laparoscopy or laparotomy. 
7) 
Completion of preoperative systemic chemotherapy. 
 
Exclusion: 
1) 
Distant metastatic disease not limited to peritoneum: 
 
a. Solid organ metastases (liver, central nervous system, lung). 
2) 
Any distant metastatic disease visualized on preoperative imaging: 
 
a. Solid organ metastases 
b. Clear radiologic evidence of carcinomatosis. 
3)  
Infections such as pneumonia or wound infections that would preclude protocol therapy. 
4)  
Women with a positive urine or serum pregnancy test are excluded from this study; women 
of childbearing potential (defined as those who have not undergone a hysterectomy or who have 
not been postmenopausal for at least 24 consecutive months) must agree to refrain from breast 
feeding and practice adequate contraception as specified in the informed consent. Adequate 
contraception consists of oral contraceptive, implantable contraceptives, injectable contraceptives, a 
double barrier method, or abstinence. 
5) 
Subjects with unstable angina or New York Heart Association Grade II or greater congestive 
heart failure. 
6)   
Subjects deemed unable to comply with study and/or follow-up procedures. 
7) 
Subjects with a known hypersensitivity to protocol systemic chemotherapy that was life-
threatening, required hospitalization or prolongation of existing hospitalization, or resulted in 
persistent or significant disability or incapacity. 
 
4.0 DESIGN AND METHODS 
Subjects with gastric and gastroesophageal adenocarcinoma and positive peritoneal cytology or 
radiologically-occult carcinomatosis that have completed treatment with systemic chemotherapy will 
be offered participation in the study.  Type and duration of systemic chemotherapy will be left to the 
discretion of the treating medical oncologist.  Subjects may be inpatients or outpatients.  Subjects 
should have a contrast CT scan, MRI, or PET/CT scan within 6 weeks (42 days) of enrollment. 
Patients will have completed standard systemic therapy prior to enrollment.  Lack of imaging 
evidence of metastatic disease will be defined based on radiologic (CT scan, MRI, or PET/CT) 


2013-0989 
August 19, 2015 
Page 7 
 
imaging. Evidence of carcinomatosis or positive cytology will be based on laparoscopic clinical 
criteria (see eligibility criteria). HIPEC will be administered as defined by the protocol. Patients will 
undergo laparoscopic HIPEC as displayed in Figure 1.  Laparoscopic HIPEC will consist of 
Mitomycin C 30 mg and Cisplatin 200 mg in 3-7 liters of infusate circulated using an extracorporeal 
circulation device at a flow rate of 700-1500 mL/minute for 60 minutes, performed no sooner than 3 
weeks after completion of systemic chemotherapy.  The Laparoscopic HIPEC procedure may be 
performed up to 5 times, with a minimum of 3 weeks between procedures.  At the completion of this 
treatment, the subjects will undergo restaging CT scan, MRI, or PET/CT scan. Restaging will define 
two groups of subjects: 1) those whose disease progressed locally or who developed imaging 
evidence of distant metastatic disease, and 2) those whose disease has responded or remained 
stable. In addition, diagnostic laparoscopy with peritoneal cytology and biopsy of any suspicious 
lesions will be performed at the initiation of the laparoscopic HIPEC and will provide clinically 
significant information regarding the persistence of peritoneal disease.  After laparoscopic HIPEC, 
subjects whose disease did not progress will proceed to surgery with diagnostic laparoscopy and 
possibly exploratory laparotomy to assess resectability, and if their cancer is resectable will undergo 
gastrectomy. After completion of study–related treatment, subjects will be followed until recurrence 
and/or death for up to five years. 
 
