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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Unicancer

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

17 Jan 2025 → ongoing

Decision date (initial)

2024-11-20

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

PHRC-K (INCa)

External identifiers

EU CT number

2023-509963-25-00

ClinicalTrials.gov

NCT06475352

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Dose response

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

Secondary objectives 5

1. Define the recommended FP dose in DPD deficient patients according to plasma uracil level based on toxicity observed during the first 4 cycles of FP-based chemotherapy
2. Describe dose adjustments occurring during the first 4 cycles of FP-based chemotherapy
3. Describe the proportion of patients with dose modifications
4. Describe all grade of FP-induced toxicities observed during the first 4 cycles of FP-based chemotherapy.
5. Assess the impact of FP dose adaptations on disease outcomes in a homogeneous subgroup (likely to be the majority) of patients in terms of: o Disease free-survival (DFS) for patients with stage III colon cancer o Overall survival (OS) for patients with stage III colon cancer o Progression-free survival (PFS) for patients with stage IV colorectal cancer

Conditions and MedDRA coding

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

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. Patients with pre-treatment screening based on [U] value according to INCa/HAS recommendations.
2. Patients must be affiliated to a Social Security System (or equivalent).
3. 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.
4. ECOG PS ≤2
5. 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
6. Age ≥ 18 years
7. Patients eligible for full standard FP and oxaliplatin doses regardless of DPD deficiency
8. 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
9. 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.
10. Women of childbearing potential must have a negative serum or urine pregnancy test.
11. 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.

Exclusion criteria 10

1. Patients with complete DPD deficiency based on [U] ≥150 ng/mL
2. Any prior treatment including a FP
3. Patients with any contraindication to treatment with FP or oxaliplatin regardless of DPD deficiency
4. Patients not eligible for full standard dose FP and oxaliplatin for clinical reasons including older age and/or comorbidity regardless of a DPD deficiency
5. 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
6. Recent or concomitant treatment with brivudine
7. Pregnant or breastfeeding woman.
8. Participation in another therapeutic trial within 30 days prior to inclusion.
9. Persons deprived of their liberty or under protective custody or guardianship.
10. Any peripheral sensitive neuropathy with functional impairment

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 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 endpoints 7

1. 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
2. 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
3. Percentage of patients in whom FP dose is increased or decreased during the first 4 cycles of chemotherapy
4. 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.
5. 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.
6. 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
7. 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

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Auxiliary 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Unicancer

Sponsor organisation

Unicancer

Address

101 Rue De Tolbiac

City

Paris

Postcode

75013

Country

France

Scientific contact point

Organisation

Unicancer

Contact name

Nourredine AIT RAHMOUNE

Public contact point

Organisation

Unicancer

Contact name

Nourredine AIT RAHMOUNE

Locations

1 EU/EEA country · 43 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 10 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications