Trial Title:
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
NCT ID:
NCT05655780
Condition:
Colorectal Neoplasms
Conditions: Official terms:
Colorectal Neoplasms
Study type:
Observational
Overall status:
Recruiting
Study design:
Time perspective:
Prospective
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.
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).
Criteria for eligibility:
Study pop:
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.
Sampling method:
Non-Probability Sample
Criteria:
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.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Maastricht UMC+
Address:
City:
Maastricht
Zip:
6229 HX
Country:
Netherlands
Status:
Recruiting
Contact:
Last name:
Marjolein Smidt, Prof. Dr.
Email:
m.smidt@mumc.nl
Start date:
January 9, 2023
Completion date:
December 2028
Lead sponsor:
Agency:
Maastricht University Medical Center
Agency class:
Other
Collaborator:
Agency:
Maastricht University
Agency class:
Other
Collaborator:
Agency:
Wageningen University & Research
Agency class:
Other
Collaborator:
Agency:
Fontys Hogeschool
Agency class:
Other
Collaborator:
Agency:
Amsterdam UMC - Locatie AMC
Agency class:
Other
Collaborator:
Agency:
Erasmus Medical Center
Agency class:
Other
Collaborator:
Agency:
Catharina Ziekenhuis
Agency class:
Other
Collaborator:
Agency:
University of North Carolina (USA)
Agency class:
Other
Collaborator:
Agency:
Oncology patientenpanel MUMC
Agency class:
Other
Collaborator:
Agency:
Stichting Kanker.nl
Agency class:
Other
Collaborator:
Agency:
Van Weel-Bethesda Ziekenhuis
Agency class:
Other
Collaborator:
Agency:
VieCuri Medisch Centrum voor Noord-Limburg
Agency class:
Other
Collaborator:
Agency:
Gelderse Vallei Hospital
Agency class:
Other
Collaborator:
Agency:
Danone Nutricia Research
Agency class:
Industry
Collaborator:
Agency:
Clinical Trial Center Maastricht B.V.
Agency class:
Other
Collaborator:
Agency:
Dutch Colorectal Cancer Group (DCCG)
Agency class:
Other
Collaborator:
Agency:
Prospectief Landelijk CRC Cohort (PLCRC)
Agency class:
Other
Collaborator:
Agency:
CRC-guideline committee
Agency class:
Other
Collaborator:
Agency:
CZ zorgverzekeraar
Agency class:
Other
Collaborator:
Agency:
Landelijke Werkgroep Diëtisten Oncologie (LWDO)
Agency class:
Other
Source:
Maastricht University Medical Center
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05655780