 
Figure 1. 
Single Arm, Phase II 
 
 
 
 
 
Positive Peritoneal Cytology or 
Peritoneal Disease on Laparoscopy 
/Exploratory Laparotomy 
Systemic 
Chemotherapy   
Laparoscopic 
HIPEC 
Mitomycin C 30 mg 
Cisplatin 200 mg  
- No Imaging Metastases 
- Imaging Metastases 
- No carcinomatosis 
- Negative cytology 
Proceed with Exploratory 
Laparotomy & Possible 
Gastrectomy 
 
No Gastrectomy 
 
≥ 3 weeks 
≥ 2 weeks from HIPEC 


2013-0989 
August 19, 2015 
Page 8 
 
Study Calendar 
*See the Study Calendar Footnotes  
Study Calendar Footnotes: 
 
a. Vital signs: blood pressure and pulse rate. 
b. Serum Chemistries: albumin, alkaline phosphatase, ALT, AST, bilirubin, calcium, chloride, CO2, creatinine, glucose, LDH, magnesium, 
phosphorus, potassium, sodium,].  
c. Complete Blood Count (CBC): Hemoglobin, hematocrit, red blood cells [RBC], white blood cells [WBC], platelets, and differential blood 
cell counts such as: neutrophils, lymphocytes, monocytes, eosinophils, basophils). 
d. Imaging can include CT Chest/Abdomen/Pelvis, Abdominal/Pelvis MRI, or PET/CT scan and may be within 6 weeks of enrollment.  
e. All adverse events occurring during any part of the study will be reported appropriately to the IRB. 
f. Laparoscopic hyperthermic intraperitoneal chemotherapy administration. 
 
STUDY CALENDAR 
 
Pre-
Treatment 
Evaluation 
≤ 28 days 
Treatment 
Initiation 
 
 
 Post-Treatment 
(Post-operative) 
Evaluation 
Pre-Gastrectomy 
Evaluation  
Gastrectomy 
Week ≥ 2 
weeks after 
HIPEC 
Post Gastrectomy 
Evaluation 
≤8 weeks after 
surgery 
Survival 
Follow-up Q 6 
months 
H&P & Concurrent Meds 
X 
 
 
X 
 
X 
X 
Consent 
X 
 
 
 
 
 
 
Vital Signsa 
X 
X 
X 
X 
 
X 
 
ECOG Performance Status  
X 
 
 
 
 
 
 
Serum Chemistriesb 
X 
 
 
 
 
 
 
CBCc 
X 
 
 
 
 
 
 
Pregnancy Test (urine or serum) 
X 
 
 
 
 
 
 
Imagingd 
X 
 
 
X 
 
 
X 
Adverse Eventse 
 
X 
X 
X 
X 
X 
 
LS HIPECf 
 
X 
 
 
 
 
 
Gastrectomy 
 
 
 
 
X 
 
 
Tissue for correlative studies 
 
 
 
 
X 
 
 


2013-0989 
August 19, 2015 
Page 9 
 
Informed Consent will be obtained. 
 
Type of Study: Prospective phase II, single institution clinical trial. 
 
Procedures and Treatment Plan 
1. Laparoscopic HIPEC: Mitomycin C 30 mg and Cisplatin 200 mg in 3-7 liters of infusate 
will be administered using a rolling pump with hyperthermia for 60 minutes. 
Pathology 
For those patients that undergo gastrectomy, esophageal, gastric, or duodenal margins will be 
evaluated on frozen section.  Recorded on permanent section will be tumor depth, degree of 
differentiation, margin status, lymph node status, and degree of treatment effect. 
 
Pretreatment Evaluation 
Within 28 days Prior to Study Enrollment the following procedures will be performed:  
a)  (Complete blood count: hemoglobin, hematocrit, red blood cells [RBC], white blood 
cells [WBC], platelets, and differential blood cell counts (neutrophils, lymphocytes, 
monocytes, eosinophils, basophils). ;  
 
b) Serum chemistries (albumin, alkaline phosphatase, ALT, AST, bilirubin, calcium, 
chloride, CO2, creatinine, glucose, LDH, magnesium, phosphorus, potassium, sodium).  
 
c) Pregnancy test) conducted prior to study enrollment to meet eligibility criteria.  
 
d) A history and physical exam. 
 
e) ECOG Performance status.  
 
f) Concurrent medications.  
 
g) Vital signs will also be collected during the pre-treatment evaluation.  
 
h) Within 6 weeks subjects must have undergone staging radiographic studies (CT chest, 
abdomen and pelvis, Abdominal/Pelvis MRI, or PET/CT scan). These studies are 
considered standard of care in the evaluation and treatment of patients with gastric 
cancer. 
Post-treatment Evaluation 
After laparoscopic HIPEC, patients will be monitored during their inpatient postoperative stay 
with standard of care postoperative laboratory analysis and daily vital signs.  
 
