LONsurf and G-CSF Use: Being On A Right Dose-intensity to Optimize Treatment Efficacy

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Unpublished analyses that various clinical parameters may be associated with the risk of neutropenia: age ≥ 65 years, female sex, level of leukocytes at baseline, and time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.

Inclusion criteria

• Signed and dated informed consent,
• Patients willing and able to comply with protocol requirements,
• Histologically proven colorectal adenocarcinoma,
• Stage IV disease,
• Have life expectancy of at least 6 months,
• 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),
• At least one measurable or evaluable lesion as assessed by computed tomography (CT)-scan or magnetic resonance imaging (MRI) according to RECIST v1.1,
• Age ≥ 18 years,
• ECOG PS 0-1,
• Adequate hematologic function: neutrophils > 1.5 x 109 /L; platelets > 100 x 109 /L; hemoglobin ≥ 9 g/dL,
• Calculated creatinine clearance ≥ 30 mL/min,
• 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,

• 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,
• 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,
• Registration with the French National Health Care System or PUMA (Protection Universelle MAladie).

Exclusion criteria

• 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),
• Local or locally advanced disease (stage I to III),
• Treatment with warfarin,
• Uncontrolled hypercalcemia,
• Concomitant unplanned antitumor therapy (e.g. chemotherapy, molecular targeted therapy, immunotherapy),
• Known complete dihydropyrimidine dehydrogenase (DPD) deficiency,
• Treatment with any other investigational medicinal product within 28 days prior to study entry,
• Symptomatic carcinomatosis with occlusive symptoms or ascites requiring paracentesis,
• 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),
• HIV-infected patients or otherwise known to be HIV-positive,
• Untreated hepatitis B or C,
• 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,
• Concomitant administration of prophylactic phenytoin and live attenuated virus vaccine such as yellow fever vaccine 28 days prior to the first dose of treatment.
• Patient under guardianship, curatorship or under the protection of justice