Ignite Creation Date:
2024-05-06 @ 8:50 AM
Last Modification Date:
2024-10-26 @ 12:06 PM
Study NCT ID:
NCT02838745
Status:
TERMINATED
Last Update Posted:
2022-03-31
First Post:
2016-07-16
Brief Title:
Study of Cytoreductive Surgery and Hyperthermic Intraoperative Chemotherapy With Pemetrexed and Cisplatin for MPM
Sponsor:
Baylor College of Medicine
Organization:
Baylor College of Medicine
Study Overview
Official Title:
Phase I Study of Cytoreductive Surgery and Hyperthermic Intraoperative Chemotherapy With Pemetrexed and Cisplatin for Malignant Pleural Mesotheliomas
Status:
TERMINATED
Status Verified Date:
2022-03
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Change in research plan
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief 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
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
Detailed 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 pleurectomydecortication 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 05cc 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 surgeons 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 pemetrexedcisplatin is stable for 4 hours and should be prepared and delivered immediately before use in the OR The length of the pemetrexedcisplatin 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 mgm2 B 400 mgm2 C 500 mgm2 D 600 mgm2 E 700 mgm2 F 800 mgm2 Stop to Analyze Safety G 900 mgm2 H 1000 mgm2 Stop to Analyze Safety
The standard dose of pemetrexed for systemic administration is 500 mgm2 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 mgm2 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 escalationde-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 mgm2 if the MTD is not reached to assure that delayed toxicities dont 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 patients 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
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 pleurectomydecortication 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 05cc 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 surgeons 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 pemetrexedcisplatin is stable for 4 hours and should be prepared and delivered immediately before use in the OR The length of the pemetrexedcisplatin 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 mgm2 B 400 mgm2 C 500 mgm2 D 600 mgm2 E 700 mgm2 F 800 mgm2 Stop to Analyze Safety G 900 mgm2 H 1000 mgm2 Stop to Analyze Safety
The standard dose of pemetrexed for systemic administration is 500 mgm2 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 mgm2 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 escalationde-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 mgm2 if the MTD is not reached to assure that delayed toxicities dont 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 patients 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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None