Heated Intra-peritoneal Chemotherapy With Doxorubicin and Cisplatin for the Treatment of Resectable, Refractory, or Recurrent Abdominal or Pelvic Tumors in Pediatric Patients, T.O.A.S.T. I.T. Study

Study Overview
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Brief Summary
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This early phase I trial studies how well heated intra-peritoneal chemotherapy with doxorubicin and cisplatin work for the treatment of abdominal or pelvic tumors that can be removed by surgery (resectable), does not respond to treatment (refractory), or has come back (recurrent). Heated intra-peritoneal chemotherapy is a procedure performed in combination with abdominal surgery for cancer that has spread to the abdomen. It involves the infusion of a heated chemotherapy solution that circulates into the abdominal cavity. Chemotherapy drugs, such as doxorubicin and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Heating a chemotherapy solution and infusing it directly into the abdomen may kill more cells.

Detailed Description
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PRIMARY OBJECTIVES: I. To assess the feasibility of heated intra-peritoneal chemotherapy (HIPEC) with doxorubicin (DOXO) and cisplatin (CDDP) after surgical resection of pediatric pelvic and abdominal tumors. II. To assess morbidity, hospital length of stay and peri-operative mortality outcomes for pediatric patients with intraperitoneal sarcoma undergoing hyperthermic intraperitoneal chemotherapy. SECONDARY OBJECTIVE: I. Evaluate disease recurrence patterns: locoregional versus distant. OUTLINE: Patients undergo cytoreduction. Patients also undergo HIPEC over 60 minutes consisting of doxorubicin and cisplatin. Patients then receive sodium thiosulfate intravenously (IV) over 12 hours. After completion of the study treatment, patients are followed every 6 months for 5 years.

Official Title
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A Prospective Study of Heated Intra-Peritoneal Chemotherapy (H.I.P.E.C.) With Doxorubicin and Cisplatin in Pediatric Patients With Pelvic and Abdominal Tumors. The TOAST IT Trial (Trial Of Adjuvant Surgical Treatment With Intraperitoneal Chemotherapy)

Conditions
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Malignant Abdominal Neoplasm, Malignant Pelvic Neoplasm, Recurrent Colon Carcinoma, Recurrent Desmoplastic Small Round Cell Tumor, Recurrent Fallopian Tube Carcinoma, Recurrent Gastric Carcinoma, Recurrent Liposarcoma, Recurrent Malignant Mesothelioma, Recurrent Ovarian Carcinoma, Recurrent Primary Peritoneal Carcinoma, Recurrent Rectal Carcinoma, Recurrent Rhabdomyosarcoma, Recurrent Sarcoma, Refractory Colon Carcinoma, Refractory Desmoplastic Small Round Cell Tumor, Refractory Fallopian Tube Carcinoma, Refractory Gastric Carcinoma, Refractory Liposarcoma, Refractory Malignant Mesothelioma, Refractory Ovarian Carcinoma, Refractory Primary Peritoneal Carcinoma, Refractory Rectal Carcinoma, Refractory Rhabdomyosarcoma, Refractory Sarcoma, Resectable Liposarcoma, Resectable Malignant Mesothelioma, Resectable Sarcoma

