Clinical trial NCT02040142
Conditions: Peritoneal Carcinomatosis Colorectal Cancer Appendiceal Cancer Peritoneal Mesothelioma Pseudomyxoma Peritonei Gastric Cancer
Keywords: Hyperthermic Intraperitoneal Mitomycin c HIPEC Cytoreduction
Sponsor: Albert Einstein College of Medicine
Start date: 2011-11-01; Completion date: 2024-08-19
Enrollment: 51 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a clinical study investigating the new treatment of surgery combined with intraperitoneal mitomycin-C for patients with gastrointestinal cancer that has spread to the peritoneal (abdominal cavity) surface. Mitomycin-C to be used in this procedure is approved by the U.S. Food and Drug Administration (FDA)for many different cancers including gastrointestinal cancer. Giving mitomycin C via the intraperitoneal route is not FDA approved and is an investigation therapy. Cytoreductive surgery plus intraperitoneal chemotherapy can be offered as standard of care outside of a clinical trial. However, since this is an unproven and potentially more effective but a more toxic approach, the investigators are performing this procedure under an IRB approved clinical trial in order to better evaluate the risks and benefits of this approach.

A standardized, evidence-based approach is currently lacking for patients with peritoneal surface malignancy from gastrointestinal origin. A clinical trial with surgical quality assurance and modern hyperthermic intraperitoneal chemotherapy incorporating critical assessment of disease burden, determinants of complete cytoreduction, treatment-related toxicity, quality of life and survival is imperative. Theoretically, cytoreductive surgery is performed to treat macroscopic disease, and hyperthermic intraperitoneal chemotherapy is used to treat microscopic residual disease with the objective of removing disease completely in a single procedure.

Detailed description:
Patients with peritoneal surface malignancy from gastrointestinal (GI) cancers almost uniformly succumb to advanced locoregional disease in the form of intractable ascites, malignant visceral obstruction and cancer cachexia. The natural history of peritoneal carcinomatosis from GI malignancies is inexorably lethal with median overall survival of approximately 5 months 7, as patients with disease confined to the peritoneum remain at increased risk of synchronous occult hematogenous metastases. While systemic therapy improves outcome in patients with hematogenous disease spread, improvements are needed in the control of peritoneal surface malignancy, which is known to be relatively resistant to systemic agents owing principally to the presence of a peritoneal-plasma partition. Moreover, the results of surgical resection alone for peritoneal dissemination of GI cancer have been disappointing given the difficulty in clearing surgically all microscopic disease foci. The infusion of chemotherapy into the peritoneal cavity provides distinct pharmacokinetic advantages. The addition of hyperthermia potentiates the effect of intra-peritoneal chemotherapy through anti-tumor synergism, without systemic drug absorption.

Mitomycin- C is the cytotoxic agent of choice for this purpose, one that has been studied most extensively for hyperthermic intra-peritoneal chemotherapy in patients with peritoneal carcinomatosis of gastrointestinal origin. Mitomycin- C has also been shown to demonstrate consistent pharmacokinetics, favorable toxicity profile, and hyperthermia-facilitated tumor cytotoxicity, which is enhanced under conditions of tumor hypoxia; furthermore, Mitomycin- C contributes to improved outcomes after optimal cytoreduction. Hence, the delivery of intra-peritoneal heated chemotherapy has the advantage of dose-dense regional delivery of cytotoxic agents with relatively little systemic toxicity. Current clinical experience suggests that adding cytoreductive surgery and hyperthermic intra-peritoneal chemotherapy to modern systemic chemotherapy regimens may significantly improve oncological outcomes.

The Montefiore-Einstein Center for Cancer Care has an on-going cooperative Cancer Bio-specimen Repository and correlative/translational research program to identify prognostic factors for patients with malignant tumors, as well as factors predictive of response to and toxicity of treatment. To support this important scientific work, tissue block submission \[primary tumor and peritoneal surface malignancy\] along with serum specimens will be mandatory for all patients providing informed consent for bio-specimen submission so that complete tissue microarrays (TMA) may be studied. These inquiries will establish molecular profiles of biomarkers of prognostic and predictive value in patients with gastrointestinal carcinomatosis undergoing treatment in the context of this trial.

The primary endpoint for analysis is to evaluate the technical parameters including completeness of cytoreduction, achievement of hyperthermia, morbidity and mortality in patients with peritoneal carcinomatosis undergoing CRS and hyperthermic intraperitoneal chemotherapy (HIPEC) with Mitomycin- C. Patients who have satisfied the inclusion criteria will be taken to the operating room for exploration and cytoreductive surgery. We will record the completeness of cytoreduction (CC 0 - CC 3) as described below. Complete cytoreduction will be defined as a CC 0 or CC 1. Ability to achieve adequate hyperthermia will be defined as target intraperitoneal temperature of 41-43º C. Adverse events will be assessed through enrollment following study treatment. The severity of adverse events will be evaluated using NCI-CTCAE version 4. Adverse events which are assessed as possibly, probably, or definitely related to study treatment will be followed until the AE is resolved or the subject is clinically stable. Other safety data including physical examinations, vital signs, hematology, clinical chemistry, and urinalysis will be collected from time of informed consent signed up through subject discontinuation or 12 months after initial study treatment, whichever occurs first.

For every multi-modality (CRS-HIPEC) case, the following will be required in the context of this clinical trial:

1. Patient eligibility for the trial will be determined and cross-sectional imaging reviewed;
2. Pre-operative Peritoneal Cancer Index (PCI) score will be determined by CT and/or laparoscopy;
3. Cytoreductive surgery will be undertaken involving any or all of the six principal peritonectomy procedures, based on volume and distribution of peritoneal surface disease, at the surgeon's discretion, in an effort to achieve complete resection of all grossly apparent peritoneal surface disease. Intraoperative PCI will be determined at the beginning of cytoreductive surgery;
4. Heated intra-operative intra-peritoneal chemotherapy will be delivered;
5. At the completion of the perfusion, the abdomen will be re-explored, residual fluid aspirated and reconstruction completed if not already completed prior to HIPEC;
6. Post resection PCI will be determined and completeness of cytoreduction will be estimated and using the CC and Response Rate (RR) systems;
7. Intra-peritoneal tubes and drains will be placed and the incision will be left open or closed in the usual fashion at the surgeon's discretion;

5.4 Surgical quality assurance and control (QA/QC)

5.4.1 Surgical QA/QC strategy

For every multi-modality (CRS-HIPEC) case, the following will be required in the context of this clinical trial:

1. Patient eligibility for the trial will be determined and cross-sectional imaging reviewed;
2. Pre-operative PCI score will be determined by CT and/or laparoscopy;
3. Cytoreductive surgery will be undertaken involving any or all of the six principal peritonectomy procedures, based on volume and distribution of peritoneal surface disease, at the surgeon's discretion, in an effort to achieve complete resection of all grossly apparent peritoneal surface disease. Intraoperative PCI will be determined at the beginning of cytoreductive surgery;
4. Heated intra-operative intra-peritoneal chemotherapy will be delivered;
5. At the completion of the perfusion, the abdomen will be re-explored, residual fluid aspirated and reconstruction completed if not already completed prior to HIPEC;
6. Post resection PCI will be determined and completeness of cytoreduction will be estimated and using the CC and RR systems defined above in section 5.2;
7. Intra-peritoneal tubes and drains will be placed and the incision will be left open or closed in the usual fashion at the surgeon's discretion; 5.5 Supportive care All appropriate supportive care for any side effects or toxicity will be provided by the physicians in the Montefiore-Einstein Center for Cancer Care of Montefiore Medical Center. Patients may be admitted as necessary to manage issues related to study treatment procedure.

7.1 Definitions for adverse event reporting Adverse event (AE) assessment, data collection and reporting will be done to ensure the safety of patients enrolled in this study. Adverse events secondary to both cytoreductive surgery and the utilization of intraperitoneal chemotherapy will be monitored closely, recorded appropriately and reported as required. The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting. All appropriate treatment areas should have access to a copy of the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be downloaded from the Cancer Therapy Evaluation Program (CTEP) web site (http://ctep.cancer.gov).

Timely reporting of serious and unexpected adverse events will be conducted throughout the trial period. Only commercial agents (not provided under IND) will be utilized in this study. The study subject will be informed of the indications, nature, alternatives, expected outcome, risks and benefits of all procedures and therapies provided in the context of this study. Clearly, there are potential, foreseeable risks or discomforts to participants in this study. Detailed information on adverse events or complications, which may be related to HIPEC or operative procedures provided in this trial, will be collected during the course of the study.

The CTEP CTCAE version 4.0 will be used to identify the type, and to grade the severity of adverse events in this trial. An adverse event will be considered a Serious Adverse Event (SAE) if that event led to death, resulted in a life-threatening illness or injury, resulted in permanent impairment of a body structure or body function, required inpatient hospitalization or prolongation of existing hospitalization, or resulted in medical or surgical intervention to prevent permanent impairment to body structure or body function.

An Unanticipated Adverse Event (UAE) will be considered any serious adverse effect on health or safety or any life-threatening problem or death caused by, or associated with, the commercial agent and/or surgical procedure, if that effect, problem, or death is not identified in nature, severity, or degree of incidence in this investigational plan or any other unanticipated serious problem associated with the commercial agent and/or operation that relates to the rights, safety, or welfare of the subjects participating in this study.

7.2 Adverse event assessment The severity type and grade of the adverse events will be identified using the NCI CTCAE, Version 4.0. Attribution/treatment relation of adverse events will be defined by the study doctor as Unrelated, Unlikely, Possible, Probable, or Definite.

An adverse event is defined as any unfavorable and unintended sign, including an abnormal laboratory finding, symptom, or disease temporally associated with the use of an investigational product, whether or not related to the investigational product. This includes any occurrence that was new in onset or aggravated in severity or frequency from the baseline condition. Adverse events (AEs) assessments will begin at time of signing of informed consent and will continue until 30 days following study treatment. AEs which are assessed as possibly, probably, or definitely related to study treatment must be followed until the AE is resolved or until the patient is clinically stable. Other safety assessments, including physical examinations, vital signs, hematology, clinical chemistry, and urinalysis, will be done through subject discontinuation or 12 months after initial study treatment, whichever occurs first.

The condition which is detected by the diagnostic procedure conducted to test the efficacy of the investigational agent is not considered an AE.

Symptoms or clinically significant laboratory or instrumental abnormalities of a pre-existing disease, such as cancer or other disease should not be considered an AE. However, occurrence of new symptoms or laboratory or instrumental abnormalities, as well as worsening of pre-existing ones, is considered AEs.

Abnormal results of diagnostic procedures, including laboratory test abnormalities, are considered adverse events if they result in:

* Discontinuation from the study.
* Treatment or any other therapeutic intervention.
* Further diagnostic evaluation (excluding a repetition of the same procedure to confirm the abnormality).
* Associated clinical signs or symptoms that would have a significant clinical impact, as determined by the Investigator.

Any untoward medical event that occurs from the time of signed informed consent to the time immediately prior to the first study treatment procedure will be reported as a "pre-treatment event" in the Medical History case report form (CRF).

All adverse events that occur following study treatment will be documented on the AE CRF with indications of onset, duration, severity (NCI CTCAEs), presumed relationship to study procedure /medication (not related, unlikely, possibly, probably, definitely), remedial actions taken, and outcome.

Surgical complications will be defined as secondary events deviating from the ideal course of convalescence that occurred during or following the operation, resulting in changes in management (diagnostic or therapeutic intervention) and delay in complete recovery and/or adjuvant therapy, or chronic disability.

Surgical complications will be scored according to a five-tier surgical morbidity and mortality scale (according to the intensity of therapy required for the treatment of the defined complication):

Grade Intensity of Treatment

1. Oral medications (e.g. oral antibiotics for surgical site infection or bedside care)
2. Intravenous medications or nutrition (e.g. antiarrhythmic therapy for supraventricular tachycardia)
3. Endoscopy, interventional radiology or reoperation (e.g. operative drainage of an abscess)
4. Chronic disability or major organ resection (e.g. reduction in performance status following post respiratory failure)
5. Death 7.3 Expedited Reporting of Adverse Events

   Expedited adverse event reporting for patients receiving commercial agents is required for:
   * All Grade 4 and 5 unexpected adverse events that are possibly, probably or definitely related to therapy.
   * All Grade 5 adverse events, regardless of attribution, occurring within 30 days of the end of therapy

   Expedited adverse event reporting will NOT be required for the following:

   • Adverse events related to surgery
   * Adverse events related to radiation
   * Adverse events that occur following the first cancer recurrence or second primary cancer development 7.4 Routine Reporting of Adverse Events All Grade 3-5 AEs must be recorded on the appropriate data form. Expedited reporting is in addition to, and does not supplant, the reporting of AEs as part of the data submission requirements for the study.

   Adverse events will be categorized by body system (such as cardiovascular-related, renal-related, etc.) and will be reported to the Montefiore institutional review board (IRB) as required by the IRB.

