Study of Cytoreductive Surgery and Hyperthermic Intraoperative Chemotherapy With Pemetrexed and Cisplatin for MPM

Mesothelioma Clinical Trial

Official title: Phase I Study of Cytoreductive Surgery and Hyperthermic Intraoperative Chemotherapy With Pemetrexed and Cisplatin for Malignant Pleural Mesotheliomas

Status Terminated

Clinical Trial Summary

Primary Objective

To determine the maximum tolerated dose (MTD) of intrathoracic administration of pemetrexed when given in conjunction with cisplatin in patients with resectable malignant pleural mesothelioma MPM.

Secondary Objectives

To determine the toxicity and grades associated with cytoreductive surgery and Hyperthermic Intraoperative Chemotherapy HIOC with cisplatin and pemetrexed in patients with resectable MPM.

To assess overall survival and progression-free survival after PD or EPP and HIOC with cisplatin and pemetrexed for MPM

Correlative Objectives

To characterize the pharmacokinetics and pharmacodynamics of pemetrexed when administered as a hyperthermic intrathoracic lavage after PD or EPP

To determine whether the degree of thymidylate synthase and ERCC1 gene expression in MPM tissue correlates with clinical response to pemetrexed.

Clinical Trial Description

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. ;

Related Conditions & MeSH terms

• Mesothelioma
• Mesothelioma, Malignant

• NCT number: NCT02838745
• Study type: Interventional
• Source: Baylor College of Medicine
• Status: Terminated
• Phase: Phase 1
• Start date: September 2016
• Completion date: September 5, 2019