Intraperitoneal Irinotecan With Concomitant FOLFOX and Bevacizumab (INTERACT-II)

Intraperitoneal Irinotecan With Concomitant FOLFOX and Bevacizumab for Patients With Unresectable Colorectal Peritoneal Metastases

The rationale of the current study is that the addition of intraperitoneal irinotecan (75 mg) to palliative systemic therapy is feasible and safe, and might result in an increased overall and progression free survival in patients with unresectable colorectal peritoneal metastases. The primary objectives are to explore the overall survival for the addition of intraperitoneal irinotecan (75 mg) to palliative systemic therapy in patients with unresectable colorectal peritoneal metastases. Secondary objectives are to assess the progression-free survival, toxicity profile, patient reported outcomes, costs, tumor response during trial treatment, and the systemic and intraperitoneal pharmacokinetics of irinotecan and SN-38. This is a single-arm, open-label, phase II study and patients will receive intraperitoneal irinotecan (75 mg) in combination with modified FOLFOX4 + bevacizumab.

Study Overview

• Status: Recruiting
• Conditions: Colorectal Cancer; Peritoneal Metastases
• Intervention / Treatment: Drug: Irinotecan; Drug: FOLFOX regimen; Drug: Bevacizumab

• Study Type: Interventional
• Enrollment (Estimated): 85
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Pim Burger, MD, PhD; Phone Number: 0031402397150; Email: pim.burger@catharinaziekenhuis.nl

Study Locations

• Netherlands
  • Eindhoven, Netherlands
    • Recruiting
    • Catharina Hospital
    • Contact: Teun van den Heuvel, MD; Phone Number: 0031 40 239 6351; Email: teun.vd.heuvel@catharinaziekenhuis.nl
  • Rotterdam, Netherlands
    • Recruiting
    • Erasmus Medical Centre
    • Contact: Niels Guchelaar; Phone Number: 0031 10 703 9640; Email: n.guchelaar@erasmusmc.nl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Histologically confirmed colorectal cancer;
• Radiologically and clinically or pathologically confirmed unresectable colorectal peritoneal metastases (e.g. PCI >20, extensive small bowel involvement, unresectable disease due to anatomical location);
• WHO performance score of 0-1 with a life expectancy of >3 months;
• Aged 18 years or older;
• Written informed consent;

Exclusion Criteria:

• Presence of extensive systemic metastases that are deemed to be the dominant factor determining prognosis in terms of life expectancy and performance status [e.g. no imminent threat of impaired organ functioning due to the presence of systemic metastases]);
• Prior cytoreductive surgery;
• Prior palliative systemic therapy for colorectal cancer;
• Prior neo-adjuvant/adjuvant systemic therapy for colorectal cancer within the last 6 months;
• Homozygous UGT1A1*28 genotype;
• Homozygous dihydropyrimidine dehydrogenase (DPD) deficiency
• Microsatellite instable (MSI) primary tumor
• Any contra-indication for the planned chemotherapy (e.g. active infection, serious concomitant disease, severe allergy), as determined by the medical oncologist;
• Inadequate organ functions, defined as an haemoglobin of <5 mmol/L, an absolute neutrophil count of <1.5 x 109/L, platelet count of <100 x 109/L, serum creatinine of >1.5 x ULN, creatinine clearance of <30 ml/min, Bilirubin > 2x ULN and liver transaminases of >5 x ULN.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Intraperitoneal irinotecan 75 mg + mFOLFOX-4 and bevacizumab; Intraperitoneal irinotecan, 75 mg flat dose + systemic oxaliplatin, 5-Fluorouracil and bevacizumab (mFOLFOX+beva) (dose via standard of care)

Drug: Irinotecan; 2 weekly IP irinotecan (max 12 cycles), dose 75 mg flat dose; Other Names: Intraperitoneal irinotecan; Drug: FOLFOX regimen; FOLFOX-4 regimens consist of 85 mg/m2 oxaliplatin plus 200 mg/m2 LV and 5-FU 400 mg/m2 bolus on day 1 followed by 1600 mg/m2 5-FU as a 46-h infusion; Other Names: 5-FU + oxaliplatin; Drug: Bevacizumab; Bevacizumab according to standard of care; Other Names: Avastin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival	calculated from (a) the interval from diagnosis of peritoneal metastases until death or last follow-up; (b) the interval from the first day of the first cycle until death or last follow-up).	3 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival	calculated from the interval from the start of trial treatment until first evidence of intraperitoneal and/or systemic disease progression, and/or start of second-line systemic therapy, or last follow-up	3 year
Toxicity in CTCAE grading	Defined as the number of patients who experience / the total number of Common Terminology Criteria for Adverse Events (CTCAE, version 5.0) grade 3-5 adverse events, measured up to four weeks after the last cycle of intraperitoneal irinotecan (75 mg) with concomitant palliative systemic therapy. With the exception of peripheral neuropathy, which will be reported indefinitely, ranging from CTCAE grade 1-5.	28 weeks. Each cycle is 2 weeks, maximum of 12 cycles. Toxicity measured up to four weeks after last cycle.
Patient-reported outcomes (PROs) with EQ-5D-5L	Assessed with the 5-level EQ-5D by EuroQol group (EQ-5D-5L) at baseline, one week after the first cycle, one week after the fourth cycle, one week after the eighth cycle, and one week after the twelfth cycle. The EQ-5D-5L essentially consists of 2 pages: the EQ-5D descriptive system and the EQ visual analogue scale (EQ VAS).The descriptive system comprises five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems. The digits for the five dimensions can be combined into a 5-digit number that describes the patient's health state.The EQ VAS records the patient's self-rated health on a vertical visual analogue scale, where the endpoints are labelled 'The best health you can imagine' and 'The worst health you can imagine'. The VAS can be used as a quantitative measure of health outcome that reflect the patient's own judgement.	24 weeks. Each cycle is 2 weeks, maximum of 12 cycles. Measured one week after the first cycle, one week after the fourth cycle, one week after the eighth cycle, and one week after the twelfth cycle.
Patient-reported outcomes (PROs) with EORTC QLQ-C30	Assessed with the European Organization for Research and Treatment for Cancer Quality of Life Questionnaire (EORTC QLQ-C30) at baseline, one week after the first cycle, one week after the fourth cycle, one week after the eighth cycle, and one week after the twelfth cycle. The EORTC QLQ-C30 comprises 30 items, 24 of which are aggregated into nine multi-item scales, that is, five functioning scales, three symptom scales and one global health status scale. The remaining six single-item assess symptoms. All of the scales and single-item measures range in score from 0 to 100. Higher score for the functioning scales and global health status denote a better level of functioning (i.e. a better state of the patient), while higher scores on the symptom and single-item scales indicate a higher level of symptoms (i.e. a worse state of the patient).	24 weeks. Each cycle is 2 weeks, maximum of 12 cycles. Measured one week after the first cycle, one week after the fourth cycle, one week after the eighth cycle, and one week after the twelfth cycle.
Patient-reported outcomes (PROs) with EORTC QLQ-CR29	Assessed with the European Organization for Research and Treatment for Cancer Quality of Life Questionnaire, specifically for colorectal cancer (EORTC QLQ-CR29) at baseline, one week after the first cycle, one week after the fourth cycle, one week after the eighth cycle, and one week after the twelfth cycle. The resulting QLQ-CR29 consisted of four scales and 19 individual items. Higher scores indicate a higher level of symptoms (i.e. a worse state of the patient).	24 weeks. Each cycle is 2 weeks, maximum of 12 cycles. Measured one week after the first cycle, one week after the fourth cycle, one week after the eighth cycle, and one week after the twelfth cycle.
Healthcare costs	According to the Dutch manual for cost analysis in health care research, and assessed with the iMTA Medical Consumption Questionnaire at baseline, one week after the first cycle, one week after the fourth cycle, one week after the eighth cycle, and one week after the twelfth cycle. The volumes of used healthcare costs were multiplied with the unit costs of these corresponding services.	24 weeks. Each cycle is 2 weeks, maximum of 12 cycles. Measured one week after the first cycle, one week after the fourth cycle, one week after the eighth cycle, and one week after the twelfth cycle.
Productivity loss costs.	Assessed with the iMTA Productivity Cost Questionnaire at baseline, one week after the first cycle, one week after the fourth cycle, one week after the eighth cycle, and one week after the twelfth cycle.	24 weeks. Each cycle is 2 weeks, maximum of 12 cycles. Measured one week after the first cycle, one week after the fourth cycle, one week after the eighth cycle, and one week after the twelfth cycle.
Occurrence and degree of nephrotoxicity	Assessed during standard-of-care laboratory assessment for nephrotoxicity (creatinine, eGFR, and ureum) analysis before each subsequent cycle and graded according to Common Terminology Criteria for Adverse Events (CTCAE, version 5.0).	24 weeks. Each cycle is 2 weeks, maximum of 12 cycles.
Occurrence and degree of hepatotoxicity	Assessed during standard-of-care laboratory assessment for hepatotoxicity (albumin, bilirubin, AST, ALT, LD, AF, yGT) analysis before each subsequent cycle and graded according to Common Terminology Criteria for Adverse Events (CTCAE, version 5.0).	24 weeks. Each cycle is 2 weeks, maximum of 12 cycles.
Occurrence and degree of haematological toxicity	Assessed during standard-of-care laboratory assessment for haematological toxicity (haemoglobin, leucocytes, thrombocyte) analysis before each subsequent cycle and graded according to Common Terminology Criteria for Adverse Events (CTCAE, version 5.0).	24 weeks. Each cycle is 2 weeks, maximum of 12 cycles.
Response of Tumor marker during treatment	Assessed by carcino-embryonic antigen (CEA) analysis during standard laboratory analysis before each subsequent cycle	24 weeks. Each cycle is 2 weeks, maximum of 12 cycles.
Number of patients that completed twelve cycles	To determine the number of patients completing twelve cycles of treatment with intraperitoneal irinotecan (75 mg) and concomitant palliative systemic therapy, required dose reductions, and reasons for discontinuation.	24 weeks. Each cycle is 2 weeks, maximum of 12 cycles.
Objective radiological response	assessed by thoracoabdominal CT at baseline, after the fourth cycle, after the eighth cycle, and after the twelfth cycle according to RECIST.	24 weeks. Each cycle is 2 weeks, maximum of 12 cycles. Measured at baseline, after the fourth cycle, after the eighth cycle, and after the twelfth cycle.
Peritoneum/plasma ratio of intraperitoneal irinotecan	To determine the the peritoneum/plasma ratio of intraperitoneal during the first and fourth cycle of intraperitoneal irinotecan (75 mg) and concomitant palliative systemic therapy. Whole blood and peritoneal fluid will be drawn from a peripheral intravenous access and the peritoneal access port, respectively, and collected in 3 mL lithium heparin tubes and 2 mL cryotubes, respectively, at the following moments after the start of irinotecan infusion; t=0, at the end of infusion (EOI), t=30 minutes after EOI and t =2 hrs after EOI and t = 4hrs after EOI. The ratio between the Area Under the Curve (AUC) between irinotecan measured in the peritoneum and measured in the plasma is taken.	8 weeks. Each cycles is 2 weeks. Measured during cycle 1 and cycle 4.

Collaborators and Investigators

• Sponsor: Catharina Ziekenhuis Eindhoven

Study record dates

Study Major Dates

• Study Start (Actual): December 27, 2022
• Primary Completion (Estimated): January 1, 2025
• Study Completion (Estimated): January 1, 2025

Study Registration Dates

• First Submitted: November 8, 2022
• First Submitted That Met QC Criteria: August 15, 2023
• First Posted (Actual): August 22, 2023

Study Record Updates

• Last Update Posted (Actual): August 22, 2023
• Last Update Submitted That Met QC Criteria: August 15, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: colorectal cancer; Intraperitoneal; Irinotecan; Peritoneal metastases
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Neoplastic Processes; Colorectal Neoplasms; Neoplasm Metastasis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Topoisomerase I Inhibitors; Oxaliplatin; Bevacizumab; Irinotecan
• Other Study ID Numbers: NL81672.100.22

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No