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

Sponsor

Maastricht University Medical Center (Other)

Overall Status

Recruiting

CT.gov ID

NCT05655780

Collaborator

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

104

Enrollment

Location

70.7

Anticipated Duration (Months)

1.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
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 Design

Study Type:

Observational

Anticipated Enrollment :

104 participants

Observational Model:

Cohort

Time Perspective:

Prospective

Official Title:

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)

Actual Study Start Date :

Jan 9, 2023

Anticipated Primary Completion Date :

Oct 1, 2025

Anticipated Study Completion Date :

Dec 1, 2028

Outcome Measures

Primary Outcome Measures

Bacterial beta-glucuronidase activity [2022-2028]
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.
UGT1A1 (uridine diphosphate glucuronosyltransferase) [2022-2028]
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.
Molecular profile of the tumor [2022-2028]
Associations between the baseline molecular profile of the tumor (e.g. CMS) and response to irinotecan-based treatment

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Adult patient: 18 years of age or older
Patients diagnosed with metastatic or irresectable CRC, who will be treated with irinotecan-based combination therapy (FOLFIRI/FOLFOXIRI) +/- bevacizumab as first line 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
Prior treatment with irinotecan
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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Maastricht UMC+	Maastricht	Limburg	Netherlands	6229 HX

Investigators

Principal Investigator: Marjolein Smidt, Prof. dr., Maastricht University Medical Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

Responsible Party:

Maastricht University Medical Center

ClinicalTrials.gov Identifier:

NCT05655780

Other Study ID Numbers:

METC 2022-3247

First Posted:

Dec 19, 2022

Last Update Posted:

Jan 11, 2023

Last Verified:

Jan 1, 2023

Studies a U.S. FDA-regulated Drug Product:

Studies a U.S. FDA-regulated Device Product:

Additional relevant MeSH terms:

Colorectal Neoplasms

Study Results

No Results Posted as of Jan 11, 2023