Efficacy of Hyperthermic Intraperitoneal Chemotherapy

Study Overview
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Brief Summary
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A dose titration study and a combined superiority registry-based open-label randomized control trial is planned to answer the trial objectives. The study will be registry-based to allow simpler and more comprehensive follow-up. Patients with colorectal cancer will be treated with cytoreductive surgery (CRS) together with either standard oxaliplatin HIPEC (the control for the efficacy study) or oxaliplatin/irinotecan HIPEC in combination with 5-FU 24-hour EPIC. The 5-FU will be administered postoperatively when the abdomen is completely sutured. The drug is divided equally into 2 injections of 200 ml each and injected through two abdominal drains that are clamped for 16 hours. For dose escalation, the titration groups (á 3 or 6 patients) are followed for 30 days postoperatively after which the Data Monitoring Committee (DMC) will determine whether or not to increase the 5-FU dose for the following group of patients. To study efficacy, randomization is performed intraoperatively. The patient is followed up postoperatively for a total of 3 years for the secondary endpoints which may be extended by the study committee to 5 years. Since the trial is registry based, the long-term follow-up does not require separate eCRF evaluations. These evaluations can be automatically retrieved from the registry - both recurrence data, quality of life, and morbidity data. Some specific eCRF evaluations will be integrated as a separate study part of the HIPEC registry, such as inclusion/exclusion criteria and adverse event reporting (including SUSAR reporting).

Detailed Description
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Not detailed description entered.

Official Title
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EFFIPEC - Efficacy of Hyperthermic Intraperitoneal Chemotherapy, Single-arm Phase I Study, Followed by an Open-label, Randomized, Controlled Registry-based Phase III Trial

Conditions
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Colorectal Cancer, Peritoneal Metastases

Intervention / Treatment
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* Drug: 5Fluorouracil
* Drug: Irinotecan
* Drug: Oxaliplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provision of written informed consent prior to any study specific procedures. ECOG Performance Status Score 0,1 or 2 Adequate kidney, liver, bone marrow function according to laboratory tests For females of childbearing potential, a negative pregnancy test must be documented ≥ 18 years old and <75 years old Colorectal cancer with peritoneal metastases All patients deemed eligible for CRS and HIPEC according to clinical routine management during a HIPEC multidisciplinary board at each respective hospital can be included. Exclusion Criteria: Previous severe toxicity/allergic reactions to systemic chemotherapy agents oxaliplatin or irinotecan or 5-fluorouracil Unable to tolerate intensified HIPEC treatment due to comorbidity Metastasis other than peritoneum Pregnant or lactating (nursing) women Active infections requiring antibiotics Active liver disease with positive serology for active hepatitis B, C, or known HIV Concurrent administration of any cancer therapy other than planned study treatment within 4 weeks prior to and up to 4 weeks after study treatment Incomplete cytoreduction defined as completeness of cytoreduction score 1-3 Histopathology of other origin than colorectal cancer

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 74 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard HIPEC<br>Injection of oxaliplatin 460 mg/m2 and an intraoperational IV of 5-fluorouracil 400 mg/m2, and calcium folinate 60 mg/m2. | Drug: Oxaliplatin<br>* Injection of 460 mg/m2<br>* Other names: Oxaliplatin Fresenius Kabi;|
| Experimental: Intensified HIPEC+EPIC<br>Injection of irinotecan 360 mg/m2 and 5-fluorouracil 24-hr EPIC 250-850 mg/m2 in combination with Oxaliplatin 360 mg/m2 and an intraoperational IV of 5-fluorouracil bolus 400 mg/m2 with calcium folinate 60mg/m2. The EPIC treatment is given after the abdomen is completely sutured in the operating theater. The dose will be divided equally into 2 injections á 200ml each through two abdominal drains. | Drug: 5Fluorouracil<br>* Injection of 250-850 mg/m2.<br>* Other names: Fluorouracil Tevo;Drug: Irinotecan<br>* Injection of 360 mg/m2<br>* Other names: Irinotecan Fresenius Kabi;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recurrence-free survival | To study the recurrence-free survival (RFS) of patients | 12 months after treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | Survival is followed through the HIPEC registry. | 5 years after treatment | 
| Recurrence-free survival | Survival is followed through the HIPEC registry. The RECIST criteria are used to determine recurrence and site of first recurrence | 5 years after treatment | 
| Postoperative complication rate | Morbidity is registered in the HIPEC registry within 30 days of treatment administration. | Within 30 days after treatment | 
| Patient evaluations of quality of life | EORTC QLQ questionnaire filled out at baseline, 12 and 36 months after surgery using the established QoL database. | 3 years after treatment |