Clinical trial NCT04166604: LONsurf and G-CSF Use: Being On A Right Dose-intensity to Optimize Treatment Efficacy
Official title: LONsurf and G-CSF Use: Being On A Right Dose-intensity to Optimize Treatment Efficacy
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Metastatic Colorectal Cancer
Keywords: trifluridine/ tipiracil
G-CSF
neutropenia
Lead sponsor: GERCOR - Multidisciplinary Oncology Cooperative Group
Sponsor class: OTHER
First posted: 2019-11-18
Enrollment: 176
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: It was planned to include 250 patients in a prospective cohort, to obtained 89 patients in the phase II (experience a grade 3-4 neutropenia)
Primary purpose: TREATMENT

Brief summary: Prospective cohort of patients treated with trifluridine/tipiracil, maximal sample size 250 patients. It is expected, that 89 patients will experience a grade 3-4 neutropenia and will be included in the phase II.

Detailed description: Trifluridine/tipiracil has demonstrated its efficacy in patients with metastatic colorectal cancer (mCRC) resistant to standard drugs (fluoropyrimidine, oxaliplatin, irinotecan, bevacizumab, and panitumumab or cetuximab in case of RAS wild-type tumors). This treatment has a marketing authorization.

Neutropenia is a classic complication of cytotoxic treatments. Febrile neutropenia are associated with a mortality rate of 9.5% and a hospitalization of 6 days in median. Recent meta-analyses have reported that the use of granulocyte-colony stimulating factor (GCSF) allows to maintain the dose-intensity of cytotoxic treatment and was associated with a better overall survival (OS).

There is currently no clear recommendation for the use of G-CSF with trifluridine/tipiracil.

Unpublished analyses that various clinical parameters may be associated with the risk of neutropenia: age ≥ 65 years, female sex, level of leukocytes at baseline, and time of initial diagnostic to randomization ≥ 36 months.These data are too preliminary to allow proposing a G-CSF primary prophylaxis in a defined subgroup of patients. However, a secondary prophylaxis based on the administration of G-CSF seems efficient, with a prescription from day 14 to day 18.

The aim of this phase II study is to assess the efficacy of the secondary prophylaxis with G-CSF in case of first episode of grade 3-4 neutropenia in the aim to maintain the optimal dose intensity.

Eligibility criteria: Inclusion Criteria:

1. Signed and dated informed consent,
2. Patients willing and able to comply with protocol requirements,
3. Histologically proven colorectal adenocarcinoma,
4. Stage IV disease,
5. Have life expectancy of at least 6 months,
6. Previous chemotherapy regimens with each of the following agents: fluoropyrimidine, oxaliplatin, irinotecan, anti-vascular endothelial growth factor (VEGF) therapy (bevacizumab, aflibercept), and anti-epidermal growth factor receptor (EGFR) therapy (cetuximab or panitumumab for tumors with wild-type RAS and/or BRAF wild type),
7. At least one measurable or evaluable lesion as assessed by computed tomography (CT)-scan or magnetic resonance imaging (MRI) according to RECIST v1.1,
8. Age ≥ 18 years,
9. ECOG PS 0-1,
10. Adequate hematologic function: neutrophils \> 1.5 x 109 /L; platelets \> 100 x 109 /L; hemoglobin ≥ 9 g/dL,
11. Calculated creatinine clearance ≥ 30 mL/min,
12. Adequate liver function: aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x upper limit normal ULN;

    ≤ 5 x ULN in case of liver metastasis), total bilirubin ≤ 1.5 x ULN (\< 2 x ULN if hyperbilirubinemia is due to Gilbert's syndrome), albumin ≥ 25 g/L,
13. Baseline evaluations: clinical and blood evaluations no more than 14 days prior to inclusion and start of trifluridine/tipiracil, Tumor assessment (CT-scan or MRI, evaluation of non-measurable lesions) no more than 21 days prior to inclusion and start of trifluridine/tipiracil,
14. Female patients must be surgically sterile, or be postmenopausal, or must commit to using reliable and appropriate methods of contraception during the study (must have a negative pregnancy test within 7 days prior to enrollment) and during at least 6 months after the end of the last dose of study treatment (when applicable). All female patients with reproductive potential must have a negative pregnancy test (β-HCG) within 72 hours prior to starting trifluridine/tipiracil treatment. Breastfeeding is not allowed. Male patients must agree to use effective contraception in addition to having their partner use a contraceptive method as well during the trial and during at least 6 months after the end of the study treatment,
15. Registration with the French National Health Care System or PUMA (Protection Universelle MAladie).