   Any serious event, including death from any cause that occurs through 30 days following study treatment, whether or not related to the investigational drug, must be reported to PI immediately (within 24 hours) via telephone, fax, or e-mail. If initially reported via telephone or e-mail, this must be followed-up by a written faxed report to be submitted within 24 hours of the initial report.

   Initial Reports

   Within 24 hours of the investigator's knowledge of a serious adverse event:

   • Complete a Serious Adverse Event Report Form (SAER), sign it, and fax it to the PI.
   * Place the initial version of SAER in the subject's file.

   Follow-Up Reports

   New information received spontaneously or by request of the Medical Monitor or Safety Surveillance. Within 48 hours of the receipt of new information:

   • Complete a new SAER with the new information. Sign and fax the form to PI.

   • Fax copies of supporting documents (e.g., hospital discharge summaries, lab test results with normal ranges, autopsy or biopsy reports) to PI.
   * Place the follow-up version of the SAE and all supporting documentation in the subject's file.

   Final Report

   Within 48 hours of the receipt of final information:

   • Determine that there is no further information available and this update may be considered final.
   * Complete a new SAER form with the new and final information. Sign and fax the form to PI. As above, send copies of any additional supporting information.
   * Place this version of the final SAER into the subject's file.

   It is imperative that IRB be informed within 24 hours of a serious adverse experience so that reporting to the FDA can be met within the required time frame (7 or 15 calendar days).

   Because of the need to report to health authorities all serious adverse experiences in a timely manner, it is vitally important that an Investigator report immediately any adverse experiences, which would be considered serious, even if the Investigator does not consider the adverse experience to be clinically significant or drug-related.

   Should the Investigator become aware of an SAE (regardless of relationship to study treatment) that occurs while the subject is on the study, the SAE must be reported in accordance with the procedures specified in this protocol.

   If the subject is withdrawn less than 30 days after study treatment, any SAEs which occur within 30 days after study treatment must be reported in accordance with the procedures specified in this protocol.

   All serious adverse events that are assessed as possibly, probably, or definitely related to study treatment are to be followed until either: the adverse event resolves, the adverse event stabilizes, the adverse event returns to baseline values (if a baseline value is available), or it is shown that the adverse event is not attributable to the study treatment or study conduct.

   8.1 Bio-specimen collection

   Collection and submission of primary tumor (in cases of synchronous disease), peritoneal surface malignancy, peritoneal cytology and perfusate, and serum samples are required for patients who consent to participation in the correlative science studies.

   Frozen tumor tissue or tumor tissue (primary cancer and peritoneal surface) blocks, peritoneal fluid for cytology, peritoneal perfusate and serum samples will be used for correlative science studies described below. Patients also may consent to storage of unused samples for future research. Analysis results will not be reported to the study subject and will not have any impact on how the study subject is treated and followed on protocol.

   The tumor samples, peritoneal fluid washings and perfusate samples will be processed by Cancer Bio-specimen Repository (CBSR) in accordance with routine tissue banking policy which includes:

   • Safeguards to address medical-legal concerns of submitting pathologists

   • Quality control of storage and sectioning of tissue and tissue blocks

   • Quality assurance of stored/sectioned tissue and tissue blocks

   • Scientific review process for utilization of human biological specimens in CBSR approved protocols.

   The CBSR core laboratory is affiliated with Einstein-Montefiore Institute for Clinical and Translational Research (ICTR) and is located at

   9.0 ETHICAL CONSIDERATIONS 9.1 IRB review The study will be conducted in the Montefiore Medical Center, in compliance with Title 21 of the Code of Federal Regulations (CFR), Part 50 (Protection of Human Subjects), and Part 56 (Institutional Review Board) as well as the principles of the Declaration of Helsinki and its amendments. The Montefiore Institutional Review Board (IRB) will review the protocol and informed consent. The study will not be initiated without IRB approval. All subjects will be required to give written informed consent prior to participation in the study. This study will be performed in accordance with Good Clinical Practices (GCP) by qualified Investigators.

   The study specifically incorporates the following features:
   * Single arm study design
   * Prospectively stated objectives and analytical plan
   * Accepted, pre-specified outcome measures for safety and efficacy
   * Compliance with Good Clinical Practices (GCP), with assessment via regular monitoring.

   Quality assurance procedures will be performed to assure that safety and efficacy data were adequate and well documented.

   In order to maintain patient confidentiality, all case report forms, study reports and communications relating to the study will identify subjects by initials and assigned subject numbers; subjects should not be identified by name. In accordance with local, national or federal regulations, the Investigator will allow the personnel of data monitoring committee access to all pertinent medical records in order to verify the data gathered on the case report forms. Regulatory agencies such as the US Food and Drug Administration (FDA) may also request access to all study records, including source documentation for inspection. Clinical information will not be released without the written permission of the subject as outlined in the subject consent form.

   Researchers will ensure the confidentiality of the information gathered in the study by using following methods:
   * Paper based records will be kept in a secured location and only accessible to personnel involved in the study.
   * All study data will be kept in locked file cabinets and password protected files.
   * Computer based files will only be made available to personnel involved in the study through the use of access privileges and passwords.
   * Prior to accessing any study-related information, personnel will be required to sign statements agreeing to protect the security and confidentiality of identifiable health information.
   * Whenever feasible, identifiers will be removed from study-related information.

10\. STATISTICAL CONSIDERATION 10.1 Sample size

The target number of patients proposed for this protocol is based on our primary objective, assessing completeness of cytoreduction. The achievement of hyperthermia as well as postoperative morbidity and mortality will be important factors at the interim analysis also. The latent goal is to utilize these estimates for generating future research hypotheses and protocol development as well as to benchmark our data against published data.

Sample size calculations are based on our primary objective. Our target sample size is 50 patients unless undue toxicity is encountered or the accrual is terminated at the interim analyses. A sample size of n=50, would produce a two-sided 95% confidence interval with a maximum width of 0.289 for a proportion of 0.5 and 0.267 for a proportion of 0.70. Calculations are based on exact binomial distribution. In a large multi-institutional study, 75% of patients were classified as Complete continuous remission 0 (CCR) and 17% CCR-1 1.

10.2 Statistical Data Analysis

Data will be entered on an excel spreadsheet and analyzed with Statistical Analysis Software (SAS) v9.2. Data analysis will be preceded by quality control of our data which will include checks for accuracy, completeness and internal validity.

Rates of completeness of cytoreduction, achievement of hyperthermia and postoperative morbidity and mortality will be computed and reported with their 95% confidence intervals. Descriptive data analysis will be conducted and all adverse events and overall patient characteristics will be described. Bivariate analysis will be conducted to examine factors associated with complete cytoreduction and achievement of hyperthermia. Categorical variables will be analyzed using the Fisher's exact test. Continuous variables whose distribution meets normality assumptions will be analyzed with the t-test. Variables whose distribution does not approximate normality will be analyzed using the Wilcoxon rank sum test.

For our secondary endpoints to evaluate time to progression, progression-free survival and overall survival we will use Kaplan-Meier methods. Progression-free survival will be calculated from time of surgery to date of recurrence or censored at time patient is last seen. Overall survival will be calculated from time of surgery to time of death or censored at the time patient is last seen. Log-rank test will be used to compare survival of patients who achieved complete cytoreduction with those who did not. We will compute 95% confidence intervals using Greenwood's formula.

QOL data will be collected using the Functional Assessment of Cancer Treatment (FACT-C) instrument. The feasibility of collecting QOL data will be assessed and rates of missing data will be computed. Reasons for missing data will be characterized to the extent possible. In addition to this, QOL data will be described using mean, standard deviation, median, inter-quartiles and range as well as graphically. For exploratory analysis of QOL data over time we will examine the use of hierarchical linear models.

Epigenetic and genomic data will be examined in an exploratory manner with the goal of informing the formulation of new research hypothesis.

10.2.1 Interim Analysis Decision Rules Interim analysis will be performed after the first enrolled 20 cases to assess the safety of the proposed treatment. Stopping rules will be based on 30-day postoperative mortality.

The overall mortality rate reported by Glehen et al in the largest retrospective series of patients with Peritoneal Carcinomatosis (PC) treated with Cytoreductive Surgery in combination with HIPEC was 4.1%. Based on Glehen's data, the upper limit of the 95% confidence interval around the 4.1% mortality rate is 5.3%.

While it is anticipated a mortality rate of 5% - comparable to that reported by Glehen - given the variability in origin of PC, given some variability in reports of mortality rates as reported by Koppe eta! 58 and given that patients undergoing this approach have very advanced disease and often progress through all other therapies- we will consider a 30-day mortality rate (from the therapy) of greater than I 0% to be unacceptable since this rate is higher than one would expect from the largest retrospective series available.

The 30-day mortality will be evaluated after the first 20 patients have been enrolled. If no more than 2 patients (I 0%) suffer a mortality within 30 days that is attributable to the therapy and not the underlying disease or unrelated to the therapy, we will continue to 50 patients. If 3 or more patients suffer a mortality within 30 days of the therapy that is directly attributable to the therapy, we will suspend accrual and will investigate the causes of the higher mortality.

After the root cause of the operative mortality has been determined, the study team will confer with the IRB and will make a determination as to whether accrual can be resumed.

10.3 Patient Accrual:

Based on our experience at the Montefiore-Einstein Center for Cancer Care and based on numbers of patients seen during the first half of the year, we expect to screen 30 patients yearly. We estimate 2/3 of these patients will meet inclusion criteria into the study. We expect high rates of participation into this protocol and estimate that it will take us 2-3 years to recruit the proposed sample of 50 patients. We will follow-up these patients until evidence of progression or for a total study time of 5 years.

10.4 Interim Reports

Interim reports will be prepared every 12 months. These will include:

* Monthly patient accrual rate
* Descriptive patient's demographic characteristics
* Descriptive clinical data
* Frequency and severity of adverse events

  11\. DATA COLLECTION AND REPORTING 11.1 Data collection

Complete research records or medical records must be maintained on each patient treated on the protocol for both scheduled and unscheduled evaluations. These records should include primary documentation (e.g. laboratory reports, X-ray reports, scan reports, pathology reports, physician's notes, etc.) which confirm that:

* The patient meet all eligibility criteria
* Signed informed consent will be obtained prior to treatment
* Treatment will be given according to protocol (dated notes about doses given, complications, and clinical outcomes).
* Toxicity will be assessed according to protocol.
* Response will be assessed according to protocol (X-ray, CT-scan, MRI, lab reports, date noted on clinical assessment, as appropriate).
* Montefiore Medical Center (MMC) Drug Accountability Records will be kept for each patient.
* The patient should use a diary to document daily adverse events.

11.2 Data Safety Monitoring Plan The PI and the research personnel will meet at least monthly to review all adverse events. Unexpected adverse events and/or serious adverse events will be reported to the MMC IRB. If trends are noted and /or risks warrant it, accrual will be interrupted and /or the protocol and/or consent will be modified accordingly. The MMC IRB will review submitted adverse events monthly to also evaluate trends and will require follow up plans from the principal investigator whenever a trend is identified.

11\. 3 Data Reporting All patients must have signed an informed consent form and an on-study (confirmation of eligibility) form filled out and signed by a participating Investigator before entering on the study.

Patients will be followed at least monthly during therapy for development of toxicity. Toxicity will be scored using CTCAE Version 4.0 for toxicity and adverse event reporting. All adverse clinical experiences, whether observed by the investigator or reported by the patient, must be recorded, with details about the duration and intensity of each episode, the action taken with respect to the study treatment, and the patient's outcome. The investigator must evaluate each adverse experience for its relationship to the study treatment and for its seriousness.

11.3.1 Routine Data Reporting:

Data will be captured in the MMC C3D web based reporting system. A minimum of 25% of the data will be source data verified. Grade 1 and 2 lab toxicities and medications used to treat adverse events will be maintained in the source documents but will not be captured in C3D. Only the following outside labs will be captured in C3D:

• Hemoglobin, WBC, ANC, Platelets, alanine aminotransferase/ aspartate aminotransferase (ALT/AST), total bilirubin, Creatinine {other labs associated with a serious adverse event may be captured as appropriate}

11.3.2 Expedited Reporting of Deaths on Study and Adverse Events

The protocol PI will report to the MMC-IRB:

* All deaths
* All grade 3 and 4 (CTCAE) events that are not listed in the consent form and that are possibly, probably or definitely related to the research
* All serious adverse events (SAEs) that are not listed in the consent form, but are possibly, probably or definitely related to the research. An SAE is defined as an untoward medical occurrence that:

  * Resulted in death
  * Was life-threatening
  * Required or prolonged hospitalization
  * Caused persistent or significant disability/incapacity
  * Resulted in congenital anomalies or birth defects
  * Required intervention to prevent permanent impairment or death
  * Is an important medical event
  * Suspected positive Pregnancy

11.3.3 Adverse Event Reporting in the Continuing Review Report

Data will be submitted for review by the IRB annually. The MMC-IRB requires a summary report of adverse events that have occurred on the protocol since the previous continuing review. The method of presentation should provide the MMC-IRB with the information necessary to clearly identify risks to participants and to make a risk: benefit determination. The summary report is based on the following guidance:

* Any unexpected severity and/or unexpected frequency of expected events needs to be reported and interpreted in relation to the risk: benefit of study participants in the narrative.
* Grade 1 events are not required.
* Grade 2 unexpected related to the research events is required.
* Grade 3 and 4 expected and unexpected events related to the research are required.
* All Serious Events regardless of attribution.
* Grade 5 (all) events are included regardless of attribution. Based on protocol-associated risks to participants, the MMC-IRB retains the authority to establish more frequent Continuing Review periods than the customary annual review period.

