The Role of the Tumor Molecular Profile (CMS), UGT1A1 Genotype and Beta-glucuronidase Activity of the Intestinal Microbiota for Treatment Efficiency, Toxicity, Survival and Quality of Life in Patients With Metastatic or Unresectable Colorectal Cancer During Irinotecan-based Systemic Treatment (OPTIMA)

Optimal Survival and Quality of Life in Patients With Metastatic Colorectal Cancer With Irinotecan Dosing Based on UGT1A1 Genotype and Gut Microbiota Enzyme Activity Including a Dietary Intervention (OPTIMA)

Irinotecan-based systemic therapy is a treatment option for metastatic or unresectable colorectal cancer. However, this therapy has two major disadvantages, namely, an unpredictable response to the treatment and severe side effects, for instance diarrhea or a low white blood cell count (neutropenia). Therefore, the OPTIMA study was developed to find out if biomarkers, such as the molecular profile of the tumor, the UGT1A1 genotype and activity of the bacterial enzyme β-glucuronidase, can predict response and side effects during irinotecan treatment. By looking at these biomarkers, treatments could be more personalized, resulting into enhanced therapy efficiency, increased optimal survival and a better quality of life.

Study Overview

• Status: Recruiting
• Conditions: Colorectal Neoplasms

Detailed Description

Irinotecan-based systemic therapy is shown to have promising results in metastatic or unresectable colorectal cancer. However, this therapy has two major disadvantages, including an unpredictable individual treatment response and late-onset systemic and gastrointestinal toxicity. To target these problems, biomarkers are needed which could be used to predict treatment response and toxicity before start of the treatment. The molecular profile of the tumor (consensus molecular subtypes (CMS)), the UGT1A1 genotype and the gut microbiota-derived enzyme β-glucuronidase are promising candidates in this context. Recent research demonstrated that irinotecan-based systemic therapy increased both progression free survival (PFS) and optimal survival (OS) predominantly in patients with CMS4 cancers, as well as in preclinical models representing this subtype. For the other CMS subtypes (CMS1-3), irinotecan-based systemic therapy was shown to be significantly less efficient. For the UGT1A1 genotypes, decreased activity of the UGT1A1 enzyme (converting the toxic metabolite SN-38 into the inactive SN-38G) will increase the concentration of toxic SN-38, resulting in systemic toxicity. Lastly, the importance of studying bacterial β-glucuronidase (β-GUS) activity in CRC patients during treatment with irinotecan can be derived from recent animal studies, and indirect human evidence. Previous research has shown that high bacterial β-GUS activity (converting the inactive SN-38G into the toxic SN-38) might be a possible indicator for irinotecan-induced late-onset gastrointestinal toxicity due to SN-38 accumulation. Therefore, the OPTIMA study was developed to combine prediction of tumor sensitivity towards irinotecan (by CMS classification), UGT1A1 expression for irinotecan dose determination, and β-GUS for risk assessment for late-onset gastrointestinal toxicity. The aim of the study is to investigate whether the molecular profile of the tumor (e.g. based on CMS), the UGT1A1 genotype and β-GUS activity can act as a predictor for therapy efficiency, late-onset systemic and gastrointestinal toxicity, as well as OS and quality of life (QoL).

• Study Type: Observational
• Enrollment (Estimated): 104

Contacts and Locations

• Study Contact: Name: Janine Ziemons, M.Sc.; Phone Number: +31 (0)433881558; Email: j.ziemons@maastrichtuniversity.nl

Study Locations

• Netherlands
  • Limburg
    • Maastricht, Limburg, Netherlands, 6229 HX
      • Recruiting
      • Maastricht UMC+
      • Contact: Marjolein Smidt, Prof. Dr.; Email: m.smidt@mumc.nl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

A total of 104 participants will be included for this study. The patients will be addressed for participation in several hospitals in the Netherlands, including the Maastricht University Medical Centre+, Catharina Hospital, Amsterdam UMC, Hospital Gelderse Vallei, Van Weel-Bethesda Hospital and VieCuri Hospital. All participants are asked to sign an informed consent.