Expected postoperative hospital length of stay is 3 to 7 days. 


2013-0989 
August 19, 2015 
Page 10 
 
Pre-Gastrectomy Evaluation 
1. The subjects will be assessed as follows: 
a. Standard of care preoperative laboratory analysis 
b. History and physical and concurrent medications will be collected. 
c. Vital signs (blood pressure and pulse rate) will be collected. 
2. After completion of the laparoscopic HIPEC procedures, subjects without peritoneal 
carcinomatosis or positive cytology will be considered for gastrectomy.  Subjects will 
have a minimum 2 week rest period after the laparoscopic HIPEC to allow for recovery 
prior to gastrectomy. 
Post-resection Evaluation 
Within 8 weeks of completion of gastrectomy, the subject will have: 
1. History and physical and concurrent medications will be collected. 
2. Vital signs (blood pressure and pulse rate) on days of clinic evaluation. 
3. Standard of care postoperative laboratory analysis. 
Survival 
1. The primary endpoint in this study is overall survival, as measured from the time of 
diagnosis. Patterns of tumor recurrence and survival will be assessed by reviewing 
routine surveillance imaging. 
2. After completion of the treatment (HIPEC or gastrectomy), all subjects will be followed 
with imaging approximately every 6 months for five years. 
 
Criteria for Removal from Study: 
1. Inability of subject to comply with study requirements 
2. Determination by the investigator that it is no longer safe for the subject to continue 
therapy 
Correlative Studies: Tissue Banking 
All tissue samples will be collected according to MD Anderson Tissue Protocol LAB01-543 
SOPs. An IRB approved protocol in standard format is on file with the IRB (PI: Jaffer A. Ajani, 
M.D.).  Patients are consented prior to any endoscopic procedures performed at MD Anderson.  
Per the protocol and consent, if the patient requires surgery as part of his/her treatment, a 
portion of the remaining tissue will be stored.  No additional surgical maneuvers or procedures 
are necessary for the collection of study tissues, since all tissue samples will be collected from 
tissue that has already been removed as part of standard care. When feasible, tissue adequate 


2013-0989 
August 19, 2015 
Page 11 
 
for preparation of 50 slides (5 mm thick) will be stored from each collection. In brief, the 
objectives of this protocol are to: 
1. To collect and store, both prospectively and retrospectively, tissue, blood, body fluids 
and information for the sole purpose of banking pre-malignant and malignant lesions of 
the gastrointestinal tract. An IRB approved Informed Consent in standard format is on 
file with the IRB. 
2. To collect, store, and analyze, both prospectively and retrospectively, data on disease 
characterization, treatment and outcomes for patients with suspected premalignant and 
malignant lesions of the gastrointestinal tract at the University of Texas M. D. Anderson 
Cancer Center (UTMDACC). 
3. To collect, store, and analyze data on patients with gastrointestinal malignancies of the 
University of Texas M. D. Anderson Cancer Center (UTMDACC) from patients’ primary 
physicians or other treatment centers prior to, during and after the patients’ visits at 
UTMDACC. 
4. To collect, store or discard residual tissue, blood and other body fluids obtained during 
the performance of research activities for which consent and authorization have been 
obtained from the participant.  
 