Exclusion Criteria:

1. Medical history or evidence of CNS metastasis upon physical examination, unless adequately treated (e.g. non-irradiated CNS metastasis, seizure not controlled with standard medical therapy, patients are stable without evidence of progression for at least 28 days prior to the first dose of treatment),
2. Local or locally advanced disease (stage I to III),
3. Treatment with warfarin,
4. Uncontrolled hypercalcemia,
5. Concomitant unplanned antitumor therapy (e.g. chemotherapy, molecular targeted therapy, immunotherapy),
6. Known complete dihydropyrimidine dehydrogenase (DPD) deficiency,
7. Treatment with any other investigational medicinal product within 28 days prior to study entry,
8. Symptomatic carcinomatosis with occlusive symptoms or ascites requiring paracentesis,
9. Other serious and uncontrolled non-malignant disease (e.g. active infection requiring systemic therapy, coronary stenting or myocardial infarction, or stroke in the past 6 months),
10. HIV-infected patients or otherwise known to be HIV-positive,
11. Untreated hepatitis B or C,
12. Other concomitant or previous malignancy, except: i/ adequately treated in-situ carcinoma of the uterine cervix, ii/ basal or squamous cell carcinoma of the skin, iii/ cancer in complete remission for \> 5 years,
13. Concomitant administration of prophylactic phenytoin and live attenuated virus vaccine such as yellow fever vaccine 28 days prior to the first dose of treatment.
14. Patient under guardianship, curatorship or under the protection of justice

Primary outcomes:
measure: Rate of patients free of trifluridine/tipiracil dose reduction or postponement of cycles of > 7 days at 6 months or at progression or death or stop of treatment for another cause than neutropenia if observed in 6 months.
timeFrame: At 6 months
Secondary outcomes:
measure: Overall survival (OS)
timeFrame: Up to 30 months
measure: Progression free survival (PFS)
timeFrame: Up to 30 months
measure: Objective response rate (ORR)
timeFrame: Up to 30 months
measure: Disease control rate (DCR)
timeFrame: Up to 30 months
measure: Safety descriptive analysis
timeFrame: Up to 30 months
measure: The rate of dose reductions
timeFrame: Up to 30 months
measure: Clinical or biological factors at baseline associated with the occurrence of grade 3-4 neutropenia
timeFrame: Up to 30 months
Other outcomes:
Locations:
city: Amiens
country: France
facility: CHU Amiens
city: Angers
country: France
facility: Institut de cancérologie de l'Ouest
city: Besançon
country: France
facility: CHRU Jean Minjoz
city: Beuvry
country: France
facility: centre Pierre Curie
city: Bordeaux
country: France
facility: Polyclinique Bordeaux Nord
city: Chauny
country: France
facility: Centre hospitalier de Chauny
city: Compiègne
country: France
facility: Polyclinique Sainte Côme
city: Coudekerque-Branche
country: France
facility: Clinique de Flandre
city: Créteil
country: France
facility: Hôpital Henri Mondor
city: Dijon
country: France
facility: Centre Georges François Leclerc
city: La Roche-sur-Yon
country: France
facility: CHD Vendée
city: Levallois-Perret
country: France
facility: Hôpital Franco-Britannique
city: Lyon
country: France
facility: Hôpital Privé Jean Mermoz
city: Marseille
country: France
facility: Hôpital Européen
city: Mont-de-Marsan
country: France
facility: Hôpital Layne
city: Montbéliard
country: France
facility: Hôpital Nord Franche Comté
city: Paris
country: France
facility: Groupe Hospitalier Pitié Sapêtrière
city: Paris
country: France
facility: Hôpital Cochin
city: Paris
country: France
facility: Hôpital Saint Antoine
city: Pessac
country: France
facility: Hôpital Haut Lévêque
city: Poitiers
country: France
facility: CHU Poitiers
city: Reims
country: France
facility: CHU Robert Debré
Study officials:
affiliation: Hôpital Pitié Salpêtrière
name: Jean Baptiste BACHET, MD
role: PRINCIPAL_INVESTIGATOR
References: