Concentration- Versus Body Surface Area-based HIPEC in Colorectal Peritoneal Carcinomatosis' Treatment

NCT03028155 | Unknown Phase 3

• 1 other identifier: ZOLCOBOX1
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 1

Brief Summary

Colorectal Cancer (CRC) is the third most common cancer and the fourth most common cause of cancer-related death worldwide. CRC frequently gives rise to transcoelomic spread of tumor cells in the peritoneal cavity, which ultimately leads to Peritoneal Carcinomatosis (PC). A new loco-regional treatment modality combines Cytoreductive Surgery (CRS) and Hyperthermic Intraperitoneal Peroperative Chemotherapy (HIPEC). The current HIPEC dosing regimens for the treatment of colorectal PC can be divided into body surface area (BSA)-based protocols and concentration-based protocols. Most groups currently use a drug dose based on calculated BSA (mg/m2) in analogy to systemic chemotherapy regimens. These regimens take BSA as a measure for the effective contact area, represented as the peritoneal surface in the formula for dose intensification. However, an imperfect correlation exists between actual peritoneal surface area and calculated BSA. Sex differences, but also altered pathophysiological characteristics or frequent complications in patients (ascites) are responsible for differences in peritoneal surface areas, which in turn affect absorption characteristics. This takes us away from the initial homogenous drug concentration desired, increasing the variability in the systemic and tumor exposure to the drug. Pharmacokinetic changes induced by the volume of chemotherapy solution with constant drug dose, administered intraperitoneally, have already been reported. This resulted in less precise predictions of the toxicity associated with the treatment. By contrast, some groups use a totally different dosimetry regimen based on concentration. From a pharmacologic point of view, the big advantage of a concentration-based system is that the residual tumor nodules after CRS are exposed to a constant diffusional force and, thus, cytotoxicity. Unfortunately the prize to be paid for a better prediction of the efficacy of the IP chemotherapy is a high unpredictability of the levels of plasmatic cancer chemotherapy and, thus, toxicity. This randomised non-blinded phase III clinical trial will be the first trial to pharmacologically evaluate the two dosing regimens, BSA-based and concentration-based, both applied as standard of care in current practice.

Conditions

Colorectal Peritoneal Carcinomatosis

Outcome Measures

Primary Outcomes (4)

• Assessment of pharmacologic advantage

  the area-under-the-curve (AUC) ratio of the intraperitoneal (IP) exposure over the AUC of the intravenous (IV) exposure to oxaliplatin. Intraoperative sampling of plasma and peritoneal fluid at seven time points (0, 5, 10, 15, 20, 25 and 30 minutes) during the 30-minute HIPEC procedure. The concentration of oxaliplatin will be determined in plasma and peritoneal fluid by means of a validated inductively coupled plasma mass spectrometry (ICP-MS). A concentration versus time curve will be set-up and the AUC will be determined.

  Day 2

• Assessment of Pt excretion in urine

  Intraoperative sampling of urine at seven time points (0, 5, 10, 15, 20, 25 and 30 minutes) during the 30-minute HIPEC procedure. The concentration of oxaliplatin will be determined in urine by means of a validated ICP-MS. A concentration versus time curve will be set-up and the AUC will be determined.

  day 2

• Assessment of efficacy in the tumor nodule as pharmacologic endpoint.

  At the day of surgery (day 2): intraoperative sampling of tumor nodules at seven time points (0, 5, 10, 15, 20, 25 and 30 minutes) during the 30-minute HIPEC procedure. The concentration of oxaliplatin will be determined in tumor nodules by means of a validated ICP-MS. A concentration versus time curve will be set-up and the AUC will be determined.

  day 2

• Assessment of 3-month overall morbidity and mortality

  Morbidity and mortality will be evaluated using the Clavien-Dindo classification. This classification consists of five grades: grade I, deviation from standard post-operative course within 'allowed therapeutic regimens'; grade II, complication requiring surgical, endoscopic or radiological intervention; grade IV, complication requiring ICU admission and grade V, complication resulting in death.

  During 3 months postoperative.

Secondary Outcomes (7)

• Assessment of one-year overall survival

  During one year postoperative.

• Assessment of health related quality of life (HRQOL): EORTC QLQ-C-30

  Day 1

• Assessment of health related quality of life (HRQOL): SF-36

  Day 1

• Assessment of health related quality of life (HRQOL): EORTC QLQ-C-30

  up to 2 months

• Assessment of health related quality of life (HRQOL): SF-36

  up to 2 months

Study Arms (2)

Oxaliplatin: BSA-based HIPEC

ACTIVE COMPARATOR

Intervention: oxaliplatin: BSA-based HIPEC HIPEC will be performed using oxaliplatin as chemotherapeutic agent at a dose of 460 mg/m2 mixed in 0.9% saline carrier solution during 30 minutes. Volume of the carrier solution: depended on the capacity of the abdominal cavity of the patient.

Drug: Oxaliplatin: BSA-based HIPEC

Oxaliplatin: Concentration-based HIPEC

ACTIVE COMPARATOR

Intervention: oxaliplatin: concentration-based HIPEC HIPEC will be performed using oxaliplatin as chemotherapeutic agent at a dose of 460 mg/m2 mixed in 0.9% saline carrier solution at 2L/m2, which equals a concentration of 230 mg/L during 30 minutes.

Drug: Oxaliplatin: Concentration-based HIPEC

Interventions

Oxaliplatin: BSA-based HIPEC DRUG

oxaliplatin: 460 mg/m2 volume: dependent on the capacity of the peritoneal cavity of the patient

Oxaliplatin: BSA-based HIPEC

Oxaliplatin: Concentration-based HIPEC DRUG

oxaliplatin: 230 mg/L

Oxaliplatin: Concentration-based HIPEC

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Males and females with histologically proven synchronous or metachronous peritoneal metastases from colorectal origin
• Karnofsky index \> 70%
• Age \>18 years
• Fit for major surgery
• Mentally capable of understanding the proposed treatment and the provided informed consent
• Estimated life expectancy of \> 6 months
• Absence of other malignant disease
• Serum creatinine \< or = 1.5 mg/dL or calculated glomerular filtration rate \> or = 60 mL/min/1.73m2
• Serum total bilirubin \< or = 1.5 mg/dL except for known Gilbert's disease
• Platelet count \> 100,000/µL
• Hemoglobin \> 9 g/dL
• Neutrophil granulocytes \> 1,500/mL
• International normalized ratio \< or = 2

You may not qualify if:

• Alcohol or drug abuse
• Chronic systemic immune therapy
• Chemotherapy or hormone therapy not indicated in the study protocol
• Severe organ insufficiency
• Pregnancy or breast feeding
• Appearance of distant metastases (liver, lung) of a CT scan of the abdomen of chest X-ray
• Severe or uncontrolled cardiac pathology
• \> 6 months occurrence of myocardial infarction
• Presence of congestive cardiac failure of symptomatic angor pectoris despite optimal medical treatment
• Presence of congestive cardiac failure of cardiac arrhythmia requiring medical treatment with insufficient rhythm control
• Uncontrolled arterial hypertension
• Active bacterial, viral or fungal infection
• Active gastrointestinal ulcer
• Any stage cirrhosis
• Uncontrolled diabetes mellitus

Sponsors & Collaborators

• Hasselt University: lead
• Ziekenhuis Oost-Limburg: collaborator

Study Sites (1)

Ziekenhuis Oost-Limburg

Genk, 3600, Belgium

RECRUITING

Central Study Contacts

Kurt Van der Speeten, prof. dr.

CONTACT

kurt.vanderspeeten@zol.be

Lieselotte Lemoine, drs.

CONTACT

lieselotte.lemoine@uhasselt.be

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: prof. dr.

Study Record Dates

• First Submitted: December 24, 2016
• First Posted: January 23, 2017
• Study Start: November 1, 2016
• Primary Completion: August 1, 2018
• Study Completion: August 1, 2018
• Last Updated: January 23, 2017

Record last verified: 2017-01

Data Sharing

• IPD Sharing: Will not share

Locations

BE (1)