 
5.0 ADVERSE EVENTS REPORTING REQUIREMENTS 
 
Investigators are required to report to the MD Anderson IRB ALL serious treatment emergent 
adverse event (STEAE) as soon as possible. The methods for collecting safety data are 
described below.  
Adverse Events 
1. Definitions 
The definitions of adverse events (AEs), serious adverse events (SAEs) and other significant 
adverse events (OAEs) are given below.  It is of the utmost importance that all staff involved in 
the study is familiar with the content of this section.  The principal investigator is responsible for 
ensuring this. 
2. Adverse Event (AE) 
An adverse event is the development of an undesirable medical condition or the deterioration 
of a pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered causally related to the product.  An undesirable medical condition 
can be symptoms (e.g., nausea, chest pain), or signs (e.g., tachycardia, enlarged liver).  In 
clinical studies, an AE can include an undesirable medical condition occurring at any time, 
including run-in or washout periods, even if no study treatment has been administered.   
3. Serious Adverse Event (SAE) 


2013-0989 
August 19, 2015 
Page 12 
 
A serious adverse event is an AE occurring during any study phase (i.e., run-in, treatment, 
washout, follow-up), and at any dose of the investigational product, comparator or placebo, 
that fulfills one or more of the following criteria: 
a. Results in death 
b. Is immediately life-threatening 
c. Requires in-subject hospitalization or prolongation of existing hospitalization 
d. Results in persistent or significant disability or incapacity 
e. Is a congenital abnormality or birth defect in the offspring of the subject 
f. Is an important medical even that may jeopardize the subject or may require 
medical intervention to prevent one of the outcomes listed above.  
Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life-threatening, or result in death or hospitalization but may jeopardize the patient or may 
require intervention to prevent one of the other outcomes listed in the definition above. These 
should also usually be considered serious. 
 
The causality of SAEs (i.e., their relationship to study treatment) will be assessed by the 
investigator(s), who in completing the relevant case report form must answer “yes” or “no” to 
the question “Do you consider that there is a reasonable possibility that the event may have 
been caused by the drug?”   
 
4. Other Significant Adverse Event (OAE) 
OAEs will be identified by the Drug Safety Physician and if applicable also by the Clinical Study 
Team Physician during the evaluation of safety data for the Clinical Study Report.  Significant 
adverse events of particular clinical importance, other than SAEs and those AEs leading to 
discontinuation of the subject from study treatment, will be classified as OAEs.  Examples of 
these are marked hematological and other laboratory abnormalities, and certain events that 
lead to intervention (other than those already classified as serious), dose reduction or 
significant additional treatment.  For each OAE, a narrative may be written and included in the 
Clinical Study Report. 
Recording of Adverse Events: 
Any detrimental change in a subject’s condition, subsequent to the subject entering the study 
should be considered an AE. AE reporting will be performing using CTCAE version 4.0. 
Method of detecting AE/SAE: 
At each visit the method of detecting AE and SAEs in this study will be by: 
1. Information volunteered by the subject, or caregiver 


2013-0989 
August 19, 2015 
Page 13 
 
2. Open-ended and non-leading verbal questioning of the subject at every visit such as the 
following: How are you feeling? Have you had any (other) medical problems since your 
last visit 
3. Observation by the investigational team, other care providers or relatives 
 
6.0 STATISTICAL CONSIDERATIONS 
For the futility monitoring of overall survival (OS), we have assumed a median OS of 11 
months for historical treatment and a median of 15 months (i.e., 4 months improvement) with 
the experimental therapy based on the preliminary data (Appendix C). For toxicity monitoring, 
we have assumed that 30% or higher rate of toxicity is intolerable.  
 
This is a single arm phase II study to assess the efficacy and safety of laparoscopic 
hyperthermic intraperitoneal chemoperfusion for gastric carcinomatosis or positive cytology. 
The primary objective of this study is to assess the overall survival (OS) in subjects with stage 
IV gastric cancer representing positive cytology or imaging occult carcinomatosis after 
laparoscopic hyperthermic intraperitoneal chemotherapy administration.  
 
