Heated Intraperitoneal Chemotherapy in Primary Ovarian Cancer Patients

Heated Intraperitoneal chemotherapy (HIPEC) has several potential benefits. High-dose
chemotherapy can be used due to the plasma-peritoneal barrier resulting in little absorption
into the blood stream. Additionally, there is higher peritoneal penetration in comparison to
IV regimen, and does not have the limitation of traditional IP regimen of post-operative
adhesions. Hyperthermia itself has cytotoxic effects and can increase the depth of tumor
penetration by the chemotherapeutic agent up to 3 millimeters; moreover, hyperthermia can
potentiate its antineoplastic effects.

In recent times, morbidity and mortality associated with HIPEC has drastically improved. One
large retrospective review of 694 patients, treated between 2005 and 2011, utilizing the
American College of Surgeons National Surgical Quality Improvement Program (ACS NSQUIP)
database, demonstrated a complication rate of 33% and 30-day mortality of 2.3%, both rates
consistent with outcomes for other major complex abdominal operations.

Recently, a Phase I dose escalation study to evaluate maximum tolerated dose (MTD) of HIPEC
administration of cisplatin in recurrent epithelial ovarian cancer (EOC) patients was
published. The MTD of cisplatin was 100 milligrams per meter squared (mg/m2) with no
mortality or safety concerns. While the trial had only 12 patients, all were able to receive
post-operative IV chemotherapy, with all patients completing at least five cycles.

In protocol Gynecologic Oncology Group (GOG)-0172, intraperitoneal cisplatin and paclitaxel,
plus intravenous paclitaxel, demonstrated the longest median survival reported in optimally
debulked stage III ovarian cancer. Currently, the GOG is studying variations of the
intraperitoneal (IP) regimen to preserve the survival advantage, but make it tolerable for
patients to receive 6 cycles without discontinuing therapy due to distress and toxicity. The
importance of developing an acceptable GOG-0172 alternative is emphasized by the recent
National Cancer Institute (NCI) Clinical Announcement recognizing the superiority of
intraperitoneal chemotherapy in the optimal disease setting.

Inclusion Criteria:

- Ability to understand and the willingness to sign a written informed consent.

- Patients with a histologic diagnosis of epithelial ovarian, fallopian tube, or primary
peritoneal carcinoma, Stage 3(III)B - 3(III)C with optimal (≤ 1 centimeter) residual
disease.

- Patients with the following histologic epithelial cell types are eligible:

- Serous adenocarcinoma, endometrioid adenocarcinoma, mucinous adenocarcinoma,
undifferentiated carcinoma, clear cell adenocarcinoma, mixed epithelial carcinoma, or
adenocarcinoma not otherwise specified.

- No previous HIPEC.

- Patient has a planned cytoreduction surgery - Note: registration occurs during surgery
and not before; if, during surgery, the Principal Investigator/Sub-Investigator
discerns that all disease cannot be removed surgically, the participant will be
considered a "screen failure", HIPEC will not be performed, and the participant will
be removed from the study.

- Age ≥ 18 years.

- Performance Status Eastern Cooperative Group (ECOG) 0- 2

- Adequate organ and marrow function as defined below:

1. absolute neutrophil count ≥ 1.5 kilograms per microliter (K/UL)

2. platelets ≥ 100 K / UL

3. total bilirubin within 1.5 x normal institutional limits

4. Aspartate Aminotransferase (AST) / Serum Glutamic Oxaloacetic Transaminase (SGOT)
≤ 2.5 X institutional upper limit of normal

5. Alanine Aminotransferase (ALT) / Serum Glutamic Pyruvic Transaminase (SPGT) ≤ 2.5
X institutional upper limit of normal

6. creatinine within 1.5 x normal institutional limits

- Note: If a potential participant has non-clinically significant variances
related to the organ and marrow parameters listed above, PI review and
approval is required before enrollment.

- Women of child-bearing potential and their male partners also of child-bearing
potential must agree to use adequate contraception (hormonal or barrier method of
birth control; abstinence) prior to study entry, for the duration of study
participation, and for 90 days following completion of therapy. Should a woman become
pregnant or suspect she is pregnant while participating in this study, she should
inform her treating physician immediately.

*A woman of child-bearing potential is any female (regardless of sexual orientation,
having undergone a tubal ligation, or remaining celibate by choice) who meets the
following criteria:

- Has not undergone a hysterectomy or bilateral oophorectomy; OR Has not been naturally
postmenopausal for at least 12 consecutive months (has had menses at any time in the
preceding 12 consecutive months)

*Note: Acceptable forms of birth control are listed below:

- One Barrier method (cervical cap with spermicide plus male condom; diaphragm with
spermicide plus male condom) Plus Hormonal method (oral contraceptives, implants, or
injections) or an intrauterine device (e.g., Copper-T).

Exclusion Criteria:

Participants meeting any of the exclusion criteria listed below at screening will be
excluded from study participation.

- Current or anticipated use of other investigational agents.

- Patient has received chemotherapy or radiotherapy within 4 weeks prior to entering the
study or has not recovered sufficiently (PI will judge patient recovery status) from
adverse events due to agents administered more than 4 weeks earlier.

- Patient has history of or currently has non-peritoneal surface macroscopic metastatic
disease in addition to peritoneal surface malignancy such as macroscopic pulmonary
disease or other macroscopic disease outside of the peritoneal cavity.

- Patients with a current diagnosis of borderline epithelial ovarian tumor (formerly
"tumors of low malignant potential") or recurrent invasive epithelial ovarian cancer
treated with surgery only (such as those with stage Ia or Ib low Grade lesions) are
not eligible. Patients with a prior diagnosis of a borderline tumor that was
surgically resected and who subsequently develop an unrelated, new invasive epithelial
ovarian or peritoneal primary cancer are eligible, provided that they have not
received prior chemotherapy for any ovarian tumor.

- Patients with synchronous primary endometrial cancer, or a past history of primary
endometrial cancer, are excluded, unless all of the following conditions are met:
Stage not greater than I-B; no more than superficial myometrial invasion, without
vascular or lymphatic invasion; no poorly differentiated subtypes, including papillary
serous, clear cell or other International Federation of Gynecology and Obstetrics
(FIGO) Grade 3 lesions.

- ECOG 3 - 4

- Patients with history or current diagnosis of inflammatory bowel disease are not
eligible.

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to Cisplatin, carboplatin and paclitaxel or other agents used in study.

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia

- Current psychiatric illness/social situations that would limit compliance with study
requirements.

- Pregnant or nursing. There is a potential for congenital abnormalities and for this
regimen to harm nursing infants.