Study of Cytoreductive Surgery and Hyperthermic Intraoperative Chemotherapy With Pemetrexed and Cisplatin for Malignant Pleural Mesotheliomas

TREATMENT PLAN

PREOPERATIVE HYDRATION According to our observations, preoperative hydration reduces the risk
of nephrotoxicity from intrathoracic infusion of hyperthermic cisplatin. Therefore, all
patients will be admitted the night before surgery and receive intravenous hydration.

CYTOREDUCTIVE SURGERY

Eligible patients will undergo an extrapleural pneumonectomy (EPP) or
pleurectomy/decortication (PD) by a Baylor College of Medicine board-certified thoracic
surgeon. Patients will be given ondansetron 8mg x 1 dose after induction of anesthesia,
before initiation of chemotherapy lavage. The anti-emetics will be adjusted if grade III
toxicity is still encountered. Patients will then undergo cytoreductive surgery (PD or EPP)
with curative intent. In the event that not all of the tumor can be removed then the
investigators will allow a total of 1 cm3 or less of disease in one or more areas. If the
tumor is unresectable and debulking cannot be obtained, then the patient will receive
additional treatment off protocol. Mediastinal lymph node sampling will be performed. In the
event that the diaphragm and pericardium are resected, they will be reconstructed with
polytetrafluoroethylene (PTFE).

RENAL PROTECTION STRATEGY

The investigators will continue our established perioperative renal protection strategy to
minimize the risk of cisplatin-induced nephrotoxicity.

Perioperative Intravenous Hydration:

The patient will be admitted the night before surgery for intravenous hydration.

During the operation, the anesthesiologist will monitor urine output. At his or her
discretion, diuretics, renal dose dopamine, or fluid challenge will be instituted to maintain
the urine output at least 100 cc per hour.

In the immediate postoperative setting, the patient will be aggressively hydrated; a
pulmonary artery catheter will be used to guide management. Cisplatin-induced diuresis (more
than 100 cc per hour) will be replaced with crystalloid for the first 24 hours after surgery
at the following rate: 1cc crystalloid per 1cc of urine after PD and 0.5cc crystalloid per
1cc of urine after EPP.

Amifostine and Sodium Thiosulfate Per Protocol.

HEATED INTRAOPERATIVE CHEMOTHERAPY PERFUSION

The procedure is as follows:

- After the cancer resection is complete, the perfusion cannulae will be placed within the
open hemithorax.

- A total of three temperature probes will be placed within the hemithorax or upper
abdomen (via the chest since the diaphragm is no longer present after most PDs and after
all EPPs) and the esophagus.

- Another two temperature probes will be used to monitor the temperature of the solution
in the circuit.

- An open well will be created over the thoracotomy using an Omni tract retractor, using
monofilament suture between the skin edges and the retractor, and enclosing the area
with a plastic covering.

- A slit in the plastic cover is made just large enough to allow the surgeon's
double-gloved hand into the hemithorax to evenly distribute the perfusate. The surgeon
gently (but repeatedly) manipulates all exposed areas to allow uniform distribution of
the heated chemotherapy.

- Pemetrexed and cisplatin will be admixed together in 1 liter of normal saline. The
admixture of pemetrexed/cisplatin is stable for 4 hours and should be prepared and
delivered immediately before use in the OR. The length of the pemetrexed/cisplatin
lavage will be 1 hour.

- A roller pump forces the heated chemotherapy into the chest and abdomen through the
inflow cannula and pulls it out via an outflow cannula.

- If the perfusate solution does not fill the chest cavity, one or more intact bags of
saline will be placed in the chest cavity to displace the perfusate. In this manner, the
chest cavity can be filled without diluting the perfusate.

- A heat exchanger keeps the fluid being infused at 43-45 degrees Celsius so that the
intrathoracic fluid is 42 degrees Celsius.

- A smoke evacuator is used to pull air from beneath the plastic cover through activated
charcoal, preventing any possible contamination of air in the operating room by
chemotherapy aerosols.

Pharmacokinetics will be drawn per protocol.

Dose Levels

Cohort Pemetrexed Dose A 300 mg/m2 B 400 mg/m2 C 500 mg/m2 D 600 mg/m2 E 700 mg/m2 F 800
mg/m2 Stop to Analyze Safety G 900 mg/m2 H 1000 mg/m2 Stop to Analyze Safety

The standard dose of pemetrexed for systemic administration is 500 mg/m2. However, because
pemetrexed has not been previously studied for direct administration into the chest, the
initial cohorts will receive a slightly lower dose to ensure this method of administering
pemetrexed is safe. Once safety has been established at lower doses, the investigators will
feel confident that pemetrexed intrathoracic doses that are slightly higher than the standard
systemic dose (500 mg/m2) can be given safely. In animal models, these higher doses resulted
in a systemic concentration of pemetrexed (which is correlated with systemic toxicities) that
is potentially lower after intracavitary infusion than after systemic administration 2. These
higher doses may result in superior long-term clinical outcomes.

Schedule Assignment for Dose Levels

Patients will be enrolled in cohorts of 3 according the dose escalation/de-escalation rules
specified. For the purposes of executing the dose escalation scheme, toxicity will be
assessed until 4 weeks after treatment. Additional patient cohorts will not be enrolled until
all toxicity evaluable patients treated at the current dose have completed the observation
period. In addition, the investigators will pause after completion of the 800 mg/m2, if the
MTD is not reached, to assure that delayed toxicities don't manifest. If the MTD is not
exceeded at the highest dose level, the escalation schedule may be expanded.

Dose limiting toxicity (DLT) is defined as:

- Grade 4 treatment-related hematologic toxicity that lasts more than for 5 days or grade
3 thrombocytopenia with grade 3 or 4 bleeding

- Febrile neutropenia

- Grade 3 or greater treatment related non-hematologic toxicity with the following
exceptions:

- Grade 3 diarrhea is a DLT only if the patient was compliant with an anti-diarrheal
program consistent with best clinical practice

- Grade 3 or 4 nausea and vomiting is a DLT only if the patient was compliant with an
antiemetic program consistent with best clinical practice

- Alopecia

Supportive Care Guidelines All supportive measures consistent with optimal patient care will
be given throughout the study.

Duration of Therapy

Patients will receive protocol therapy unless:

1. Extraordinary medical circumstances: If at any time the constraints of this protocol are
detrimental to the patient's health, protocol treatment will be discontinued

2. Patient withdraws consent

3. There is evidence of progressive disease or unacceptable toxicity

4. The treating physician thinks a change of therapy would be in the best interest of the
patient

Follow-up All patients, including those who discontinue protocol therapy early, will be
followed by their oncologist or primary care providers. The date of death will be recorded.

Inclusion Criteria:

1. Histologically proven malignant pleural mesothelioma MPM that is considered resectable
according to the following criteria:

- Confined to one pleural space

- No chest wall invasion

- No transdiaphragmatic involvement

- No invasion of mediastinal structures

2. Age ≥ 18 years

3. Eastern Cooperative Oncology Group performance status 0-1 (Appendix A)

4. Adequate cardiopulmonary reserve defined as follows as assessed within 4 months of
study entry:

- Predicted postoperative forced expiratory volume FEV1 > 1L

- Normal left ventricular function (Ejection Fraction EF ≥ 45%) and right
ventricular function

- No pulmonary hypertension noted on preoperative transthoracic echocardiography

5. Must have adequate hematologic, renal and hepatic function as defined by the following
laboratory values (completed within 60 days of surgery) Hematologic: Hemoglobin ≥ 9.0
g/dL, absolute neutrophil count (ANC) ≥ 1500/mm3, platelet count ≥ 100,000/mm Renal:
Calculated creatinine clearance ≥ 60 mL/min

The creatinine clearance CrCl is determined by the Cockcroft-Gault formula:

Males:

Creatinine Clearance CrCl (mL)/min) = weight (kg) x (140-age) 72 x serum creatinine
(mg/dL)

Females:

Creatinine Clearance CrCl (mL)/min) = weight (kg) x (140-age) x 0.85 72 x serum
creatinine (mg/dL)

Hepatic: Total bilirubin < 1.5 times the upper limit of institutional normal value;
Aspartate aminotransferase AST (Serum glutamic oxaloacetic transaminase SGOT) and
alanine aminotransferase ALT (Serum glutamic pyruvic transaminase SGPT) < 3 times the
upper limit of the institutional normal Coagulation: international normalized ratio
INR ≤ 1.5 in patients not utilizing systemic anticoagulation as part of their medical
regimen

6. Women of child bearing potential and sexually active males must use an accepted and
effective non-hormonal method of contraception

7. Patients must be deemed by the investigators to be fully recovered from both acute and
late effects of any prior surgery, radiotherapy, or other antineoplastic therapy

8. Voluntary written informed consent before performance of any study-related procedure
not part of normal medical care, with the understanding that consent may be withdrawn
by the subject at any time without prejudice to future medical care.

9. The ability to interrupt non-steroidal anti-inflammatory drugs NSAIDS 2 days before (5
days for long-acting NSAIDs), the day of, and 2 days following administration of
Pemetrexed.

10. The ability to take folic acid, Vitamin B12, and dexamethasone according to protocol.

Exclusion Criteria:

1. Not pregnant or breastfeeding - the drugs used in this study are Pregnancy Category D
(clear evidence of risk in pregnancy). A negative pregnancy test is required within 14
days of registration for pre- or perimenopausal (i.e., last menstrual period within
one year of registration) women.

2. Patients with a history of another neoplasm, with the exception of non-metastatic,
non-melanoma skin cancers, carcinoma in situ of the cervix, or cancer cured by surgery
or small field radiotherapy, within 5 years of registration will be excluded.

3. Patients with uncontrolled cardiovascular disease (a history of hospitalization for
acute myocardial infarction, arrhythmia, or congestive heart failure within 3 months
prior to registration) will be excluded

4. Registered patients with an active infection or with a fever of ≥ 38.5°C within 24
hours of the first scheduled day of protocol initiation will be excluded until their
infection and/or fever resolves.

5. Any other medical condition, including mental illness or substance abuse, deemed by
the Investigator to be likely to interfere with a patient's ability to sign informed
consent, cooperate and participate in the study, or interfere with the interpretation
of the results.

6. Inability to interrupt use of non-steroidal anti-inflammatory drugs (NSAIDS)

7. Peripheral neuropathy Grade 2 (Common Terminology Criteria for Adverse Events CTCAE)

8. Systemic chemotherapy within 3 weeks of registration

9. Prior Allergies: History of allergic reactions attributed to compounds of similar
chemical or biologic composition to cisplatin and pemetrexed

10. Presence of third space fluid which cannot be controlled by drainage.