The study will be continuously monitored for the primary endpoint, OS, using the method of 
Thall, Wooten, and Tannir.2  It is assumed that the OS for each patient is exponentially 
distributed with a median of λE among patients who receive the experimental treatment and a 
median of λH for the historical treatment.   Further, λH was assumed to follow an inverse 
gamma distribution, i.e., λH ~ IG(60, 649),  which has a mean of  11 months and variance of 
2.09. To reflect the little prior knowledge of λE we assumed an inverse gamma prior distribution 
with the same mean of 11 months and a much larger variance of 121, i.e., λE ~ IG(3, 22).  The 
trial will be stopped early if Pr(λE  > λH +δdata) < pL, where δ = 4 months and pL=0.03 and 
this  monitoring rule will be first applied when 3 patients have been enrolled. A maximum of 30 
patients will be enrolled into this study at an expected accrual rate of 1 to 2 patients per month.   
The trial will be conducted using the Clinical Trial Conduct (CTC) website 
(https://biostatistics.mdanderson.org/ClinicalTrialConduct/) maintained by the Department of 
Biostatistics at MDACC.  
 
The operating characteristics of the design, based on an overall assumed accrual rate of 1-2 
patients per month with 5000 simulated trials per scenario, are given in the following table: 
 
Scenario True Median  
(months) 
Pr(Stopped 
Early) 
Mean  
No. patients 
Average Trial 
Duration  
(months) 
1 
7 
0.788 
19 
27.6 
2  
9 
0.475 
24 
29.9 
3 
11 
0.254 
27 
31.3 
4 
13 
0.153 
28 
32.0 
5 
15 
0.075 
29 
32.4 
 
7.0 Toxicity Monitoring 


2013-0989 
August 19, 2015 
Page 14 
 
 
For the purpose of monitoring, toxicity is defined as > 30% Grade III or Grade IV toxicities 
occurring during the HIPEC and within 14 days after the HIPEC, as defined by Common 
Terminology Criteria for Adverse Events v4.0. The toxicity will be monitored using the method 
of Thall, Simon, and Estey.11, 12  Following are the rules for the monitoring of toxicities for the 
experimental treatment: the probability of toxicity is denoted by PE. We assume PE ~ beta 
(0.6, 1.4).  Our stopping rule is given by the following probability statement: Pr(PE > 0.30 | 
data)>0.95. That is, we will stop the study if, at any time during the study, we determine that 
there is more than 95% chance that the toxicity rate is more than 30%. The stopping 
boundaries for toxicities, based on these assumptions and monitoring conditions are found in 
table “Stopping boundaries for toxicities”. We will apply these stopping boundaries starting 
from the 3rd patient and then in cohorts of 3. For example, accrual will cease if 5 patients 
experience a toxicity among in the first 6 patients treated. The operating characteristics are 
summarized in “Operating characteristics for Toxicity Monitoring”. Both the decision rule and 
operating characteristics were calculated using the stopbound procedure in Stata version 12.1. 
 
 


2013-0989 
August 19, 2015 
Page 15 
 
Stopping boundaries for toxicities 
Stop accrual if the number of toxicities is greater than or equal to indicated (i.e., # 
patients with toxicities) among the number of patients evaluated. 
The number of patients 
evaluated for toxicities 
3 
6 
9 
12 
15 
18 
21 
24 
27 
30 
The number of patients with 
DLTs 
3 
5 
6 
7 
8 
9 
11 
12 
13 
14 
 
Operating characteristics for Toxicity Monitoring 
 
True Toxicity Rate 
Early Stopping Probability 
Sample Size 
25th percentile 
Median 
75th 
percentile 
0.10 
0.001 
30 
30 
30 
0.20 
0.015 
30 
30 
30 
0.30 
0.118 
30 
30 
30 
0.40 
0.382 
15 
30 
30 
0.50 
0.750 
9 
15 
27 
 
The joint stopping probabilities for Toxicity and for OS are shown in the table below. 
True Toxicity Rate 
Pr(Stopping Early) 
True Median 
(months) 
Pr(Stopping Early) 
Joint  
Stopping 
Probability 
0.10 
0.001 
7 
0.788 
0.788 
0.20 
0.015 
7 
0.788 
0.791 
0.30 
0.118 
7 
0.788 
0.813 
0.40 
0.382 
7 
0.788 
0.869 
0.50 
0.750 
7 
0.788 
0.947 
 