Intervention / Treatment
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* Drug: Cisplatin
* Procedure: Cytoreductive Surgery
* Drug: Doxorubicin
* Drug: Hyperthermic Intraperitoneal Chemotherapy
* Drug: Sodium Thiosulfate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have resectable, primary refractory or recurrent intra-abdominal or pelvic tumors based on imaging studies with measurable disease (>= 1 cm in 2 perpendicular planes), or primary tumor with peritoneal implants in whom no known other curative treatment exists, and/or patients not on up-front clinical trial Evidence of macroscopic or microscopic intra-peritoneal seeding (separate from the primary tumor) identified at the time of exploratory surgery with or without primary tumor resection Peritoneal cancer index (PCI) =< 20 and surgeons deem high likelihood of complete residual tumor stage R0 (R0) resection No evidence of distant metastases at the time of enrollment Histologies to be considered include: rhabdomyosarcoma, liposarcoma, sarcoma (other), ovarian cancer, fallopian tube cancer, gastric cancer, colon cancer, rectal cancer, mesothelioma, and desmoplastic small-round-cell tumor Patients may be included in the study independent of the regimen of previous surgical, radiation, or chemotherapy treatments administered. Given the increased risk of entero-cutaneous fistulae observed in patients treated with HIPEC AFTER radiation therapy, patients may be excluded based on the assessment of risk by our radiation oncology team Karnofsky / Lansky performance score of >= 40 or Eastern Cooperative Oncology Group (ECOG) performance score of 3 or less Platelet count >= 50,000 (independent of transfusion) (performed no later than 14 days before surgery) Prothrombin and partial thromboplastin times =< 1.2 X normal (performed no later than 14 days before surgery) Total bilirubin =< 2 X normal (performed no later than 14 days before surgery) Serum glutamic-oxaloacetic transaminase (SGOT) =< 2 X normal (performed no later than 14 days before surgery) Serum glutamate pyruvate transaminase (SGPT) =< 2 X normal (performed no later than 14 days before surgery) Lactate dehydrogenase (LDH) =< 2 X normal (performed no later than 14 days before surgery) Alkaline phosphatase =< 2 X normal (performed no later than 14 days before surgery) Neutrophil count >= 750 (performed no later than 14 days before surgery) Patients must have adequate renal function defined as creatinine clearance (performed no later than 14 days before surgery) or radioisotope GFR (glomerular filtration rate) >= 70 mL/min/1.73 m^2 or a serum creatinine based on age/gender less than the following values: 1 to < 2 years 0.6mg/dL for both males and females 2 to < 6 years 0.8mg/dL for both males and females 6 to <10 years 1.0mg/dL for both males and females A signed informed consent form (and assent form when appropriate) approved by the Mayo Clinic (Institutional Review Board [IRB]) will be required for patient enrollment into the study. Patients must be able to read and understand the informed consent document and must sign the informed consent indicating that they are aware of the investigational nature of this study Exclusion Criteria: Females who are pregnant or breast-feeding during the study period will be excluded Distant metastatic disease not limited to peritoneum: Solid organ metastases (liver, central nervous system, lung) Known bone marrow involvement No critical cumulative dose of previous chemotherapy (total anthracycline dose not >= 435 mg / m^2) Prior HIPEC within 3 months Patients with an active infection requiring treatment or having an unexplained febrile illness (Tmax > 99.5 Fahrenheit [F]), patients with known immune deficiency disorder or known human immunodeficiency virus infection Patients must not have any systemic illness which precludes them from being an operative candidate as determined by anesthesia preoperative evaluation. This includes but is not limited to, sepsis, liver failure, renal failure, cardiovascular failure, pulmonary failure Subjects deemed unable to comply with study and/or follow-up procedures Subjects with a known hypersensitivity to protocol systemic chemotherapy that was life-threatening, required hospitalization or prolongation of existing hospitalization, or resulted in persistent or significant disability or incapacitation

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 25 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (cytoreduction, HIPEC)<br>Patients undergo cytoreduction. Patients also undergo HIPEC over 60 minutes consisting of doxorubicin and cisplatin. Patients then receive sodium thiosulfate IV over 12 hours. | Drug: Cisplatin<br>* Undergo HIPEC with doxorubicin and cisplatin<br>* Other names: Platosin;Procedure: Cytoreductive Surgery<br>* Undergo cytoreduction<br>* Other names: Cytoreduction;Drug: Doxorubicin<br>* Undergo HIPEC with doxorubicin and cisplatin<br>* Other names: Hydroxyldaunorubicin;Drug: Hyperthermic Intraperitoneal Chemotherapy<br>* Undergo HIPEC with doxorubicin and cisplatin<br>* Other names: HIPEC;Drug: Sodium Thiosulfate<br>* Given IV<br>* Other names: Thiosulfuric Acid Disodium Salt;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events of cytoreductive surgery (CRS) with heated intra-peritoneal chemotherapy (HIPEC) in this patient population | To assess the feasibility of heated intra-peritoneal chemotherapy (HIPEC) with doxorubicin (DOXO) and cisplatin (CDDP) after surgical resection of pediatric pelvic and abdominal tumors. | Up to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) | Will be estimated using the Kaplan-Meier method. Patterns of tumor recurrence and survival will be assessed by reviewing routine surveillance imaging. Patient contact may be contacted by telephone. | From the time of diagnosis of cancer up, assessed to 5 years | 
| Disease-free survival (DFS) | Patterns of tumor recurrence and survival will be assessed by reviewing routine surveillance imaging. Patient contact may be contacted by telephone. | From the time of diagnosis of cancer up to 5 years | 
| Peritoneal-free recurrence | Patterns of tumor recurrence and survival will be assessed by reviewing routine surveillance imaging. Patient contact may be contacted by telephone. | From the time of diagnosis of cancer up to 5 years | 
| Incidence of morbidity | Will be measured using the Clavien Dindo scale and the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5. | 30, 60, and, 90 days post-HIPEC procedure | 
| Incidence of mortality | Will be tracked using NCI CTCAE version 5. | 30 days post-HIPEC procedure | 
| Hospital length of stay | Will be tracked using NCI CTCAE version 5. | Up to 5 years | 
| Estimated blood loss (EBL) |  | Up to 5 years | 
| Operative time |  | Up to 5 years | 
| Progression free survival (PFS) | The PFS is defined as the time between initiation of protocol treatment and the first occurrence of disease. It will be defined radiologically. | From the time protocol treatment is initiated, assessed up to 5 years |