Dose individualization of chemotherapy in patients with gastrointestinal cancers lacking a specific liver enzyme

Phase 2

Recruiting

Conditions: Fluoropyrimidine (FP)-naive patients with gastrointestinal (GI) cancer and available pre-treatment uracilemia ([U]) starting chemotherapy combining FP (5FU or capecitabine) and oxaliplatin for any indication

Registration Number: 2023-509963-25-00

Lead Sponsor: Unicancer

Brief Summary: To assess different strategies of FP-dose adjustment according to [U] in DPD-deficient patients in terms of early severe FP-induced toxicity (i.e. during the first 2 cycles of FOLFOX or CAPOX-based regimens) in order to generate guidelines for dose reduction in patients with DPD deficiency

Detailed Description: Multicenter phase II trial evaluating different strategies of pre-specified fluoropyrimidine-dose adjustment according to \[U\] in DPD-deficient patients with gastrointestinal cancer.

Recruitment & Eligibility

Status: Ongoing, recruiting

Sex: Not specified

Target Recruitment: 400

Inclusion Criteria

Patients with pre-treatment screening based on [U] value according to INCa/HAS recommendations.

Women of childbearing potential must have a negative serum or urine pregnancy test.

Patients must agree to remain abstinent or use contraceptive methods with a failure rate of < 1% per year for the duration of study treatment and within 6 months after completing treatment.

Patients must be affiliated to a Social Security System (or equivalent).

Patient is willing and able to comply with the protocol for the duration of the trial including undergoing treatment and scheduled visits, and examinations including follow-up.

ECOG PS ≤2

FP-naïve patients with GI cancer starting chemotherapy combining FP (5FU or capecitabine) and oxaliplatin whatever the context (adjuvant, neoadjuvant, palliative) including the following regimens (the most frequently prescribed in GI cancers): - biweekly 5-FU and oxaliplatin (FOLFOX) +/- targeted therapy (TT) - three-weekly capecitabine and oxaliplatin (CAPOX) +/- TT

Age ≥ 18 years

Patients eligible for full standard FP and oxaliplatin doses regardless of DPD deficiency

Adequate bone marrow function (cell blood count (CBC)), estimated glomerular filtration rate (DFG) ≥ 60 ml/min, ALP/ASAT/ALAT ≤ 5 upper limit of normal (ULN), and bilirubin ≤ 50 micromol/L

Patient must have signed and dated a written informed consent form prior to any trial specific procedures. When the patient is physically unable to give their written consent, a trusted person of their choice, independent from the investigator or the sponsor, can confirm in writing the patient’s consent.

Exclusion Criteria

Patients with complete DPD deficiency based on [U] ≥150 ng/mL

Any peripheral sensitive neuropathy with functional impairment

Any prior treatment including a FP

Patients with any contraindication to treatment with FP or oxaliplatin regardless of DPD deficiency

Patients not eligible for full standard dose FP and oxaliplatin for clinical reasons including older age and/or comorbidity regardless of a DPD deficiency

Patients unwilling or unable to comply with trial obligations for geographic, social, or physical reasons, or who are unable to understand the purpose and procedures of the trial

Recent or concomitant treatment with brivudine

Pregnant or breastfeeding woman.

Participation in another therapeutic trial within 30 days prior to inclusion.

Persons deprived of their liberty or under protective custody or guardianship.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Primary Outcome Measures

Name	Time	Method
Proportion of FP-induced grade ≥ 3 haematological and gastrointestinal toxicity after 2 cycles (4 weeks for FOLFOX +/- TT or 6 weeks for 2 CAPOX +/- TT) according to the National Cancer Institute - common terminology criteria for adverse events (NCI CTCAE) version 5.0 in patients treated for a GI cancer in the (neo-)adjuvant or the metastatic setting.		Proportion of FP-induced grade ≥ 3 haematological and gastrointestinal toxicity after 2 cycles (4 weeks for FOLFOX +/- TT or 6 weeks for 2 CAPOX +/- TT) according to the National Cancer Institute - common terminology criteria for adverse events (NCI CTCAE) version 5.0 in patients treated for a GI cancer in the (neo-)adjuvant or the metastatic setting.

Secondary Outcome Measures

Name	Time	Method
The recommended FP dose will be estimated by comparing the rate of FP-induced grade ≥ 3 haematological and gastrointestinal toxicity in each [U]-based group of DPD-deficient patients (according to [U] level) to the one observed in non DPD-deficient patients (control arm) during the first 4 cycles of chemotherapy		The recommended FP dose will be estimated by comparing the rate of FP-induced grade ≥ 3 haematological and gastrointestinal toxicity in each [U]-based group of DPD-deficient patients (according to [U] level) to the one observed in non DPD-deficient patients (control arm) during the first 4 cycles of chemotherapy
Description of FP doses administered during the first 4 chemotherapy cycles in all patients, along with reasons of dose-modifications or treatment discontinuation for limiting toxicity		Description of FP doses administered during the first 4 chemotherapy cycles in all patients, along with reasons of dose-modifications or treatment discontinuation for limiting toxicity
Percentage of patients in whom FP dose is increased or decreased during the first 4 cycles of chemotherapy		Percentage of patients in whom FP dose is increased or decreased during the first 4 cycles of chemotherapy
All grade FP-induced toxicities at each cycle 1 to 4, related (neutropenia, febrile neutropenia, anemia, thrombocytopenia, diarrhea, mucositis) or not including (hand-foot syndrome, central neurotoxicity, cardiotoxicity) to DPD-deficiency (NCI CTC-AE). All other FP induced toxicity related or not will be also described.		All grade FP-induced toxicities at each cycle 1 to 4, related (neutropenia, febrile neutropenia, anemia, thrombocytopenia, diarrhea, mucositis) or not including (hand-foot syndrome, central neurotoxicity, cardiotoxicity) to DPD-deficiency (NCI CTC-AE). All other FP induced toxicity related or not will be also described.
Treatment efficacy will be evaluate in terms of: o DFS defined as the time from surgery to disease recurrence (radiological or clinical) in the subgroup of patients with stage III colon cancer and especially the 3-year DFS.		Treatment efficacy will be evaluate in terms of: o DFS defined as the time from surgery to disease recurrence (radiological or clinical) in the subgroup of patients with stage III colon cancer and especially the 3-year DFS.
Treatment efficacy will be evaluate in terms of: o OS defined as the time from surgery until death from any cause in the subgroup of patients with stage III colon cancer		Treatment efficacy will be evaluate in terms of: o OS defined as the time from surgery until death from any cause in the subgroup of patients with stage III colon cancer
Treatment efficacy will be evaluate in terms of: o PFS defined as the time from inclusion to disease progression (radiological or clinical) or death of any cause, whichever occurs first, in the subgroup of patients with stage IV colorectal cancer		Treatment efficacy will be evaluate in terms of: o PFS defined as the time from inclusion to disease progression (radiological or clinical) or death of any cause, whichever occurs first, in the subgroup of patients with stage IV colorectal cancer

Trial Locations

Locations (38): Grand Hopital De L Est Francilien
🇫🇷
Meaux, France
Hopital nord franche comté
🇫🇷
Montbéliard, France
Centre Hospitalier Universitaire D Orleans
🇫🇷
Orleans Cedex 2, France
Georges-Pompidou European Hospital
🇫🇷
Paris, France
Centre Hospitalier Aunay Bayeux
🇫🇷
Bayeux, France
CHU Henri Mondor
🇫🇷
Créteil Cedex, France
Centre Hospitalier Universitaire De Dijon
🇫🇷
Dijon, France
Institut Godinot
🇫🇷
Reims, France
University Hospital Of Clermont-Ferrand
🇫🇷
Clermont-Ferrand, France
Union Mut Gestion Groupe Hosp Mutualiste De Grenoble
🇫🇷
Grenoble, France
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Grand Hopital De L Est Francilien
🇫🇷Meaux, France
Christophe LOCHER
Site contact
0164353853
clocher@ghef.fr