Single Arm Study Treating Patients of Peritoneal Surface Malignancy (Colorectal, Appendical, Pseudomyxoma, Gastric) With Cytoreductive Surgery and Hyperthermic Intraperitoneal Mitomycin-C
Single Arm Study Treating Patients of Peritoneal Surface Malignancy (Colorectal, Appendical, Pseudomyxoma, Gastric) With Cytoreductive Surgery and Hyperthermic Intraperitoneal Mitomycin-C
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.
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 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 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;

 5.4 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 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).

 -  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.
Inclusion Criteria:

 -  Age ≥ 18 years

 -  Capable of providing informed consent.

 -  The patient who has not previously received hyperthermic intraperitoneal chemotherapy
 must have histopathologically or cytologically confirmed cancer of colorectal,
 appendiceal, peritoneal mesothelioma, pseudomyxoma or gastric origin with known
 synchronous or metachronous disease dissemination limited to the peritoneal surfaces.

 -  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

 -  Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1

 -  Absolute neutrophil count (ANC) > 1200/mm3, white blood cell count (WBC) > 4000/mm3
 and platelet count > 150,000/mm3

 -  An international normalized ratio (INR) ≤ 1.5 (patients who are therapeutically
 anticoagulated for unrelated medical conditions such as atrial fibrillation and whose
 antithrombotic treatment can be withheld for operation will be eligible).

 -  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

 -  Serum renal functional parameters, blood urea nitrogen (BUN) and creatinine are within
 normal limits

 -  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).

 -  Patients who have met the above criteria and who have undergone CRS and HIPEC in the
 past 18 months for the beforementioned disease processes without evidence of
 recurrence will be eligible for participation in this study for analyzing ability to
 achieve complete cytoreduction, morbidity, progression and survival.

 Exclusion Criteria:

 -  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

 -  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.

 -  Active systemic infections, coagulation disorders, or other major medical illnesses
 precluding major surgery.

 -  Childs B or C cirrhosis or with evidence of severe portal hypertension by history,
 endoscopy or radiologic studies.