PIPAC for Peritoneal Metastases of Colorectal Cancer

Colorectal Neoplasms Clinical Trial

— CRC-PIPAC  

Official title:

Repetitive Electrostatic Pressurised Intraperitoneal Aerosol Chemotherapy With Oxaliplatin (ePIPAC-OX) as a Palliative Monotherapy for Isolated Unresectable Colorectal Peritoneal Metastases: Protocol of a Multicentre, Open-label, Single-arm, Phase II Study (CRC-PIPAC)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03246321
• Other study ID #: NL60405.100.17
• Secondary ID: 2017-000927-29NT
• Status: Completed
• Phase: Phase 2
• Start date: October 1, 2017
• Est. completion date: October 1, 2019

Study information

• Verified date: October 2019
• Source: Catharina Ziekenhuis Eindhoven
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is multicentre, open-label, single-arm phase II study that investigates the feasibility, safety, tolerability, preliminary efficacy, costs, and pharmacokinetics or repetitive electrostatic pressurised intraperitoneal aerosol chemotherapy (ePIPAC-OX) as a palliative monotherapy for patients with isolated unresectable colorectal peritoneal metastases.

Description:

Rationale: repetitive electrostatic pressurised intraperitoneal aerosol chemotherapy with oxaliplatin (ePIPAC-OX) is offered as a palliative treatment option for patients with isolated unresectable colorectal peritoneal metastases (PM) in several centres worldwide. However, little is known about its feasibility, safety, tolerability, efficacy, costs, and pharmacokinetics in this setting.

Objectives: to prospectively explore the feasibility, safety, tolerability, preliminary efficacy, costs, and pharmacokinetic profile of repetitive ePIPAC-OX as a palliative monotherapy for isolated unresectable colorectal PM under controlled circumstances.

Study design: multicentre, open-label, single-arm, phase II study.

Setting: two Dutch tertiary referral hospitals for the surgical treatment of colorectal PM.

Study population: adults who have a World Health Organisation (WHO) performance status of 0 or 1, adequate organ functions, histologically or cytologically confirmed unresectable PM of a colorectal or appendiceal carcinoma, no systemic metastases, no symptoms of gastrointestinal obstruction, no contraindications for the planned intervention, and no previous pressurised intraperitoneal aerosol chemotherapy (PIPAC).

Intervention: instead of standard palliative treatment, enrolled patients receive laparoscopy-controlled ePIPAC-OX (92 mg/m2 body-surface area [BSA]) with intravenous leucovorin (20 mg/m2 BSA) and bolus 5-fluorouracil (400 mg/m2 BSA) every six weeks. Four weeks after each procedure, patients undergo clinical, radiological, and biochemical evaluation. ePIPAC-OX is repeated until clinical, radiological, or macroscopic disease progression, after which standard palliative treatment is (re)introduced.

Outcomes: the primary outcome is the number of patients with major toxicity (grade ≥3 according to the Common Terminology Criteria for Adverse Events v4.0) up to four weeks after the last procedure. Secondary outcomes are the environmental safety of ePIPAC-OX, procedure-related characteristics, the number of procedures in each patient and reasons for discontinuation, minor toxicity, organ-specific toxicity, postoperative complications, hospital stay, readmissions, quality of life, costs, progression-free survival, overall survival, and the radiological, histopathological, cytological, biochemical, and macroscopic tumour response. Atomic absorption spectrophotometry is used to measure concentrations of oxaliplatin in plasma, plasma ultrafiltrate, urine, ascites, PM, and normal peritoneum during and after ePIPAC-OX.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 20
• Est. completion date: October 1, 2019
• Est. primary completion date: October 1, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A and older

Eligibility

Eligible patients are adults who have:

• a World Health Organisation (WHO) performance status of =1;

• histological or cytological proof of PM of a colorectal or appendiceal carcinoma;

• unresectable disease determined by abdominal computed tomography (CT) and a diagnostic laparoscopy or laparotomy;

• adequate organ functions (haemoglobin =5.0 mmol/L, neutrophils =1.5 x 109/L, platelets =100 x 109/L, serum creatinine <1.5 x ULN, creatinine clearance =30 ml/min, and liver transaminases <5 x ULN);

• no symptoms of gastrointestinal obstruction;

• no radiological evidence of systemic metastases;

• no contraindications for oxaliplatin or 5-fluorouracil/leucovorin;

• no contraindications for a laparoscopy;

• no previous PIPAC-procedures.

Enrolled patients are excluded from the analyses in case they did not receive a first ePIPAC-OX, e.g.:

• due to systemic metastases on baseline thoracoabdominal CT, or;

• due to non-access during first ePIPAC-OX, or;

• due to resectable disease during first ePIPAC-OX.

Importantly, enrolment is allowed for patients with an unresected primary tumour (if asymptomatic) and for patients in various lines of palliative treatment, including patients who refuse, have not had, or do not qualify for first-line palliative systemic therapy. All potentially eligible patients are discussed by a multidisciplinary team. Enrolled patients are informed about the potential consequences of postponing or discontinuing standard palliative treatment by a medical oncologist prior to enrolment.

Related Conditions & MeSH terms

• Appendiceal Neoplasms
• Carcinoma
• Colorectal Neoplasms
• Neoplasms
• Peritoneal Carcinomatosis
• Peritoneal Neoplasms

Intervention

Combination Product:
• repetitive ePIPAC-OX
Instead of standard palliative treatment, enrolled patients receive laparoscopy-controlled electrostatic pressurised intraperitoneal aerosol chemotherapy with oxaliplatin (ePIPAC-OX) (92 mg/m2 body-surface area [BSA]) with intravenous leucovorin (20 mg/m2 BSA) and bolus 5-fluorouracil (400 mg/m2 BSA) every six weeks. Four weeks after each procedure, patients undergo clinical, radiological, and biochemical evaluation. ePIPAC-OX is repeated until clinical, radiological, or macroscopic disease progression, after which standard palliative treatment is (re)considered.

Locations

Country	Name	City	State
Netherlands	Catharina Hospital	Eindhoven
Netherlands	St. Antonius Hospital	Nieuwegein

Sponsors (1)

Lead Sponsor	Collaborator
Koen Rovers

Country where clinical trial is conducted

Netherlands, 

References & Publications (3)

Giger-Pabst U, Tempfer CB. How to Perform Safe and Technically Optimized Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC): Experience After a Consecutive Series of 1200 Procedures. J Gastrointest Surg. 2018 Dec;22(12):2187-2193. doi: 10.1007/s11605-018-3916-5. Epub 2018 Aug 21. — View Citation

Grass F, Vuagniaux A, Teixeira-Farinha H, Lehmann K, Demartines N, Hübner M. Systematic review of pressurized intraperitoneal aerosol chemotherapy for the treatment of advanced peritoneal carcinomatosis. Br J Surg. 2017 May;104(6):669-678. doi: 10.1002/bjs.10521. Review. — View Citation

Tempfer C, Giger-Pabst U, Hilal Z, Dogan A, Rezniczek GA. Pressurized intraperitoneal aerosol chemotherapy (PIPAC) for peritoneal carcinomatosis: systematic review of clinical and experimental evidence with special emphasis on ovarian cancer. Arch Gynecol Obstet. 2018 Aug;298(2):243-257. doi: 10.1007/s00404-018-4784-7. Epub 2018 Jun 4. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Major toxicity	Number of patients with Common Terminology Criteria for Adverse Events (CTCAE) v4.0 grade III-V, up to 4 weeks after the last ePIPAC-OX	Expected (in case of three ePIPAC-OX): 16 weeks
Secondary	Minor toxicity	Number of patients with Common Terminology Criteria for Adverse Events (CTCAE) v4.0 grade II, up to 4 weeks after the last ePIPAC-OX	Expected (in case of three ePIPAC-OX): 16 weeks
Secondary	Organ-specific toxicity	Number of patients that develops bone marrow, kidney, or liver function disorders, up to four weeks after the last ePIPAC-OX	Expected (in case of three ePIPAC-OX): 16 weeks
Secondary	Major postoperative complications	Number of patients with Clavien-Dindo grade III-V postoperative complications, up to four weeks after the last ePIPAC	Expected (in case of three ePIPAC-OX): 16 weeks
Secondary	Minor postoperative complications	Number of patients with Clavien-Dindo grade II postoperative complications, up to four weeks after the last ePIPAC-OX	Expected (in case of three ePIPAC-OX): 16 weeks
Secondary	Hospital stay	Number of days between ePIPAC-OX and initial discharge, up to four weeks after the last ePIPAC-OX	Expected (in case of three ePIPAC-OX): 16 weeks
Secondary	Readmissions	Number of hospital admissions after initial discharge after ePIPAC-OX, up to four weeks after the last ePIPAC-OX	Expected (in case of three ePIPAC-OX): 16 weeks
Secondary	Radiological tumour response	Number of patients with radiological response/stable disease/progression, based on central review of thoracoabdominal CT and diffusion-weighted MRI at baseline and four weeks after each ePIPAC-OX, performed by two independent radiologists blinded to clinical outcomes (classification not defined a priori)	Expected (in case of three ePIPAC-OX): 16 weeks
Secondary	Histopathological tumour response	Peritoneal Regression Grading Score (PRGS), based on central review of collected peritoneal biopsies during each ePIPAC-OX, performed by two independent pathologists blinded to clinical outcomes	Expected (in case of three ePIPAC-OX): 12 weeks
Secondary	Cytological tumour response	Number of patients with positive/negative cytology, based on collected ascites or peritoneal washing cytology during each ePIPAC-OX	Expected (in case of three ePIPAC-OX): 12 weeks
Secondary	Macroscopic tumour response	Peritoneal Cancer Index and ascites volume during each ePIPAC-OX	Expected (in case of three ePIPAC-OX): 12 weeks
Secondary	Biochemical tumour response	Tumour marker value measured at baseline, each postoperative day, and four weeks after each ePIPAC-OX	Expected (in case of three ePIPAC-OX): 16 weeks
Secondary	Quality of life: EQ-5D-5L	EQ-5D-5L at baseline and one and four weeks after each ePIPAC-OX	Expected (in case of three ePIPAC-OX): 16 weeks
Secondary	Quality of life: QLQ-C30	QLQ-C30 at baseline and one and four weeks after each ePIPAC-OX	Expected (in case of three ePIPAC-OX): 16 weeks
Secondary	Quality of life: QLQ-CR29	QLQ-CR29 at baseline and one and four weeks after each ePIPAC-OX	Expected (in case of three ePIPAC-OX): 16 weeks
Secondary	Costs	Costs of treatment, based on questionnaires (iMTA PCQ, iMTA MCQ) four weeks after each ePIPAC-OX, derived from the Dutch costing guidelines for health care research at the time of analysis	Expected (in case of three ePIPAC-OX): 16 weeks
Secondary	Progression-free survival	Time between enrolment and clinical, radiological, or macroscopic progression, or death	24 months
Secondary	Overall survival	Time between enrolment and death	24 months
Secondary	Environmental safety of ePIPAC-OX	Platinum concentrations in the air of the operating room and on the surface of the operating room during ePIPAC-OX	1 week (measured only during the first three procedures in the study)
Secondary	Pharmacokinetics	Platinum concentrations in plasma and plasma ultrafiltrate (collected before ePIPAC-OX and 5, 10, 20, 30, 60, 120, 240, 360, and 1080 minutes after oxaliplatin injection), urine (collected before ePIPAC-OX and on postoperative days 1, 3, 5, and 7), and two pieces of normal peritoneum and two peritoneal metastases collected during each ePIPAC-OX.	Expected (in case of three ePIPAC-OX): 13 weeks
Secondary	Procedure-related characteristics: intraoperative complications	Number of procedures with intraoperative complications determined during each ePIPAC-OX	Expected (in case of three ePIPAC-OX): 12 weeks
Secondary	Procedure-related characteristics: adhesions	Zühlke score determined during each ePIPAC-OX	Expected (in case of three ePIPAC-OX): 12 weeks
Secondary	Procedure-related characteristics: operating time	Operating time in minutes determined during each ePIPAC-OX	Expected (in case of three ePIPAC-OX): 12 weeks
Secondary	Procedure-related characteristics: blood loss	Blood loss in minutes determined during each ePIPAC-OX	Expected (in case of three ePIPAC-OX): 12 weeks