Arms: arm 1: HIPEC + 40mg of Mitomycin C. Mitomycin C, 30 mg, will be administered into the inflow line of the perfusion circuit once target temperature is reached. At the 60 minute time point of the perfusion, Mitomycin C, 10 mg, will be administered into the inflow line of the perfusion circuit. Once the 90-minute perfusion period has elapsed, the perfusate will be drained into the waste reservoir. The peritoneal cavity will be rinsed/washed-out.
Interventions: intervention 1: HIPEC intervention 2: Mitomycin C
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
Phase II Trial of Cytoreduction + Hyperthermic Intraperitoneal 
Mitomycin-C + Standard Systemic Therapy In Patients With Peritoneal 
Carcinomatosis for Advanced Non-small Cell Lung Cancer
Protocol ID: 11-09-332
NCT02040142


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Abbreviated Title: HIPEC for Peritoneal Carcinomatosis
IRB Protocol Number:11-09-332
Version Date: 08/08/2024
Phase II Trial of Cytoreduction + Hyperthermic Intraperitoneal Mitomycinc+ 
Standard Systemic Therapy In Patients With Peritoneal Carcinomatosis
Principal Investigator:
Surgical Oncology: John C. McAuliffe, M.D. 
Assistant Professor and Attending Surgeon 
Department of Surgery
Email: jomcauli@montefiore.org
Biostatistician 
Patricia Friedmann, M.S. 
Department of Surgery
Email: patricia.friedmann@einstein.yu.edu
Jiyue Qin, M.S.
Department of Epidemiology & Population Health 
Email: jiyue.qin@einsteinmed.org
IRB NUMBER: 11-09-332
IRB APPROVAL DATE: 08/19/2024


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Table of Content
1. BACKGROUND .........................................................................................................................3
1.1 Rationale for doing the study.................................................................................................3
1.2 Justification for evaluating Cytoreduction plus Hyperthermic Intraperitoneal Heated 
Mitomycin C (HIPEC).................................................................................................................7
2. STUDY OBJECTIVES: REVIEW SIDE EFFECTS AND OUTCOMES..................................8
3.0 ENDPOINTS .............................................................................................................................8
3.1 Primary endpoint....................................................................................................................8
3.2 Secondary endpoints ..............................................................................................................8
4.0 ELIGIBILITY ASSESSMENT AND ENROLLMENT............................................................9
4.1 Eligibility Criteria ..................................................................................................................9
4.2 Screening and follow-up evaluation ....................................................................................11
4.3 Registration Procedures .......................................................................................................12
5. STUDY TREATMENT PLAN..................................................................................................12
5.1 Intra-peritoneal heated chemotherapy..................................................................................12
5.2 Cytoreductive surgery..........................................................................................................15
5.3 Discontinuation of study treatment......................................................................................16
5.4 Surgical quality assurance and control (QA/QC) ................................................................17
5.5 Supportive care ....................................................................................................................17
6. ASSESSMENT OF EFFICACY................................................................................................17
6.1 Response criteria in peritoneal surface malignancy:............................................................17
6.2 Evaluation of Cancer Outcomes ..........................................................................................22
7. ADVERSE EVENTS ASSESSMENT AND REPORTING .....................................................24
7.1 Definitions for adverse event reporting ...............................................................................24
7.2 Adverse event assessment....................................................................................................24
7.3 Expedited Reporting of Adverse Events..............................................................................26
7.4 Routine Reporting of Adverse Events .................................................................................26
8.0 ETHICAL CONSIDERATIONS.............................................................................................27
8.1 IRB review...........................................................................................................................27
8.2 Informed Consent.................................................................................................................28
8.3 Subject Protection ................................................................................................................28
9.0. STATISTICAL CONSIDERATION......................................................................................29
9.1 Sample Size..........................................................................................................................29
9.2 Statistical Data Analysis ......................................................................................................29
9.3 Patient Accrual.....................................................................................................................30
9.4 Interim Reports ....................................................................................................................30
10.  DATA COLLECTION AND REPORTING............................................................................31
10.1 Data collection ...................................................................................................................31
10.2 Data Safety Monitoring Plan..............................................................................................31
10.3 Data Reporting...................................................................................................................31
10.4 Protocol amendments.........................................................................................................32
11.  REFERENCES: .......................................................................................................................33
IRB NUMBER: 11-09-332
IRB APPROVAL DATE: 08/19/2024