Description

Inclusion Criteria:

• Adult patient: 18 years of age or older
• Patients diagnosed with metastatic or unresectable CRC, who will be treated with irinotecan-based systemic therapy with or without anti-eGFR treatment.
• WHO performance status 0-2

• Minimal acceptable safety laboratory values defined as:

  • ANC of ≥ 1.5 x 109 /L
  • Platelet count of ≥ 100 x 109 /L
  • Hepatic function as defined by serum bilirubin ≤ 1.5 x ULN, ALAT and ASAT ≤ 2.5 x ULN; in case of liver metastases ALAT and ASAT ≤ 5 x ULN.
  • Renal function (eGFR) ≥ 50 ml/min or OR creatinine ≤ 1.5 x ULN
• Written informed consent

Exclusion Criteria:

• Microsatellite instability (MSI) or deficient MMR proteins
• Pregnant or nursing
• Presence of ileostomy
• Asian ethnicity
• Other systemic treatment is less than one month before the start of the irinotecan-based treatment
• Therapeutic antibiotic use is less than three months before the start of the irinotecan-based treatment
• Abdominal radiotherapy is less than two weeks before the start of the irinotecan-based treatment
• Physically or mentally incapable or incompetent
• More than 25% irinotecan dose reduction at the start of treatment (dose reductions during treatment are allowed), with exception of dose reduction due to UGT1A1 mutation.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Bacterial beta-glucuronidase activity	Bacterial beta-glucuronidase activity will be measured in faecal samples by using a validated beta-glucuronidase enzyme activity assay, which is based on previous studies. If we measure beta-glucuronidase activity, we will be able to predict late-onset gastrointestinal toxicity because we can estimate the amount of toxic SN-38 that will be produced.	2022-2028
UGT1A1 (uridine diphosphate glucuronosyltransferase)	UGT1A1 will be measured by using blood samples, since decreased activity of the UGT1A1 enzyme will ensure an increase in toxic SN-38. When we measure the activity of the UGT1A1 enzyme, we can adjust the treatment dose based on this and, consequently, reduce gastrointestinal toxicity.	2022-2028
Molecular profile of the tumor	Associations between the baseline molecular profile of the tumor (e.g. CMS) and response to irinotecan-based treatment	2022-2028

Collaborators and Investigators

• Sponsor: Maastricht University Medical Center
• Collaborators: Erasmus Medical Center; Maastricht University; Gelderse Vallei Hospital; Dutch Colorectal Cancer Group (DCCG); Clinical Trial Center Maastricht B.V.; Danone Nutricia Research; Wageningen University & Research; Fontys Hogeschool; Amsterdam UMC - Locatie AMC; Catharina Ziekenhuis; University of North Carolina (USA); Oncology patientenpanel MUMC; Stichting Kanker.nl; Van Weel-Bethesda Ziekenhuis; VieCuri Medisch Centrum voor Noord-Limburg; Prospectief Landelijk CRC Cohort (PLCRC); CRC-guideline committee; CZ zorgverzekeraar; Landelijke Werkgroep Diëtisten Oncologie (LWDO); Rode Kruis Ziekenhuis Beverwijk
• Investigators: Principal Investigator: Marjolein Smidt, Prof. dr., Maastricht University Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): January 9, 2023
• Primary Completion (Estimated): October 1, 2025
• Study Completion (Estimated): December 1, 2028

Study Registration Dates

• First Submitted: December 8, 2022
• First Submitted That Met QC Criteria: December 16, 2022
• First Posted (Actual): December 19, 2022

Study Record Updates

• Last Update Posted (Actual): May 18, 2025
• Last Update Submitted That Met QC Criteria: May 16, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Intestinal Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colonic Diseases; Colorectal Neoplasms
• Other Study ID Numbers: METC 2022-3247

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No