 
 
 
 
0.10 
0.001 
9 
0.475 
0.476 


2013-0989 
August 19, 2015 
Page 16 
 
0.20 
0.015 
9 
0.475 
0.483 
0.30 
0.118 
9 
0.475 
0.567 
0.40 
0.382 
9 
0.475 
0.676 
0.50 
0.750 
9 
0.475 
0.869 
 
 
 
 
 
0.10 
0.001 
11 
0.254 
0.255 
0.20 
0.015 
11 
0.254 
0.265 
0.30 
0.118 
11 
0.254 
0.342 
0.40 
0.382 
11 
0.254 
0.539 
0.50 
0.750 
11 
0.254 
0.814 
 
 
 
 
 
0.10 
0.001 
13 
0.153 
0.154 
0.20 
0.015 
13 
0.153 
0.166 
0.30 
0.118 
13 
0.153 
0.253 
0.40 
0.382 
13 
0.153 
0.477 
0.50 
0.750 
13 
0.153 
0.788 
 
 
 
 
 
0.10 
0.001 
15 
0.075 
0.076 
0.20 
0.015 
15 
0.075 
0.089 
0.30 
0.118 
15 
0.075 
0.184 
0.40 
0.382 
15 
0.075 
0.428 
0.50 
0.750 
15 
0.075 
0.769 
 
Statistical Analysis: 
All patients who received treatment will be included in the analysis for efficacy and safety.  
Demographic/clinical characteristics and safety data of the patients will be summarized using 
descriptive statistics such as mean, standard deviation, median and range. Resection rates will 
be presented with 95% confidence intervals. The association between resection rates and 
patient’s clinical characteristics will be examined by Wilcoxon’s rank sum test or Fisher’s exact 


2013-0989 
August 19, 2015 
Page 17 
 
test. Overall survival time will be estimated using the Kaplan-Meier method. Patients who drop 
out of the study will be included in the time to event data as “censored data”.  The two-sided 
log-rank test will be used to assess the differences of time to events between groups. 
 
8.0 AUDITS AND INSPECTIONS 
Regulatory authorities or the Institutional Review Board (IRB) may perform audits or 
inspections, including source data verification.  The purpose of such an audit or inspection is to 
systematically and independently examine all study related activities and documents to 
determine whether these activities were conducted, and data were recorded, analyzed, and 
accurately reported according to the protocol, Good Clinical Practice (GCP), guidelines of the 
International Conference on Harmonization (ICH), and any applicable regulatory requirements.   
9.0 TRAINING OF STAFF 
The principal investigator will maintain a record of all individuals involved in the study (medical, 
nursing and other staff).  Dr Badgwell will ensure that appropriate training relevant to the study 
is given to all study staff, and that any new information of relevance to the performance of this 
study is forwarded to the staff involved. 
A Site Initiation Visit will be conducted at MD Anderson Cancer Center for study staff. 
 
10.0 CHANGES TO THE PROTOCOL 
 
Study procedures will not be changed without approval from the IRB. If it is necessary for the 
study protocol to be amended, the amendment or a new version of the study protocol 
(Amended Protocol) must be approved by the MD Anderson IRB, and if applicable, by the local 
regulatory authority, before implementation.  Local and federal (Food and Drug Administration 
[FDA]) requirements must be followed. 
If a protocol amendment requires a change to the Written Informed Consent Form, the IRB 
must be notified.  Approval of the revised Written Informed Consent Form by the IRB and study 
sponsor is required before the revised form is used.  
The principal investigator is responsible for the distribution of these documents to the sub-
investigators and staff involved with the study.  
11.0 ETHICS 
Ethics Review: 
The final study protocol, including the final version of the Written Informed Consent Form, must 
be approved in writing by the MD Anderson IRB.  The principal investigator is responsible for 
informing the IRB of any amendment to the protocol in accordance with local requirements.  In 
addition, the IRB must approve all advertising used to recruit subjects for the study.  The 
protocol must be re-approved by the IRB annually. 
 
 


2013-0989 
August 19, 2015 
Page 18 
 
Ethical Conduct of the Study: 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/Good Clinical Practice, and applicable 
regulatory requirements. 
Written Informed Consent: 
The principal investigator will ensure the subject is given full and adequate oral and written 
information about the nature, purpose, possible risk and benefit of the study. Subjects must 
also be notified that they are free to discontinue from the study at any time. The subject should 
be given the opportunity to ask questions and allowed time to consider the information 
provided. The subject’s signed and dated informed consent must be obtained before 
conducting any procedure specifically for the study. 
The principal investigator must store the original, signed Written Informed Consent Form in the 
subject’s medical record as well as his/her study subject file.  A copy of the signed Written 
Informed Consent Form must be given to the subject. The consent process will be documented 
in the subject’s medical records.  
Subject Data Protection: 
The Written Informed Consent Form will explain that for data verification purposes, a regulatory 
authority, and the IRB may require direct access to parts of the hospital or practice records 
relevant to the study, including subjects’ medical history. 
12.0 EMERGENCY PROCEDURES 
Procedures in Case of Medical Emergency: 
The principal investigator(s) is responsible for ensuring that procedures and expertise are 
available to handle medical emergencies during the study. 
Procedures in Case of Overdose: 
There is currently no known antidote for the systemic chemotherapy in this study.  The 
treatment of AEs associated with overdose should be supportive for the underlying adverse 
symptoms. 
Doses of study treatment in excess of that specified in the clinical study protocol are 
considered to be an overdose. Overdose, with or without associated symptoms should be 
handled in the same way as a deviation and sent to IRB.  Signs or symptoms of an overdose 
that meet the criteria of serious should be reported as a SAE in the appropriate timeframes and 
be documented as clinical sequelae to an overdose. 
 
 


2013-0989 
August 19, 2015 
Page 19 
 
13.0 DATA SAFETY MONITORING PLAN 
The principal investigator and all research staff associated with this trial have received training 
and certification in human subject protections research and are ultimately responsible for 
monitoring the safety of this trial. 
The PI will continuously monitor this trial and more frequently safety related data. This trial will 
also be reviewed periodically by physicians and research staff at the Gastric Cancer 
Multidisciplinary Group meeting.  
Monitoring will be provided by the MD Anderson Clinical Research Center for this clinical trial.  
The monitor will assure that the rights and well – being of human subjects are protected and 
the data are accurate, complete and verifiable from source documents and the trial is 
conducted in compliance with currently approved protocol/amendments, with good clinical 
practice (GCP) and the applicable regulatory requirements. 
The monitor will be familiar with the protocol, the informed consent form, any other information 
provided to the subjects, the standard operating procedures (SOP), GCP and applicable 
regulatory requirements. 
Monitors will have access to subject medical records and other study-related records. The 
principal investigator agrees to cooperate with the monitor (s) to ensure that any problems 
detected in the course of these monitoring visits are resolved.  Personal contact between the 
monitor and the investigator will be maintained throughout the clinical trial to assure that the 
investigator is fulfilling his obligations and the facilities used in the clinical trial remain 
acceptable. 
Investigational Products: 
The systemic chemotherapy in this study is the current standard of care for the treatment of 
gastric cancer.  
Monitoring Report: 
After each monitoring visit a separate monitoring report will be generated and submitted to the 
principal investigator and project manager. This report will include significant findings related to 
deficiencies and deviations from the protocol, SOPs, GCP, and the applicable regulatory 
requirements and actions taken to prevent recurrence of the detected deviations. The report 
will make recommendations for actions to be taken to secure compliance.   
Continuing Review: 
An annual report will be compiled and sent to the IRB to report on number of subjects enrolled 
in the study and safety events and accrual schedule.  
14.0 DATA QUALITY ASSURANCE AND DOCUMENTATION 
CRF’s should be filled by qualified personnel, reviewed, dated and signed by the investigator.  
The forms have to be completed in a neat and legible manner with black or blue ballpoint pen.  
No entries should be erased or over written or correction fluid or white out be used. Corrections 