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1. BACKGROUND:
1.1 Rationale for doing the study
Peritoneal carcinomatosis (PC) refers to extensive dissemination of tumors on the 
peritoneal surfaces of the abdomen. PC is a common mode of spread of cancers of 
gastrointestinal origin, gynecologic tumors and occasionally cancers from other sites. PC is a 
major cause of treatment failure, morbidity and death in cancer patients. It often causes a 
marked decline in quality of life and presents as pain, ascites, and bowel obstruction. These 
conditions are caused by progressive involvement of the peritoneal surfaces by tumor seeded 
within the peritoneal cavity.
PC is a frequent manifestation in the natural history of numerous types of malignancies 
and has been traditionally regarded as a terminal disease with short median survival 1. Colorectal 
cancer presents with metastases to the peritoneum in 10-15% of patients at the time of diagnosis
2. Cancer recurrence confined to the peritoneum occurs in up to 25% of patients who have been 
treated curatively 3. Peritoneal carcinomatosis from gastric cancer can be found in 10% to 20% 
of patients at the time of initial surgery and in up to 60% of patients who have undergone a 
curative resection for T3/T4 tumors 4. The other common primary tumors for nonovarian 
peritoneal carcinomatosis include peritoneal mesothelioma, pseudomyxoma peritonei, and 
appendiceal adenocarcinoma1, 5.
Peritoneal carcinomatosis represents a formidable treatment challenge in oncology. Once 
considered a variant of systemic spread of disease, peritoneal carcinomatosis of different tumor 
origins was traditionally treated with palliative systemic chemotherapy alone, with surgery 
reserved only for palliation of disease- or treatment-related secondary events such as bowel 
obstruction and ascites. Systemic multi-drug chemotherapy has not altered the natural history of 
peritoneal carcinomatosis, as patients suffer disease progression and functional deterioration due 
to visceral obstruction, malignant ascites and cancer cachexia over a limited median survival of 5 
to 9 months 6-9.
The biology of peritoneal carcinomatosis is quite different than hematogenous metastasis. 
Insights into the natural history of peritoneal tumor dissemination have engendered novel multi- 
modality treatment approaches to address this challenging clinical problem. Tumor 
dissemination across peritoneal surfaces occurs through established mechanisms of direct tumor 
extension, transcoelomic tumor cell spread in peritoneal fluid, and malignant peritoneal seeding 
from surgical manipulation of the tumor, and can occur in the absence of regional or distant 
nodal or systemic metastases 10-12. Confinement of disease to the parietal peritoneal surface, in 
the absence of systemic metastasis, has served as the basis for surgical eradication of disease 
through aggressive surgical cytoreduction. However, surgery alone may not achieve significant 
improvement in survival in patients with peritoneal carcinomatosis, as microscopic or grossly 
apparent disease inevitably remains after even aggressive cytoreduction 13, 14.
The ineffectiveness of systemic chemotherapy for PC can be partially attributed to viable 
tumor cells that become sequestered in avascular intra-peritoneal adhesions 15. The presence of 
an anatomic barrier between the peritoneal cavity and plasma has enabled administration of high
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local concentrations of chemotherapy at the peritoneal surface, far in excess of systemically 
administered agents, when drug delivery is intra-peritoneal 16-19. High molecular weight agents 
such as Mitomycin C, and Oxaliplatin (397 Da) have favorable pharmacokinetic profiles (AUC, 
peritoneal fluid relative to plasma: Mitomycin C, 75:1; Oxaliplatin, 25:1) permitting dose-dense 
intra-peritoneal therapy over prolonged periods with rapid tissue concentration (in residual tumor 
deposits and peritoneum), but limited systemic absorption or toxicity20-23. This particular 
therapeutic approach addresses the problem of systemic chemotherapy resistance and with its 
reduced systemic toxicity provides distinct pharmacological advantage over systemic drug 
delivery24, 25.
6, 31.
Despite the high concentrations of the chemotherapeutic agent at the peritoneal surfaces, 
a limiting factor is the narrow depth of tissue penetration by the delivered cytostatic agent 32.
Penetration of these commonly used chemotherapeutic agents is limited to ≤ 3 mm from the 
parietal peritoneal surface 23, 33, 34. Therefore, the efficacy of hyperthermic intra-peritoneal 
chemotherapy is inversely proportional to the volume of residual disease. The therapeutic 
benefit of hyperthermic intra-peritoneal chemotherapy is greatest when all grossly apparent 
disease is resected (complete cytoreduction), leaving behind only microscopic disease.
This emphasizes the importance of complete cytoreduction which is conducted with the 
intent to eradicate macroscopic deposits of tumor and optimize the efficacy of hyperthermic 
chemotherapy in obliterating minimal residual disease. Optimal therapeutic synergy is achieved 
when intra-peritoneal heated chemotherapy is administered immediately following maximal 
cytoreduction, thereby minimizing trapping of viable peritoneal tumors cells in fibrin and post- 
operative adhesions, and maximizing kill of tumor cells shed during resection 35, 36. Adhesions 
are lysed during cytoreduction to facilitate uniform distribution of perfusate, maximize direct 
contact of drug with residual peritoneal tumor cells, and harness the advantage of “thermo- 
chemotherapeutic” anti-tumor synergism 25, 36-38.
The combination of cytoreductive surgery (CS) and hyperthermic intra-peritoneal 
chemotherapy can result in longer survival than CS alone in an experimental model with 
peritoneal carcinomatosis of colorectal origin 36. This combination has also shown promising 
oncological outcomes in clinical studies 1, 39, 40.
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A multi-center registry study of over 500 patients with peritoneal carcinomatosis of 
colorectal origin treated with this approach reported median overall survival of 19.2 months, and 
3- and 5-year overall survival rates of 39% and 19%, respectively40. For patients with no 
macroscopic residual disease after cytoreduction (CCR0) in that study, 3- and 5-year overall 
survival was 47% and 31%, with median survival of 32.4 months, similar to outcomes following 
complete resection of colorectal liver metastases. Treatment with adjuvant systemic 
chemotherapy after cytoreduction and peri-operative hyperthermic chemotherapy was an 
independent predictor of improved survival on multivariate analysis. This study, though 
retrospective in nature, suggested that improved outcomes are indeed possible with a combined 
modality treatment approach incorporating cytoreductive surgery, regional intra-peritoneal 
chemotherapy with or without adjuvant systemic therapy in patients that could otherwise expect 
limited survival ranging from 5-8 months 6, 7, 14. Overall survival in a large international registry 
study was consistent with that reported in prior smaller Phase II studies of combined 
cytoreduction and perioperative hyperthermic intra-peritoneal chemotherapy for peritoneal 
carcinomatosis of colonic origin and other nonovarian origin 41-49.
A single-institution, randomized controlled (Phase III) trial demonstrated the superiority 
of this combined modality approach for patients with colorectal peritoneal carcinomatosis over 
systemic chemotherapy, with or without surgical palliation 50. One hundred five patients with 
colorectal peritoneal carcinomatosis were randomly assigned to receive “standard,” 5-FU/LV, 
systemic chemotherapy or hyperthermic intra-peritoneal chemotherapy with Mitomycin C 
(HIPEC; Mitomycin C, 35 mg/m2 at 41 degrees C for 90 minutes) following aggressive 
cytoreduction. After a median follow up time of 22 months, median survival was increased 
significantly in the HIPEC arm of the study: 22.4 vs. 12.9 months; hazard ratio = 0.55: 95% CI, 
0.32-0.95. However, the absolute survival benefit of ~10 months in that study was offset by 
considerable treatment-related morbidity (Grade 4 morbidity = 45%) and mortality (8%) in the 
study arm. A significant proportion of treatment-associated complications (median operative 
blood loss 4,000 ml; small bowel fistula, 15%; operative site infection, 6%; renal failure, 6%; 
pancreatitis, 2%) have been hypothesized to be due to the high dose of intra-peritoneal 
hyperthermic Mitomycin C, which was administered in the context of the trial. Reductions in 
intraperitoneal Mitomycin C doses have been recommended on that basis.
Others have demonstrated significantly lesser treatment-related morbidity (23%-35%) 
and mortality (0-4%) with intra-peritoneal thermo-chemotherapy utilizing reduced Mitomycin C 
doses 37, 47, 51. Acceptable therapeutic toxicity has been reported in these studies with relatively 
lower doses of intra-peritoneal Mitomycin C without apparent compromise in treatment efficacy
37. The Dutch trial demonstrated benefit of cytoreductive surgery with HIPEC for patients with 
colorectal carcinomatosis50. Patients with peritoneal carcinomatosis with metastatic disease 
confined to the peritoneal surface treated with complete (CCR0) cytoreduction and HIPEC have 
demonstrated median survival exceeding 40 months (range 28-60 months) 40-49.
Studies showed that cytoreductive surgery combined with HIPEC is a safe treatment and 
could improve survival rates of patients with nonovarian peritoneal carcinomatosis 1, 9, 39, 52. A 
retrospective, multicenter cohort study included 1290 patients from 25 institutions who 
underwent 1344 procedures between February 1989 and December 2007. HIPEC was performed 
in 1154 procedures. The principal origins of PC were colorectal adenocarcinoma (N =523),
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pseudomyxoma peritonei (N = 301), gastric adenocarcinoma (N = 159), peritoneal mesothelioma 
(N = 88), and appendiceal adenocarcinoma (N = 50). The overall morbidity and mortality rates 
were 33.6% and 4.1%, respectively. In multivariate analysis, patient age, the extent of peritoneal 
carcinomatosis, and institutional experience had a significant influence on toxicity. The overall 
median survival was 34 months; and the median survival was 30 months for patients with 
colorectal origin, not reached for patients with pseudomyxoma peritonei, 9 months for patients 
with gastric origin, 41 months for patients with peritoneal mesothelioma, and 77 months for 
patients with peritoneal carcinomatosis from appendiceal adenocarcinoma 1.
In a phase II study, a total of 101 consecutive patients were treated with cytoreductive 
surgery, HIPEC and early postoperative intraperitoneal chemotherapy 5. Tumor types included 
appendiceal (n = 58), colorectal (n = 31), and other (n = 12). Median follow-up was 28 months 
(range, 0-119 months), with minimum of 24 months among survivors. For appendiceal tumors, 
median disease-free survival (DFS) was 34 months (range, 0-119 months) and overall survival 
(OS) has not yet been defined. Three-year and 5-year DFS was 48% and 42%, respectively, and 
3-year and 5-year OS was 76% and 62%, respectively. For colorectal carcinomatosis, median 
DFS and OS was 9 months (range, 0-87 months) and 27 months (range, 0-87 months), 
respectively. Three-year and 5-year DFS was 34% and 26%, respectively, and 3-year and 5-year 
OS was 38% and 34%, respectively. The results indicated that long-term survival is achievable 
for patients with peritoneal carcinomatosis from appendiceal or colorectal primary tumors who 
received regional treatment with cytoreductive surgery and HIPEC 5.
A single-institution, randomized controlled (Phase III) trial demonstrated the efficacy and 
safety of a combination of cytoreductive surgery (CRS) plus hyperthermic intraperitoneal 
chemotherapy (HIPEC) compared to CRS alone for the treatment of peritoneal carcinomatosis 
from gastric cancer 53. Sixty-eight gastric peritoneal carcinomatosis patients were randomized 
into CRS alone (n = 34) or CRS and HIPEC (n = 34) with cisplatin 120 mg and mitomycin C
30 mg each in 6000 ml of normal saline at 43 ± 0.5°C for 60-90 min. At a median follow-up of 
32 months (7.5-83.5 months), death occurred in 33 of 34 (97.1%) cases in the CRS group and 29 
of 34 (85.3%) cases of the CRS + HIPEC group. The median survival was 6.5 months (95% 
confidence interval 4.8-8.2 months) in CRS and 11.0 months (95% confidence interval 10.0- 
11.9 months) in the CRS + HIPEC groups (P = 0.046). Four patients (11.7%) in the CRS group 
and 5 (14.7%) patients in the CRS + HIPEC group developed serious adverse events (P = 0.839). 
Multivariate analysis found CRS + HIPEC and no serious adverse events were independent 
predictors for better survival 53. Similar results were also observed in another study of 30 patients 
with peritoneal carcinomatosis of gastric origin 54. The best indications for this treatment are 
localized peritoneal carcinomatosis from resectable gastric cancer that can be completely 
removed during a peritonectomy. Complete cytoreduction and hyperthermic intraperitoneal 
chemotherapy are essential treatment modalities for improving the survival of patients with 
peritoneal carcinomatosis from gastric cancer.54
A standardized, evidence-based approach is currently lacking for patients with peritoneal 
surface malignancy from gastrointestinal origin. A clinical trial with surgical quality assurance 
and modern hyperthermic intraperitoneal chemotherapy incorporating critical assessment of 
disease burden, determinants of complete cytoreduction, treatment-related toxicity, quality of life 
and survival is imperative. Theoretically, cytoreductive surgery is performed to treat
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macroscopic disease, and hyperthermic intraperitoneal chemotherapy is used to treat microscopic 
residual disease with the objective of removing disease completely in a single procedure.
This single arm study will be conducted recognizing the importance of surgical 
standardization and quality control, as well as hyperthermic intraperitoneal mitomycin-C for 
patients with malignancy of colorectal, appendiceal, pseudomyxoma, peritoneal mesothelioma or 
gastric origin having resectable dissemination of peritoneal disease, absent apparent 
hematogenous or distant nodal disease spread, and who are considered suitable candidates for 
aggressive local-regional therapy with CRS and HIPEC.
1.2 Justification for evaluating Cytoreduction plus Hyperthermic Intraperitoneal Heated 
Mitomycin C (HIPEC)
Patients with peritoneal surface malignancy from gastrointestinal (GI) cancers almost 
uniformly succumb to advanced locoregional disease in the form of intractable ascites, malignant 
visceral obstruction and cancer cachexia. The natural history of pertitoneal carcinomatosis from 
GI malignancies is inexorably lethal with median overall survival of approximately 5 months 7, 
as patients with disease confined to the peritoneum remain at increased risk of synchronous 
occult hematogenous metastases. While systemic therapy improves outcome in patients with 
hematogenous disease spread, improvements are needed in the control of peritoneal surface 
malignancy, which is known to be relatively resistant to systemic agents owing principally to the 
presence of a peritoneal-plasma partition. Moreover, the results of surgical resection alone for 
peritoneal dissemination of GI cancer have been disappointing given the difficulty in clearing 
surgically all microscopic disease foci. The infusion of chemotherapy into the peritoneal cavity 
provides distinct pharmacokinetic advantages. The addition of hyperthermia potentiates the 
effect of intra-peritoneal chemotherapy through anti-tumor synergism, without systemic drug 
absorption 35-38.
Mitomycin C is the cytotoxic agent of choice for this purpose, one that has been studied 
most extensively for hyperthermic intra-peritoneal chemotherapy in patients with peritoneal 
carcinomatosis of gastrointestinal origin. Mitomycin C has also been shown to demonstrate 
consistent pharmacokinetics, favorable toxicity profile, and hyperthermia-facilitated tumor 
cytotoxicity, which is enhanced under conditions of tumor hypoxia; furthermore, Mitomycin C 
contributes to improved outcomes after optimal cytoreduction 26, 33, 38, 44, 46, 48, 55, 56. Hence, the 
delivery of intra-peritoneal heated chemotherapy has the advantage of dose-dense regional 
delivery of cytotoxic agents with relatively little systemic toxicity. Current clinical experience 
suggests that adding cytoreductive surgery and hyperthermic intra-peritoneal chemotherapy to 
modern systemic chemotherapy regimens may significantly improve oncological outcomes.
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2. STUDY OBJECTIVES: Review Side Effects and Outcomes
Primary objective:

This prospective trial will evaluate the technical parameters including completeness of 
cytoreduction, , morbidity and mortality in patients with peritoneal carcinomatosis of 
colorectal, gastric, appendiceal, pseudomyxoma peritonei and peritoneal mesothelioma 
origin undergoing cytoreductive surgery and hyperthermic intraperitoneal 
chemotherapy with mitomycin C.
Secondary objectives:

To evaluate time to progression and progression free survival (PFS) for patients with 
peritoneal carcinomatosis treated with CRS + HIPEC.

To evaluate overall survival for patients with peritoneal carcinomatosis treated with CRS
+ HIPEC.
3.0 ENDPOINTS
3.1 Primary endpoint
The primary endpoint for analysis is to evaluate the technical parameters including 
completeness of cytoreduction, , morbidity and mortality in patients with peritoneal 
carcinomatosis undergoing CRS and HIPEC with mitomycin C. Patients who have satisfied the 
inclusion criteria will be taken to the operating room for exploration and cytoreductive surgery. 
We will record the completeness of cytoreduction (CC 0 – CC 3) as described below. Complete 
cytoreduction will be defined as a CC 0 or CC1.. Adverse events will be assessed through 
enrollment following study treatment. The severity of adverse events will be evaluated using 
NCI-CTCAE version 4. Adverse events which are assessed as possibly, probably, or definitely 
related to study treatment will be followed until the AE is resolved or the subject is clinically 
stable. Other safety data including physical examinations, vital signs, hematology, clinical 
chemistry, and urinalysis will be collected from time of informed consent signed up through 
subject discontinuation or 12 months after initial study treatment, whichever occurs first.
3.2 Secondary endpoints
3.2.1 Progression-free survival (PFS)
PFS is defined as time from operation date to the first documentation of disease 
progression or death as a result of any cause, whichever comes first. PFS will be censored at 
the date of last documented progression-free status for patients who are still progression- 
free, alive or lost to follow-up.
Determination of disease progression will be based on:

Radiological (CT ± PET), and/or
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
Surgical (laparoscopic or open exploration) evidence of recurrent disease. 
Peritoneal disease progression will be confirmed by cytology or histology 
revealing cells morphologically consistent with malignant tumor cells
The following events are considered as disease progression/recurrence:

Symptomatic or new ascites with peritoneal cytology positive for malignancy, 8 
or more weeks following operation; and/or,

Any new peritoneal surface tumors evident after complete cytoreduction by 
helical computed tomography, and/or biopsy-positive for malignancy; or,

Fifty percent or greater increase in peritoneal surface tumors evident after 
incomplete cytoreduction by helical computed tomography (progression of 
residual disease), 8 or more weeks after operation; or,

Any post-operative small bowel obstruction requiring re-operation with 
histologically confirmed malignant obstruction; or

If other indications progression/recurrence are not present, serum CEA and/or 
CA19-9 exceeding Upper Limit of Normal (ULN), and increasing ≥50% from last 
cycle of systemic therapy, verified by two CEA and/or CA19-9 measurements, ≥2 
weeks apart, 8 or more weeks after operation.
3.2.2
Overall Survival (OS)
OS is defined as the time from operation date to death from any cause. OS will be 
censored at the date of last follow up visit for patients who are still alive or lost to follow 
up.
.
4.0 ELIGIBILITY ASSESSMENT AND ENROLLMENT
4.1 Eligibility Criteria
4.1.1 Inclusion Criteria
Patients must satisfy the following conditions to be eligible for study enrollment and 
participation.
1. Age ≥ 18 years
2. Capable of providing informed consent.
3. The patient who has not previously received hyperthermic intraperitoneal chemotherapy 
must have histopathologically or cytologically confirmed cancer from peritoneal 
mesothelioma, pseudomyxoma, or gastrointestinal malignancies (excluding pancreatic and
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hepatobiliary) with known synchronous or metachronous disease dissemination limited to 
the peritoneal surfaces.
4. The patient must have documented disease limited to the peritoneal surface, amenable to 
complete cytoreduction indicated by:

Disease confined to the peritoneal surfaces

No parenchymal liver metastases

No evidence of clinical, biochemical or radiological biliary obstruction

Small volume of disease in the gastro-hepatic ligament defined by a < 5cm mass in 
the epigastric region on cross-sectional imaging

No clinical or radiological evidence of hematogenous or distant nodal metastasis
5. ECOG performance status of ≤ 1
6. Absolute neutrophil count (ANC) > 1500/mm3, white blood cell count (WBC) > 
4000/mm3 and platelet count > 100,000/mm3
7. Adequate hepatic function must be met as evidenced by total serum bilirubin ≤ 1.5 mg/dl 
(patients with total bilirubin > 1.5 mg/dL eligible only with Gilbert’s syndrome);
• alkaline phosphatase < 2.5 times the upper limit of normal; and/or
• AST < 1.5 times upper limit of normal
(alkaline phosphatase and AST cannot both exceed the upper limit of normal)
8. Adequate renal function: Creatinine <1.5x the upper limit of normal (ULN) or calculated 
creatinine clearance of ≥50ml/min.
9. Satisfactory cardiopulmonary function (no history of severe congestive heart failure or 
severe pulmonary disease, as indicated by clinically acceptable risks to undergo major 
abdominal - cytoreductive surgery).
4.1.2 Exclusion criteria:
1. The patients have documented disease beyond the peritoneal surfaces, which prevent 
achieving complete cytoreduction as indicated by:

Evidence of distant hematogenous metastatic disease or distant nodal metastases

Evidence of parenchymal hepatic metastases

Evidence of clinical, biochemical or radiological biliary obstruction

Evidence of gross disease of the small bowel mesentery characterized by 
distortion, thickening or loss of mesenteric vascular clarity which limits ability to 
obtain complete cytoreduction
2. Significant history of a medical problem or co-morbidity that would preclude the patient 
from undergoing a major abdominal operation such as a history of severe congestive heart 
failure or active ischemic heart disease.
3. Active systemic infections, coagulation disorders, or other major medical illnesses 
precluding major surgery.
4. Childs B or C cirrhosis or with evidence of severe portal hypertension by history, 
endoscopy or radiologic studies.
5. Significant COPD or other chronic pulmonary restrictive disease with PFTs indicating a 
FEV1 less than 50% or a DLCO less than 40% predicted for age
6. Psychiatric or addictive disorders or other conditions that would preclude the patient from 
meeting the study requirements.
7. Patients in pregnant or lactating.
8. Patients with a Body Mass Index (BMI) of 40 or more.
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4.2 Screening and follow-up evaluation
All required entry and follow-up studies are listed in the study chart.
Table 1: Required Entry and Follow-up Studies
Follow-up g
Required Examsa
Screening evaluation 
(within 6 weeks before 
registration unless 
otherwise specified)
After entry, 
before
HIPEC therapy/ 
operation begins
Every 3 
months 
for 1 year
Every 6 
months 
for 4 years 
thereafter
History, Physical Exam
x
x
x
ECOG Performance
x
Adverse event assessment
x
x
Laboratory Studies
Complete Blood Count
x
x
x
CBC Differential
x
x
x
Absolute Neutrophil Count
x
x
x
Pregnancy test (women of
reproductive potential)
x
Chemistries
Serum Creatinine
x
Serum BUN
x
Serum AST
x
Serum Alkaline Phosphatase
x
Serum Bilirubin
x
Tumor Marker
Serum CEA +/- CA19-9
x
x
x
Scans, Other
Chest/Abdomen/Pelvisef
x
x
x
Laparoscopy
xb
Cardiac testing
xc
Bone Imaging
xd
Electrocardiogram
x
Quality of Life Questionnairesh
x
x
x
a. History and physical (H&P), hematological studies, chemistries, and appropriate diagnostic testing may be 
performed at more frequent intervals at the discretion of the principal investigator.
b. Laparoscopy can be used at the discretion of the evaluating surgeon to determine if the patient is a candidate for a 
complete cytoreductive surgery and HIPEC.
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c. Study subjects with intermediate clinical predictors should undergo non-invasive cardiac testing. The need for 
cardiac testing prior to patient registration will be determined in consultation with internal medicine or cardiology 
and take into consideration major clinical predictors (unstable coronary syndromes, decompensated CHF, significant 
arrhythmia, valvular heart disease), functional capacity, and intermediate clinical predictors (mild angina, prior MI, 
compensated or prior CHF, diabetes).
d. Bone scan is required if alkaline phosphatase is > ULN or if the patient has unexplained bone pain.
e. Spiral CT or MRI is required.
f. Chest/Abdomen/Pelvis imaging should be performed every 3 months for the first 1 year then every 6 months for 4 
years. More frequent scanning can be performed at the discretion of the study site principal investigator during the 
active treatment time period. CT scan should be performed at disease progression or recurrence.
g. Follow up is calculated after surgery and should be every 3 months for 1 year and then every 6 months for 4 
years. The window for follow-up procedures is +/- 2 months. As follow-up procedures are standard of care, if 
subject is seen by other medical providers, we will collect the data from those standard of care visits, including 
history and physical exams, lab work, and imaging results.
h. Quality of Life questionnaires will be collected at baseline (registration), 6, 12 and 36 months from date of 
registration.
4.3 Registration Procedures
Authorized staff must register an eligible candidate with the Clinical Trial Office prior to 
surgery. If necessary, the Clinical Trials Office will then send the registration to the appropriate 
personnel.
5. STUDY TREATMENT PLAN
5.1 Intra-peritoneal heated chemotherapy
Surgery must start within eight weeks from screening.
5.1.1 Mitomycin C
Mitomycin C must be obtained from commercial sources. Please refer to the current FDA- 
approved package inserts provided with the medication or the Physician’s Desk Reference 
for detailed additional information about possible side effects and instructions for 
preparation, handling, and storage of the drug. The FDA has not approved Mitomycin C for 
HIPEC, but numerous Phase II studies have documented a very acceptable morbidity and 
mortality for the treatment of cytoreductive surgery combined with hyperthermic intra- 
peritoneal Mitomycin C given at the time of surgery.
Description
Mitomycin C acts as a bi- or tri-functional alkylating agent that inhibits DNA synthesis and 
cross-links DNA. Its activity is most pronounced during late G1 and early S phases of the 
cell cycle.
It is soluble in water, saline or dextrose/water. Mitomycin C appears as a bluish-purple 
crystal. The clinical formulation is supplied in a sterile form in vial. Mitomycin C is 
available in vials containing 5 mg, 20 mg, and 40 mg.
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Mitomycin C is reconstituted with Sterile Water to a concentration of 0.5 mg per mL. Once 
reconstituted, Mitomycin C is stable for 14 days refrigerated or 7 days at room temperature. 
The reconstituted solution needs to be protected from light. For the purpose of this study, 
Mitomycin C 40 mg vial will be mixed with 100 mL of sterile saline for administration in 
the operating room.
The reconstituted Mitomycin C will be added to normal saline solution as specified below in 
the Intra-peritoneal heated perfusion of Mitomycin C protocol where the first dose of 
Mitomycin C (30 mg) is administered when intra-peritoneal target temperature of 40.5-
42.5°C is reached and the second dose (10 mg) is given 60 minutes later for an additional 30 
minutes.
Storage
Mitomycin C must be stored below 25oC and protected from light.
Toxicity [Given the planned doses of Mitomycin C in this study, the likelihood of drug- 
associated adverse effects listed in the following toxicity profile for Mitomycin C is 
significantly reduced with intra-peritoneal relative to intravenous administration of the 
drug.]
Hematologic: Suppression of bone marrow function as manifested by leucopenia, 
neutropenia, thrombocytopenia and anemia may occur.
Hepatic: Transient elevations of one or both serum transaminases may occur.
Renal: Hypertension, edema, hematuria, proteinuria and rarely hemolytic uremic syndrome 
(HUS) may occur. The diagnosis of HUS should be considered if the patient develops 
anemia with evidence of microangiopathic hemolysis, elevation of serum bilirubin or LDH, 
reticulocytosis, severe thrombocytopenia, and/or evidence of renal failure (elevation of 
serum creatinine or BUN). Renal failure may not be reversible even with discontinuation of 
therapy and dialysis may be required.
Gastrointestinal: Anorexia, nausea, vomiting and stomatitis may occur, most often with 
intravenous administration of the drug.
Hypersensitivity: Hypersensitivity reactions such as a rash may occur, most often with 
intravenous administration of the drug. Anaphylactic reactions are rare.
Respiratory: Parenchymal toxicity including interstitial pneumonitis and pulmonary fibrosis 
has been reported rarely.
Precautions/warnings
Hematological parameters should be monitored closely. Intra-peritoneal drug dose should be 
reduced by 25% for patients with underlying renal insufficiency (CrCl 10 to 29 mL/minute) 
Mitomycin should not be given to patients with a serum creatine greater than 1.7 mg/dL.
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Avoid intra-thoracic instillation of Mitomycin C. Pregnant women are not eligible for this 
study.
5.1.2 Pre-perfusion protocol and perfusion circuit set-up and priming
At the conclusion of cytoreductive surgery, hemodynamic stability of the patient will be 
assured and bleeding points controlled per standard practice.
Systemic body temperature will be monitored. The perfusion system will be assembled per 
the operator’s manual utilizing sterile technique. The perfusion circuit priming will be with a 
balanced electrolyte solution such as normal saline. In the absence of ascites, approximately 
3-4L of perfusate is required for the circuit and priming in an average 70-kg adult. A general 
guideline is 1.5-2.0 L/m2 perfusate. The perfusate will be primed, heated to target 
temperature at the discretion of the operating surgeon and re-circulated.
5.1.3 Placement of inflow and outflow catheters and temperature probes
Peritoneal perfusion catheters and temperature probes will be placed by the operating 
surgeon in accordance with standards of practice. Inflow catheter positioning in the sub- 
diaphragmatic region of the peritoneal cavity is preferred. Outflow catheter positioning in 
the pelvis is preferred. This protocol allows for closed delivery of heated Mitomycin C at 
surgeon discretion. Timing of intestinal reconstruction and formation of stomas will be at 
surgeon discretion. Sterile pump lines from the perfusion system will be delivered to the 
sterile field and the lines will be filled with perfusate to prevent airlocks. The inflow and 
outflow tubing will be connected and the pre-heated perfusate will be allowed to fill the 
peritoneal cavity. Usually ~3 liters of solution is required to distend the cavity and achieve 
desired flow rates.
5.1.4 Intra-peritoneal heated perfusion of Mitomycin C
Once the intra-peritoneal target temperature reaches a consistent inflow temperature of 40.5-
42.5°C and outflow temperature of 40.5-42.5°C, the therapeutic interval begins, and 
Mitomycin C will be added to the perfusate. The Mitomycin C-containing perfusion will be 
allowed to circulate within the peritoneal cavity for 90 minutes. Mitomycin C, 30 mg, will 
be administered into the inflow line of the perfusion circuit once target temperature is 
reached, as directed by the operating surgeon. Perfusate temperatures will be adjusted so as 
not to exceed target temperature. At the 60 minute time point of the perfusion, Mitomycin C, 
10 mg, will be administered into the inflow line of the perfusion circuit. During the entire 
perfusion, temperature of perfusate, volume of perfusate and flow rate will be recorded at 15 
minute intervals. Once the 90-minute perfusion period has elapsed, the perfusate will be 
drained into the waste reservoir. The peritoneal cavity will be rinsed/washed-out with 10 
liters of normal saline. The peritoneal cavity will be re-explored and the remaining fluid 
drained; the catheters and temperature probes will be removed; the circuit and contents will 
be discarded in accordance with hospital practices and guidelines for the disposal of 
chemotherapeutic waste.
5.1.5 Recommended anesthetic management and intra-operative physiological 
monitoring during HIPEC
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An epidural catheter may be placed at the discretion of the operating team (anesthesiologist 
and surgeon). Broad-spectrum antimicrobial prophylaxis is recommended prior to surgical 
incision (specific antibiotic at the discretion of the operating surgeon). Radial arterial 
cannulation may be established for arterial-line blood pressure monitoring. A triple lumen 
central venous catheter may be placed at the anesthesiologist’s discretion. A nasogastric tube 
is typically placed to decompress the stomach. A transurethral catheter is placed in the 
bladder. During cytoreductive surgery, careful attention to end tidal carbon dioxide, oxygen 
saturation and peak airway pressures is made during diaphragmatic stripping assessing for 
signs of pneumothorax. The patient’s core body temperature may be reduced to 35 degrees 
Celsius (95 degrees Fahrenheit) prior to commencing hyperthermic intraperitoneal 
chemotherapy. At the start of the hyperthermic chemotherapeutic infusion, the Bair Hugger 
may be set to blow ambient air flow over the patient. Adequate intravenous fluid hydration 
with crystalloid and/or colloid prior to initiation of the hyperthermic chemotherapeutic 
perfusion is important, as systemic vasodilatation occurs during the perfusion. Urinary 
output during HIPEC should be maintained at 0.5-1.0 ml/kg/hr. Clotting time and INR, 
serum electrolytes, blood gases, and vital signs are monitored throughout the procedure.
Standards of anesthetic practice interventions should occur when clinically appropriate. 
Fresh frozen plasma and/or Vitamin K are utilized to maintain INR ≤ 1.5 as appropriate.
5.2 Cytoreductive surgery
The abdomen is explored through a generous midline incision. If there is a midline wound from a 
prior operation, it may be resected at the surgeon’s discretion. The peritoneal cavity will be 
explored carefully in order to assess fully the distribution and volume of peritoneal surface 
disease.
Peritoneal Cancer Index (PCI) will be determined and documented on the basis of tumor size and 
distribution of the intra-peritoneal nodules for each of the 13 abdomino-pelvic regions. Tumor 
nodules present at critical anatomical sites (e.g. multiple serosal small bowel implants) will be 
documented as they portend a poor prognosis irrespective of favorable PCI. The Lesion Size 
(LS) score will be determined after the lysis of all adhesions and a complete inspection of all 
parietal and visceral peritoneal surfaces within the abdominopelvic regions. LS-0 indicates no 
implants seen. LS-1 indicates tumor implants up to 0.5 cm in longest diameter. LS-2 defines 
implants between 0.5 and 5 cm, and LS-3 implants > 5 cm in longest diameter. A confluence or 
layering of disease matting abdominal or pelvic structures together will automatically be scored 
as LS-3 even if it is a thin layer of cancerous implants. The sum of lesion sizes for the 
abdominopelvic regions will be recorded. The extent of the disease within all regions of the 
abdomen and pelvis will be indicated by a numerical score from 0 to 39 (PCI).
Any or all of the principal peritonectomy procedures will be undertaken in an effort to achieve as 
complete a cytoreduction as feasible. Only peritoneal surfaces containing tumor will be stripped 
surgically. Greater and lesser omentectomy, omental bursectomy, splenectomy, left and right 
upper quadrant and pelvic peritonectomy, cholecystectomy, total abdominal hysterectomy, low 
anterior resection and/or gastrectomy will be performed at the surgeon’s discretion based on 
volume and distribution of peritoneal surface malignancy with the aim of achieving complete 
resection of all grossly apparent disease.
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Heated intraoperative intraperitoneal chemotherapy will be delivered as above. At the 
completion of the perfusion, the abdomen will be re-explored, residual fluid aspirated, bleeding 
points controlled and reconstructive operation completed if not already done prior to HIPEC 
(anastomosis with or without diverting stoma).
Completeness of cytoreduction will be estimated and recorded using the CC and RR system 
shown below. Intra-peritoneal tubes and drains will be placed at the surgeon’s discretion and the 
incision closed in the usual fashion.
CC0 No Disease
R0 Complete removal of all visible tumor; 
Negative cytology or microscopic margin
CC1 <= 0.25 cm
R1 Complete removal of all visible tumor; 
Positive cytology or microscopic margin
CC2 0.25-2.5 cm
R2a Minimal residual tumor, nodule(s) ≤ 0.5 cm
CC3 >=2.5 cm
R2b Gross residual tumor, nodule(s), > 0.5, but ≤ 2 cm
R2c Extensive disease remaining, nodule(s) > 2 cm
5.3 Discontinuation of study treatment
5.3.1 Patient-initiated discontinuation of study
Even after a patient agrees to take part in the study, he or she may stop therapy or withdraw 
from the study at any time. If the study participant stops treatment but still allows the study 
physician to submit follow-up information, he/she should continue to be followed clinically 
according to the study schedule. Alternatively, he/she may choose to have no further 
interaction regarding the study in which case the investigator must submit the Off Treatment 
Form indicating patient refusal.
5.3.2 Investigator-initiated discontinuation of study
The investigator may require a study subject to discontinue the study in the event of one of 
the following:

the study subject develops a serious side effect that in the opinion of the 
investigator the patient cannot tolerate HIPEC.

the study subject, once in surgery, was found to have extensive disease and 
therefore was not given HIPEC.
Score Residual Disease
Score Residual Disease
RR SCORING
CC SCORING
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5.4 Surgical quality assurance and control (QA/QC)
5.4.1 Surgical QA/QC strategy
For every multi-modality (CRS-HIPEC) case, the following will be required in the context 
of this clinical trial:
1. Patient eligibility for the trial will be determined and cross-sectional imaging reviewed;
2. Pre-operative PCI score will be determined by CT and/or laparoscopy;
3. Cytoreductive surgery will be undertaken involving any or all of the six principal 
peritonectomy procedures, based on volume and distribution of peritoneal surface disease, at 
the surgeon’s discretion, in an effort to achieve complete resection of all grossly apparent 
peritoneal surface disease. Intraoperative PCI will be determined at the beginning of 
cytoreductive surgery;
4. Heated intra-operative intra-peritoneal chemotherapy will be delivered;
5. At the completion of the perfusion, the abdomen will be re-explored, residual fluid 
aspirated and reconstruction completed if not already completed prior to HIPEC;
6. Post resection PCI will be determined and completeness of cytoreduction will be 
estimated and using the CC and RR systems defined above in section 5.2;
7. Intra-peritoneal tubes and drains will be placed and the incision will be left open or closed 
in the usual fashion at the surgeon’s discretion;
5.5 Supportive care
All appropriate supportive care for any side effects or toxicity will be provided by the physicians 
in the Montefiore-Einstein Center for Cancer Care of MMC. Patients may be admitted as 
necessary to manage issues related to study treatment procedure.
6. ASSESSMENT OF EFFICACY
6.1 Response criteria in peritoneal surface malignancy:
6.1.1 Clinical (Radiological) Response Evaluation Using RECIST Guideline
Tumor 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) 57. Changes in the largest diameter (uni-dimensional measurement) of 
the tumor lesions and the short axis measurements in the case of lymph nodes are used in the 
RECIST guideline.
Note: Response/progression evaluation using RECIST Guideline will only be applicable to 
patients with measurable disease at the time of enrollment. Guidance for determination of 
recurrence/progression listed in Section 6.2 should be followed for the following situations:

Disease evaluation for patients with measurable disease at the time of enrollment;

Disease evaluation after patients receiving cytoreductive surgery;
6.1.1.1 Schedule of Evaluations:
For the purpose of this study, patients should be reevaluated according to section 4.2.
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6.1.1.2 Definitions of Measurable and Non-Measurable Disease
At time of study enrollment, measurable vs. non-measurable disease status for each 
patient will be determined according to the following sections.
6.1.1.3 Measurable Peritoneal Surface Disease
Peritoneal surface lesions are considered measurable if at least one lesion whose longest 
diameter can be accurately measured as > 1.0 cm with spiral CT scan using 5-mm 
contiguous reconstruction algorithms.
Peritoneal surface lesions in a previously irradiated area are considered nonmeasurable 
disease.
6.1.1.4 Non-Measurable Peritoneal Surface Disease
All other lesions (or sites of disease), including small lesions (longest diameter < 1 cm) 
are considered as non-measurable disease. A normal CT scan and biopsy proven 
malignant peritoneal implants are considered as non-measurable peritoneal surface 
disease.
6.1.2 Guidelines for Evaluation of Disease
6.1.2.1 Measurement Methods:

All measurements should be recorded in metric notation (i.e., decimal fractions of 
centimeters) using a ruler or calipers.

The same method of assessment and the same technique must be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
For patients having only lesions measuring at least 1 cm to less than 2 cm, CT 
imaging must be used for both pre- and post-treatment tumor assessments.

Imaging-based evaluation is preferred to evaluation by clinical examination when 
both methods have been used at the same evaluation to assess the antitumor effect 
of a treatment.
6.1.2.2 Acceptable Imaging Modalities for Measurable Disease:
Spiral (helical) chest, abdomen and pelvis CT with 5-mm contiguous reconstruction 
algorithms will be the primary method of measurement to allow minimum lesion size of
1.0 cm. All images and window settings from each CT will be included for the sake of 
completeness in the event of central radiology review.

Adequate volume of oral contrast agent will be utilized to accentuate the bowel 
against the peritoneal surface and other soft tissue masses. A consistent CT 
image acquisition method must be used on baseline and subsequent exams.

Adequate volume of suitable intravenous contrast agents must be used to 
accentuate liver and other visceral metastases, and distinguish vascular structures 
from nodal pathology. A consistent method must be used on baseline and 
subsequent spiral CT examinations.

Documented lesions (peritoneal surface tumors) must be measured on the same 
window setting on each spiral CT examination.
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6.1.2.3 Measurement at Follow-up Evaluation:

In the case of stable disease (SD), follow-up measurements must have met the SD 
criteria at least once after study entry at a minimum interval of 8 weeks (see 
Section 6.1.3.4).

The cytological confirmation of the malignant 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.

Fine needle aspiration cytology or core needle biopsy will be utilized in cases 
where distinguishing residual disease from normal tissue is difficult. When the 
evaluation of complete response (CR) depends on this determination, it is 
recommended that the residual lesion be investigated (fine needle aspirate/core 
needle biopsy) to confirm the CR status.
6.1.3 Measurement of Effect
6.1.3.1 Target Lesions

All measurable lesions (as defined in Section 6.1.1.3) up to a maximum of 2 
lesions per organ and 5 lesions in total, representative of all involved peritoneal 
surface, should be identified as target lesions and recorded and measured at 
baseline. If the protocol specified studies are performed, and there are fewer than 
5 lesions identified (as there often will be), there is no reason to perform 
additional studies beyond those specified in the protocol to discover new lesions.

Target lesions should be selected on the basis of their size (lesions with the 
longest diameter), be representative of all involved peritoneal surface, and 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.

Baseline Sum of Diameters (BSD): A sum of the diameters [longest for peritoneal 
surface lesions (see Section 6.1.1.3)] for all target lesions will be calculated and 
reported as the baseline sum of diameters (BSD). The BSD will be used as 
reference to further characterize any objective tumor response in the measurable 
dimension of the disease.

Post-Baseline Sum of the Diameters (PBSD): A sum of the diameters [peritoneal 
surface lesions (see Section 6.1.1.3)] for all target lesions will be calculated and 
reported as the post-baseline sum of diameters (PBSD). If the radiologist is able to 
provide an actual measure for the target lesion, that should be recorded, even if it 
is below 0.5 cm. If the target lesion is believed to be present and is faintly seen, 
but too small to measure, a default value of 0.5 cm should be assigned. If it is the 
opinion of the radiologist that the lesion has likely disappeared, the measurement 
should be recorded as 0 cm.

The minimum sum of the diameters (MSD) is the minimum of the BSD and the 
PBSD.
6.1.3.2 Non-Target Lesions
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All other lesions (or sites of disease) should be identified as non-target lesions and should 
also be recorded at baseline. Measurements are not required, and these lesions should be 
followed in accordance with table in section 6.1.3.3 below.
6.1.3.3 Response Criteria
All target lesions, as well as non-target lesions followed by spiral CT must be followed 
and recorded as specified above, on re-evaluation. Specifically, a change in objective 
status to either a PR or CR cannot be done without re-assessing and measuring all 
apparent lesions.

Evaluation of Target Lesions
Complete Response (CR)
Complete Disappearance of all peritoneal surface target lesions
Partial Response (PR)
At least a 30% decrease in the sum of the longest diameters of 
the target peritoneal surface lesions taking BSD as the reference 
(Section 6.1.3.1 )
Progression (PD)
At least one of the following must be true:
a) at least one new malignant lesion has become apparent;
b) at least a 20% increase in the sum of diameters of target 
peritoneal surface lesions taking MSD as the reference. In 
addition, the sum must also demonstrate an absolute increase of 
at least 0.5 cm.
Stable Disease (SD)
Neither sufficient shrinkage to qualify for PR, nor sufficient 
increase to qualify for PD taking MSD as the reference.

Evaluation of Non-Target Lesions
Complete Response (CR)
All of the following must be true:
a) disappearance of all non-target peritoneal surface lesions
b) normalization of serum CEA and/or CA19-9
Non-CR/Non-PD
Persistence of one or more non-target peritoneal surface 
lesions and/or persistence of supra-normal (>ULN) serum 
CEA and/or CA19-9 levels.
Progression (PD)
At least one of the following must be true:
c) at least one new malignant lesion has become apparent;
d) unequivocal progression of existing nontarget lesions. 
(Note: Unequivocal progression should not normally trump 
target lesion status. It must be representative of overall disease 
status change, not a single lesion increase.)
6.1.3.4 Overall Objective Status
The overall objective status for an evaluation is determined by combining the patient’s 
status on target lesions, non-target lesions, and new disease as defined in the following 
tables:
For Patients with Measurable Peritoneal Surface Disease:
Target Lesions
Non-Target Lesions
New Lesions
Overall Objective Status
CR
CR
No
CR
CR
Non-CR/Non-PD
No
PR
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PR
CR
Non-CR/Non-PD
No
PR
CR/PR
Not All Evaluated
No
SD
SD
CR
Non-CR/Non-PD 
Not All Evaluated
No
SD
Not All Evaluated
CR
Non-CR/Non-PD
No
Not Evaluated (NE)
PD
Unequivocal PD 
CR
Non-CR/Non-PD 
Not All Evaluated
Yes or No
PD
CR/PR/SD/PD
Unequivocal PD
Yes or No
PD
CR/PR/SD/PD
CR
Non-CR/Non-PD 
Not All Evaluated
Yes
PD
Note: If CEA is above the upper normal limit at time of study entry, it must normalize for 
a patient to be considered to have had a complete clinical response (CR) when all lesions 
have been resected or have disappeared radiographically on therapy.
6.1.3.5 Symptomatic Deterioration
Patients with global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time, and not either related to 
study treatment or other medical conditions, should be reported as PD due to 
“symptomatic deterioration.” Every effort should be made to document the objective 
progression even after discontinuation of treatment due to symptomatic deterioration. A 
patient is classified as having PD due to “symptomatic deterioration” if any of the 
following occur that are not either related to study treatment or other medical conditions:

Weight loss >10% of body weight.

Worsening of tumor-related symptoms.

Decline in performance status of >1 level on ECOG scale.
6.1.4 Evaluation Based on Peritoneal Cancer Index
In addition to standard RECIST1.1 criteria to assess response and PFS as secondary 
endpoints in this trial we will include a standard tool for the assessment of peritoneal surface 
disease burden according to aggregate tumor size and distribution (Peritoneal Cancer Index). 
The PCI will be used to estimate the volume and extent of carcinomatosis.
6.1.4.1 Schedule of Evaluation:

Radiologic evaluation: PCI should be evaluated for all patients each time 
abdominal-pelvic CT examination is obtained. (Schedule see section 4.2)

Surgical evaluation: PCI should be evaluated for patients receiving CRS/HIPEC 
therapy before, during and after operation.
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6.1.4.2 Guidelines for Evaluation of PCI
Measurement Methods:

The lesion size score (LS) will be used to rate the size of peritoneal surface 
nodules.
o LS-0 indicates no apparent peritoneal surface tumor.
o LS-1 denotes tumor implants up to 0.5 cm in longest diameter.
o LS-2 defines tumor implants between 0.5 and 5 cm in longest diameter, and
o LS-3 indicates tumor implants >5 cm.
o If there is a confluence of tumor, the lesion size will be scored as LS-3.

Distribution of tumor will be assessed in 13 abdominal-pelvic regions.
o Regions 0 thru 8 correspond to abdominal regions, and regions 9 thru 12 
correspond to small bowel regions that are defined by the intersection of two 
transverse and two sagittal planes dividing the abdomen into nine abdominopelvic 
regions (See figure in Appendix A).
o The small bowel will be assessed separately and designated as abdominopelvic 
regions 9 through 12 as follows: upper jejunum (region 9), lower jejunum (region 
10), upper ileum (region 11) and lower ileum (region 12), respectively.
o The summation of the lesion size score in each of the 13-abdominopelvic 
regions will define the PCI, ranging from a minimum of zero to a maximum score 
of 39 (3 x 13).
o All measurements will be taken and recorded in metric notation (centimeters, 
cm), using a ruler or calipers.
Accepable imaging modalities for radiologic evaluation:
The same method of measurement and the same technique [at a minimum - spiral 
(helical) chest, abdomen and pelvis CT with 5-mm contiguous reconstruction algorithms 
and adequate volume (based on site-specific protocols) of both oral and intravenous 
contrast agents] will be used to characterize each identified and reported peritoneal 
surface tumor at baseline and during follow-up.
6.2 Evaluation of Cancer Outcomes
In patients not rendered free of all grossly apparent peritoneal surface malignancy and at time of 
disease progression, patients will be treated in accordance with standards of practice indefinitely.
6.2.1 Disease progression for patients with measurable tumor at enrollment:
Tumor evaluation should follow the RECIST version 1.1 criteria in section 6.1.1.
6.2.2 Disease progression for patients with non-measurable tumor at enrollment
Serum CEA and/or CA19-9 exceeding Upper Limit of Normal (ULN), and increasing ≥50% 
from completion of study therapy, verified by two CEA and/or CA19-9 measurements, ≥2 
weeks apart, will be considered disease progression. If CEA is above the upper normal limit 
at time of study entry, it must normalize for a patient to be considered to have had a 
complete clinical response when all lesions have been resected.
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6.2.3 Local-regional recurrence after cytoreductive surgery

Defined as the development of tumor (one or more lesions) in an area of prior 
peritoneal surface malignancy that underwent complete response (CR, as defined in 
Section 6.1.3.3) to treatment or surgical resection, or a new peritoneal surface 
tumor(s) or mesenteric regional nodal lesions(s)

Acceptable means of confirmation of local-regional recurrence include cross 
sectional or functional (e.g. CT-PET) imaging or positive fine needle aspiration 
cytology or histological biopsy.

If peritoneal surface or mesenteric nodal lesions show(s) a 20% or greater increase in 
lesion(s) sum LD on serial imaging, disease recurrence will be confirmed.
6.2.4 Distant recurrence after cytoreductive surgery

Defined as evidence of tumor in any region of the body, outside the peritoneal 
surface (e.g. lung, liver, central nervous system, bone marrow, skin, subcutaneous 
tissue, or distant nodal (retroperitoneal, pelvic, mediastinal, peri-portal or peri-aortic 
node, etc.) metastases.

The following methods of diagnosis of extra-peritoneal surface metastases according 
to site are considered acceptable
Metastatic site
Acceptable Means of Diagnosis
Lung
Needle aspiration cytology, histological biopsy, radiological evidence of 
multiple pulmonary nodules consistent with lung metastasis
Liver
Cross-sectional, functional imaging or laparoscopy consistent with liver 
metastasis or liver cytology or tissue biopsy confirming metastasis.
Functional imaging is considered evidence of new diseases only if the PET 
was negative at baseline or corroborated radio graphically.
Central nervous system
Cross-sectional or functional imaging usually in a patient with neurological 
symptoms consistent with CNS metastases, or cytology or biopsy confirming 
meningeal metastasis
Bone marrow
Positive cross-sectional or functional imaging, or cytology or biopsy 
confirming bone marrow metastasis
Skin, soft tissue, distant 
nodal
Positive cytology, histological biopsy or radiological evidence of metastatic 
disease in skin, soft tissue, or distant nodes (iliac, para-aortic, vena caval, 
celiac, portal, mediastinal, hilar, paratracheal, etc.)
6.2.5 Cancer-specific mortality

Only death confirmed to be related to disease will be considered in disease-related 
mortality calculations.

Disease-related, treatment or other cause of death will be captured on the follow up 
case report form.
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7. ADVERSE EVENTS ASSESSMENT AND REPORTING
7.1 Definitions for adverse event reporting
Adverse event (AE) assessment, data collection and reporting will be done to ensure the safety of 
patients enrolled in this study. Adverse events secondary to both cytoreductive surgery and the 
utilization of intraperitoneal chemotherapy will be monitored closely, recorded appropriately and 
reported as required. The descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting. 
All appropriate treatment areas should have access to a copy of the CTCAE version 4.0. A copy 
of the CTCAE version 4.0 can be downloaded from the CTEP web site
(http://ctep.cancer.gov).
Timely reporting of serious and unexpected adverse events will be conducted throughout the trial 
period. Only commercial agents (not provided under IND) will be utilized in this study. The 
study subject will be informed of the indications, nature, alternatives, expected outcome, risks 
and benefits of all procedures and therapies provided in the context of this study. Clearly, there 
are potential, foreseeable risks or discomforts to participants in this study. Detailed information 
on adverse events or complications, which may be related to HIPEC or operative procedures 
provided in this trial, will be collected during the course of the study.
The CTEP CTCAE version 4.0 will be used to identify the type, and to grade the severity of 
adverse events in this trial. An adverse event will be considered a Serious Adverse Event (SAE) 
if that event led to death, resulted in a life-threatening illness or injury, resulted in permanent 
impairment of a body structure or body function, required inpatient hospitalization or 
prolongation of existing hospitalization, or resulted in medical or surgical intervention to prevent 
permanent impairment to body structure or body function.
An Unanticipated Adverse Event (UAE) will be considered any serious adverse effect on health 
or safety or any life-threatening problem or death caused by, or associated with, the commercial 
agent and/or surgical procedure, if that effect, problem, or death is not identified in nature, 
severity, or degree of incidence in this investigational plan or any other unanticipated serious 
problem associated with the commercial agent and/or operation that relates to the rights, safety, 
or welfare of the subjects participating in this study.
7.2 Adverse event assessment
The severity type and grade of the adverse events will be identified using the NCI CTCAE. 
Attribution/treatment relation of adverse events will be defined by the study doctor as Unrelated, 
Unlikely, Possible, Probable, or Definite.
An adverse event is defined as any unfavorable and unintended sign, including an abnormal 
laboratory finding, symptom, or disease temporally associated with the use of an investigational 
product, whether or not related to the investigational product. This includes any occurrence that 
was new in onset or aggravated in severity or frequency from the baseline condition. Adverse 
events (AEs) assessments will begin at time of signing of informed consent and will continue 
until 30 days following study treatment. AEs which are assessed as possibly, probably, or 
definitely related to study treatment must be followed until the AE is resolved or until the patient
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is clinically stable. Other safety assessments, including physical examinations, vital signs, 
hematology, clinical chemistry, and urinalysis, will be done through subject discontinuation or 
12 months after initial study treatment, whichever occurs first.
The condition which is detected by the diagnostic procedure conducted to test the efficacy of the 
investigational agent is not considered an AE.
Symptoms or clinically significant laboratory or instrumental abnormalities of a pre-existing 
disease, such as cancer or other disease should not be considered an AE. However, occurrence of 
new symptoms or laboratory or instrumental abnormalities, as well as worsening of pre-existing 
ones, is considered AEs.
Abnormal results of diagnostic procedures, including laboratory test abnormalities, are 
considered adverse events if they result in:

Discontinuation from the study.

Treatment or any other therapeutic intervention.

Further diagnostic evaluation (excluding a repetition of the same procedure to confirm 
the abnormality).

Associated clinical signs or symptoms that would have a significant clinical impact, as 
determined by the Investigator.
Any untoward medical event that occurs from the time of signed informed consent to the time 
immediately prior to the first study treatment procedure will be reported as a “pre-treatment 
event” in the Medical History CRF.
All adverse events that occur following study treatment will be documented on the AE CRF with 
indications of onset, duration, severity (NCI CTCAEs), presumed relationship to study procedure
/medication (not related, unlikely, possibly, probably, definitely), remedial actions taken, and 
outcome.
Surgical complications will be defined as secondary events deviating from the ideal course of 
convalescence that occurred during or following the operation, resulting in changes in 
management (diagnostic or therapeutic intervention) and delay in complete recovery and/or 
adjuvant therapy, or chronic disability.
Surgical complications will be scored according to a five-tier surgical morbidity and mortality 
scale (according to the intensity of therapy required for the treatment of the defined 
complication):
Grade Intensity of Treatment
1
oral medications (e.g. oral antibiotics for surgical site infection or bedside care)
2
intravenous medications or nutrition (e.g. antiarrhythmic therapy for 
supraventricular tachycardia)
3
endoscopy, interventional radiology or reoperation (e.g. operative drainage of an 
abscess)
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4
chronic disability or major organ resection (e.g. reduction in performance status 
following post respiratory failure)
5
death
7.3 Expedited Reporting of Adverse Events
Expedited adverse event reporting for patients receiving commercial agents is required for:

All Grade 4 and 5 unexpected adverse events that are possibly, probably or definitely 
related to therapy.

All Grade 5 adverse events, regardless of attribution, occurring within 30 days of the end 
of therapy
Expedited adverse event reporting will NOT be required for the following:

Adverse events related to surgery

Adverse events related to radiation

Adverse events that occur following the first cancer recurrence or second primary cancer 
development
7.4 Routine Reporting of Adverse Events
All Grade 3-5 AEs must be recorded on the appropriate data form. Expedited reporting is in 
addition to, and does not supplant, the reporting of AEs as part of the data submission 
requirements for the study.
Adverse events will be categorized by body system (such as cardiovascular-related, renal-related, 
etc.) and will be reported to the Montefiore institutional review board (IRB) as required by the 
IRB.
Any serious event, including death from any cause that occurs through 30 days following study 
treatment, whether or not related to the investigational drug, must be reported to PI immediately 
(within 24 hours) via telephone, fax, or e-mail. If initially reported via telephone or e-mail, this 
must be followed-up by a written faxed report to be submitted within 24 hours of the initial 
report.
Initial Reports
Within 24 hours of the investigator’s knowledge of a serious adverse event:

Complete a Serious Adverse Event Report Form (SAER), sign it, and fax it to the PI.

Place the initial version of SAER in the subject’s file.
Follow-Up Reports
New information received spontaneously or by request of the Medical Monitor or Safety 
Surveillance. Within 48 hours of the receipt of new information:

Complete a new SAER with the new information. Sign and fax the form to PI.

Fax copies of supporting documents (e.g., hospital discharge summaries, lab test 
results with normal ranges, autopsy or biopsy reports) to PI.

Place the follow-up version of the SAE and all supporting documentation in the 
subject’s file.
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Final Report
Within 48 hours of the receipt of final information:

Determine that there is no further information available and this update may be 
considered final.

Complete a new SAER form with the new and final information. Sign and fax the 
form to PI. As above, send copies of any additional supporting information.

Place this version of the final SAER into the subject’s file.
It is imperative that IRB be informed within 24 hours of a serious adverse experience so that 
reporting to the FDA can be met within the required time frame (7 or 15 calendar days).
Because of the need to report to health authorities all serious adverse experiences in a timely 
manner, it is vitally important that an Investigator report immediately any adverse experiences, 
which would be considered serious, even if the Investigator does not consider the adverse 
experience to be clinically significant or drug-related.
Should the Investigator become aware of an SAE (regardless of relationship to study treatment) 
that occurs while the subject is on the study, the SAE must be reported in accordance with the 
procedures specified in this protocol.
If the subject is withdrawn less than 30 days after study treatment, any SAEs which occur within 
30 days after study treatment must be reported in accordance with the procedures specified in 
this protocol.
All serious adverse events that are assessed as possibly, probably, or definitely related to study 
treatment are to be followed until either: the adverse event resolves, the adverse event stabilizes, 
the adverse event returns to baseline values (if a baseline value is available), or it is shown that 
the adverse event is not attributable to the study treatment or study conduct.
8.0 ETHICAL CONSIDERATIONS
8.1 IRB review
The study will be conducted in the Montefiore Medical Center, in compliance with Title 21 of 
the Code of Federal Regulations (CFR), Part 50 (Protection of Human Subjects), and Part 56 
(Institutional Review Board) as well as the principles of the Declaration of Helsinki and its 
amendments. The Montefiore Institutional Review Board (IRB) will review the protocol and 
informed consent. The study will not be initiated without IRB approval. All subjects will be 
required to give written informed consent prior to participation in the study. This study will be 
performed in accordance with Good Clinical Practices (GCP) by qualified Investigators.
The study specifically incorporates the following features:

Single arm study design

Prospectively stated objectives and analytical plan

Accepted, pre-specified outcome measures for safety and efficacy

Compliance with Good Clinical Practices (GCP), with assessment via regular monitoring.
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Quality assurance procedures will be performed to assure that safety and efficacy data were 
adequate and well documented.
8.2 Informed Consent
Consent will be obtained during patients visiting in physician’s office or hospital setting. 
Investigators or research nurse in the team will provide information to potential subjects and 
answer questions in the informed consent process. The Investigators will obtain written informed 
consent from each subject (or their authorized representative) participating in the study. The 
form must be signed, witnessed and dated.
The informed consent form will contain all the Essential Elements of Informed Consent set forth 
in 21 CFR, Part 50, and the ICH Guideline for Good Clinical Practice, and the terms of the 
Declaration of Helsinki. Copies of the signed document should be given to the subject and filed 
in the Investigator’s study file, as well as the subject’s medical record.
8.3 Subject Protection
In order to maintain patient confidentiality, all case report forms, study reports and 
communications relating to the study will identify subjects by initials and assigned subject 
numbers; subjects should not be identified by name. In accordance with local, national or federal 
regulations, the Investigator will allow the personnel of data monitoring committee access to all 
pertinent medical records in order to verify the data gathered on the case report forms.
Regulatory agencies such as the US Food and Drug Administration (FDA) may also request 
access to all study records, including source documentation for inspection. Clinical information 
will not be released without the written permission of the subject as outlined in the subject 
consent form.
Researchers will ensure the confidentiality of the information gathered in the study by using 
following methods:

Paper based records will be kept in a secured location and only accessible to personnel 
involved in the study.

All study data will be kept in locked file cabinets and password protected files.

Computer based files will only be made available to personnel involved in the study 
through the use of access privileges and passwords.

Prior to accessing any study-related information, personnel will be required to sign 
statements agreeing to protect the security and confidentiality of identifiable health 
information.

Whenever feasible, identifiers will be removed from study-related information.
The selection of subjects for this protocol will not be based on sex, race, or ethnic background.
Because mitomycin C may harm a developing baby, patients in pregnant or lactating will be 
excluded from this study. Children will not be enrolled in this study.
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9. STATISTICAL CONSIDERATION
9.1 Sample size
The target number of patients proposed for this protocol is based on our primary objective, 
assessing completeness of cytoreduction. The postoperative morbidity and mortality will be 
important factors at the interim analysis.. The latent goal is to utilize these estimates for 
generating future research hypotheses and protocol development as well as to benchmark our 
data against published data.
Sample size calculations are based on our primary objective. Our target sample size is 50 
patients unless undue toxicity is encountered or the accrual is terminated at the interim analyses. 
A sample size of n=50, would produce a two-sided 95% confidence interval with a maximum 
width of 0.289 for a proportion of 0.5 and 0.267 for a proportion of 0.70. Calculations are based 
on exact binomial distribution. In a large multi-institutional study, 75% of patients were 
classified as CCR-0 and 17% CCR-1 1.
9.2 Statistical Data Analysis
Data will be entered on an excel spreadsheet and analyzed with SAS v9.2. Data analysis will be 
preceded by quality control of our data which will include checks for accuracy, completeness 
and internal validity.
Rates of completeness of cytoreduction, and postoperative morbidity and mortality will be 
computed and reported with their 95% confidence intervals. Descriptive data analysis will be 
conducted and all adverse events and overall patient characteristics will be described. Bivariate 
analysis will be conducted to examine factors associated with complete cytoreduction. 
Categorical variables will be analyzed using the Fisher’s exact test. Continuous variables whose 
distribution meets normality assumptions will be analyzed with the t-test. Variables whose 
distribution does not approximate normality will be analyzed using the Wilcoxon rank sum test.
For our secondary endpoints to evaluate time to progression, progression-free survival and 
overall survival we will use Kaplan-Meier methods. Progression-free survival will be calculated 
from time of surgery to date of recurrence or censored at time patient is last seen. Overall 
survival will be calculated from time of surgery to time of death or censored at the time patient is 
last seen. Log-rank test will be used to compare survival of patients who achieved complete 
cytoreduction with those who did not. We will compute 95% confidence intervals using 
Greenwood’s formula.
QOL data will be collected using the Functional Assessment of Cancer Treatment (FACT-C) 
instrument. The feasibility of collecting QOL data will be assessed and rates of missing data will 
be computed. Reasons for missing data will be characterized to the extent possible. In addition 
to this, QOL data will be described using mean, standard deviation, median, inter-quartiles and 
range as well as graphically. For exploratory analysis of QOL data over time we will examine 
the use of hierarchical linear models.
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9.2.1 Interim Analysis Decision Rules
Interim analysis will be performed after the first 20 patients are treated, to assess the safety of the 
proposed treatment. Stopping rules will be based on 30-day postoperative mortality.
The overall mortality rate reported by Glehen et al in the largest retrospective series of patients 
with Peritoneal Carcinomatosis (PC) treated with Cytoreductive Surgery in combination with 
HIPEC was 4.1%. Based on Gehen's data, the upper limit of the 95% confidence interval around 
the 4.1% mortality rate is 5.3%.
While it is anticipated a mortality rate of 5% - comparable to that reported by Glehen - given the 
variability in origin of PC, given some variability in reports of mortality rates as reported by 
Koppe et al 58 and given that patients undergoing this approach have very advanced disease and 
often progress through all other therapies- we will consider a 30-day mortality
rate (from the therapy) of greater than 10% to be unacceptable since this rate is higher than one 
would expect from the largest retrospective series available.
The 30-day mortality will be evaluated after the first 20 patients have been enrolled. If no more 
than 2 patients (10%) suffer a mortality within 30 days that is attributable to the therapy and not 
the underlying disease or unrelated to the therapy, we will continue to 50patients. If 3 or more 
patients suffer a mortality within 30 days of the therapy that is directly attributable to the 
therapy, we will suspend accrual and will investigate the causes of the higher mortality.
After the root cause of the operative mortality has been determined, the study team will confer 
with the IRB and will make a determination as to whether accrual can be resumed.
9.3 Patient Accrual:
Based on our experience at the Montefiore-Einstein Center for Cancer Care and based on 
numbers of patients seen during the first half of the year, we expect to screen 30 patients yearly. 
We estimate 2/3 of these patients will meet inclusion criteria into the study. We expect high 
rates of participation into this protocol and estimate that it will take us 2-3 years to recruit the 
proposed sample of 50 patients. We will follow-up these patients until evidence of progression 
or for a total study time of 5 years.
9.4 Interim Reports
Interim reports will be prepared every 12 months. These will include:

Monthly patient accrual rate

Descriptive patient’s demographic characteristics

Descriptive clinical data

Frequency and severity of adverse events
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10. DATA COLLECTION AND REPORTING
10.1 Data collection
Complete research records or medical records must be maintained on each patient treated on the 
protocol for both scheduled and unscheduled evaluations. These records should include primary 
documentation (e.g. laboratory report slips, X-ray reports, scan reports, pathology reports, 
physician’s notes, etc.) which confirm that:

The patient meet all eligibility criteria

Signed informed consent will be obtained prior to treatment

Treatment will be given according to protocol (dated notes about doses given, 
complications, and clinical outcomes).

Toxicity will be assessed according to protocol.

Response will be assessed according to protocol (X-ray, CT-scan, lab reports, date noted 
on clinical assessment, as appropriate).

MMC Drug Accountability Records will be kept for each patient.
10.2 Data Safety Monitoring Plan
The PI and the research personnel will meet at least monthly to review all adverse events. 
Unexpected adverse events and/or serious adverse events will be reported to the MMC IRB. If 
trends are noted and /or risks warrant it, accrual will be interrupted and /or the protocol and/or 
consent will be modified accordingly. The MMC IRB will review submitted adverse events 
monthly to also evaluate trends and will require follow up plans from the principal investigator 
whenever a trend is identified.
10.3 Data Reporting
All patients must have signed an informed consent form and an on-study (confirmation of 
eligibility) form filled out and signed by a participating Investigator before entering on the study.
Patients will be followed at least monthly during therapy for development of toxicity. Toxicity 
will be scored using CTCAE Version 4.0 for toxicity and adverse event reporting. All adverse 
clinical experiences, whether observed by the investigator or reported by the patient, must be 
recorded, with details about the duration and intensity of each episode, the action taken with 
respect to the study treatment, and the patient’s outcome. The investigator must evaluate each 
adverse experience for its relationship to the study treatment and for its seriousness.
10.3.1 Routine Data Reporting:
Data will be captured in the MMC C3D web based reporting system. A minimum of 25% of 
the data will be source data verified. Grade 1 and 2 lab toxicities and medications used to 
treat adverse events will be maintained in the source documents but will not be captured in 
C3D. Only the following outside labs will be captured in C3D:

Hemoglobin, WBC, ANC, Platelets, ALT/AST, total bilirubin, Creatinine {other labs 
associated with a serious adverse event may be captured as appropriate}
10.3.2 Expedited Reporting of Deaths on Study and Adverse Events
The protocol PI will report to the MMC-IRB:
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
All deaths

All grade 3 and 4 (CTCAE) events that are not listed in the consent form and that are 
possibly, probably or definitely related to the research

All serious adverse events (SAEs) that are not listed in the consent form, but are 
possibly, probably or definitely related to the research. An SAE is defined as an 
untoward medical occurrence that:
o
Resulted in death
o
Was life-threatening
o
Required or prolonged hospitalization
o
Caused persistent or significant disability/incapacity
o
Resulted in congenital anomalies or birth defects
o
Required intervention to prevent permanent impairment or death
o
Is an important medical event
o
Suspected positive Pregnancy
Reports must be received by the MMC IRB within 7 days of notification of the event for 
Serious Adverse Event Reporting. All reportable serious events and deaths will be reported 
to the MMC IRB at:
Fax:
718-798-5687
e-mail: koconno@montefiore.org 
Phone: 718-798-0406
10.3.3 Adverse Event Reporting in the Continuing Review Report
Data will be submitted for review by the IRB annually. The MMC-IRB requires a summary 
report of adverse events that have occurred on the protocol since the previous continuing 
review. The method of presentation should provide the MMC-IRB with the information 
necessary to clearly identify risks to participants and to make a risk:benefit determination. 
The summary report is based on the following guidance:

Any unexpected severity and/or unexpected frequency of expected events needs to be 
reported and interpreted in relation to the risk:benefit of study participants in the 
narrative.

Grade 1 events are not required.

Grade 2 unexpected related to the research events is required.

Grade 3 and 4 expected and unexpected events related to the research are required.

All Serious Events regardless of attribution.

Grade 5 (all) events are included regardless of attribution.
Based on protocol-associated risks to participants, the MMC-IRB retains the authority to 
establish more frequent Continuing Review periods than the customary annual review 
period.
10.4 Protocol amendments
Any amendment to this protocol must be agreed to by the Principal Investigator. Written 
verification of IRB/EC approval will be obtained before any amendment is implemented.
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52.
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treated by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: results from a 
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Shen P, Hawksworth J, Lovato J, et al. Cytoreductive surgery and intraperitoneal 
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Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
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Appendix A: Peritoneal Carcinomatosis Index (PCI) staging system for peritoneal 
carcinomatosis
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Appendix B: Quality of life questionnaire
Please see attached forms.
1. FACT-C (Version 4)
2. SF-36
IRB NUMBER: 11-09-332
IRB APPROVAL DATE: 08/19/2024