2013-0989 
August 19, 2015 
Page 20 
 
can only be crossed out with a single line and should have the date and initials of the person 
making the change. 
Source Documents are defined as original documents with original observations and 
information about the clinical investigation.  All electronic source documents should be 21 CFR 
11 compliant.  Source documents will include progress notes, computer print outs, laboratory 
data and all recorded data from automated instruments.  Monitor will review CRF’s against 
source documentation for accuracy of the information. Subject Confidentiality will be 
maintained. CRFs will not include any personal identification information such as name etc.  
Subjects will be identified with Initials and subject study number only. 
 
15.0 RETENTION OF RECORDS 
All documentation related to this trial will be retained for 2 years after the investigator is 
complete.  
 
 


2013-0989 
August 19, 2015 
Page 21 
 
16.0 REFERENCES 
 
1. 
Chua TC, Moran BJ, Sugarbaker PH, et al. Early- and long-term outcome data of patients 
with pseudomyxoma peritonei from appendiceal origin treated by a strategy of 
cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. J Clin Oncol 2012; 
30(20):2449-56. 
2. 
Yan TD, Deraco M, Baratti D, et al. Cytoreductive surgery and hyperthermic 
intraperitoneal chemotherapy for malignant peritoneal mesothelioma: multi-institutional 
experience. J Clin Oncol 2009; 27(36):6237-42. 
3. 
Yang XJ, Huang CQ, Suo T, et al. Cytoreductive surgery and hyperthermic intraperitoneal 
chemotherapy improves survival of patients with peritoneal carcinomatosis from gastric 
cancer: final results of a phase III randomized clinical trial. Ann Surg Oncol 2011; 
18(6):1575-81. 
4. 
Yan TD, Black D, Sugarbaker PH, et al. A systematic review and meta-analysis of the 
randomized controlled trials on adjuvant intraperitoneal chemotherapy for resectable 
gastric cancer. Ann Surg Oncol 2007; 14(10):2702-13. 
5. 
Sun J, Song Y, Wang Z, et al. Benefits of hyperthermic intraperitoneal chemotherapy for 
patients with serosal invasion in gastric cancer: a meta-analysis of the randomized 
controlled trials. BMC Cancer 2012; 12:526. 
6. 
AJCC. Stomach Cancer. In: Edge S, Byrd D, Compton C, et al., eds. Cancer Staging 
Manual, 7th edition. New York: Springer; 2010:pp. 117-126. 
7. 
Badgwell B, Cormier JN, Krishnan S, et al. Does neoadjuvant treatment for gastric cancer 
patients with positive peritoneal cytology at staging laparoscopy improve survival? Ann 
Surg Oncol 2008; 15(10):2684-91. 
8. 
Lambert L, Mansfield P. Surgical Management of Noncarcinoid Epithelial Neoplasms of 
the Appendix and the Pseudomyxoma Peritonei Syndrome. In: Pollock R, Curley S, Ross 
M, Perrier N, eds. Advanced Therapy in Surgical Oncology. Ontaria: BC Decker Inc.; 
2008:pp. 257-265. 
9. 
Van der Speeten K, Stuart OA, Sugarbaker PH. Pharmacology of perioperative 
intraperitoneal and intravenous chemotherapy in patients with peritoneal surface 
malignancy. Surg Oncol Clin N Am 2012; 21(4):577-97. 
10. 
Facchiano E, Risio D, Kianmanesh R, et al. Laparoscopic hyperthermic intraperitoneal 
chemotherapy: indications, aims, and results: a systematic review of the literature. Ann 
Surg Oncol 2012; 19(9):2946-50. 
11. 
Thall PF, Simon RM, Estey EH. Bayesian sequential monitoring designs for single-arm 
clinical trials with multiple outcomes. Stat Med 1995; 14(4):357-79. 
12. 
Thall PF, Wooten LH, Tannir NM. Monitoring event times in early phase clinical trials: 
some practical issues. Clin Trials 2005; 2(6):467-78.