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

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ClinicalTrials.gov Identifier: NCT04166604
Recruitment Status : Recruiting
First Posted : November 18, 2019
Last Update Posted : July 13, 2020
Sponsor:
Information provided by (Responsible Party):
GERCOR - Multidisciplinary Oncology Cooperative Group

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.

Condition or disease Intervention/treatment Phase
Metastatic Colorectal Cancer Drug: Trifluridine/Tipiracil Phase 2

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Unpublished analyses that various clinical parameters may be associated with the risk of neutropenia: age ≥ 65 years, female sex, level of leukocytes at baseline, and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

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 250 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: 250 patients need to be included in a prospective cohort, to obtained 89 patients in the phase II (experience a grade 3-4 neutropenia)
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: LONsurf and G-CSF Use: Being On A Right Dose-intensity to Optimize Treatment Efficacy
Actual Study Start Date : May 20, 2020
Estimated Primary Completion Date : November 15, 2021
Estimated Study Completion Date : June 15, 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: trifluridine/tipiracil
35mg/m² BID (PER OS) (one cycle every 4 weeks)
Drug: Trifluridine/Tipiracil

after morning and evening meal,

Days 1 through 5: 35mg/m2 (twice daily)

Days 6 through 7: recovery

Days 8 through 12: 35mg/m2 (twice daily)

Day 13 through 28: recovery

In case of first event of grade 3-4 neutropenia : patients will not have a dose reduction and will receive a secondary prophylaxis with G-CSF (filgrastim or lenograstim) during subsequent cycle: a starting 5 mg/kg/day dose of filgrastim or lenograstim as a single daily injection, for 5 days, from day 14 to day 18

In case of secondary event of grade 3-4 neutropenia despite G-CSF secondary prophylaxis, dose adjustment of trifluridine/tipiracil will be done according to Summary of Product Characteristics (SmPC). G-CSF secondary prophylaxis will be continuing with the reduction.

dose





Primary Outcome Measures :
  1. 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 the 6 months. [ Time Frame: At 6 months ]

Secondary Outcome Measures :
  1. Overall survival (OS) [ Time Frame: Up to 30 months ]
    Overall survival (OS) is defined as the time from study enrollment to death (from any cause) or to the last date the patients was known to be alive

  2. Progression free survival (PFS) [ Time Frame: up to 30 months ]
    PFS is defined as the time (in months) from study enrollment until objective PD or death from any cause. If the patient dies before reaching PD, the date of death is considered as the date that PD was reached. For patients that had not reached PD at the time of the analysis, and for patients for whom the PD date is unknown, PFS is censored at the date of patient's final assessment prior to data cut-off.

  3. Objective response rate (ORR) [ Time Frame: Up to 30 months ]
    Objective response rate is defined as proportion of patients with reduction in tumor burden of predefined amount. It refers to the number of patients with CR, PR according to RECIST v1.1

  4. Disease control rate (DCR) [ Time Frame: Up to 30 months ]
    The disease control rate (DCR) is defined as the proportion of patients in whom the best overall response is determined as complete response, partial response or stable disease

  5. Number of participants with treatment-related adverse events grade 3-4 as assessed by National Cancer Institute-Common Terminology Criteria for Adverse Events [NCI-CTCAE] v5.0 [ Time Frame: up to 30 months ]
    Patients will be assessed for AEs throughout the study at every visit during treatment. Investigators using the NCI-CTCAE version 5.0 will grade the severity of AEs.

  6. Number of participants with dose reductions [ Time Frame: up to 30 months ]
  7. Polymorphisms analysis of ATM and XRCC3 [ Time Frame: Blood samples at baseline and at Cycle 2 Day 1 (Day 28 of cycle 1) ]
  8. Measure of the level of circulating tumor DNA [ Time Frame: Blood samples at baseline and at Cycle 2 Day 1 (Day 28 of cycle 1) ]
    Circulating cell-free DNA will be sequenced using the AmpliSeq Colon and Lung Cancer Panel V2 on an Ion Proton following the manufacturer's recommendations (Life Technology), and date will be analyzed using the BPER method.

  9. Measure of the level of seric growth factors TGF β [ Time Frame: Blood samples at baseline and at Cycle 2 Day 1 (Day 28 of cycle 1) ]
  10. Measure of the level of seric growth factors TGF α [ Time Frame: Blood samples at baseline and at Cycle 2 Day 1 (Day 28 of cycle 1) ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04166604


Contacts
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Contact: Marie Line GARCIA LARNICOL 01 40 20 85 00 gercor@gercor.com.fr

Locations
Show Show 22 study locations
Sponsors and Collaborators
GERCOR - Multidisciplinary Oncology Cooperative Group
Investigators
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Principal Investigator: Jean Baptiste BACHET, MD Hôpital Pitié Salpêtrière
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Responsible Party: GERCOR - Multidisciplinary Oncology Cooperative Group
ClinicalTrials.gov Identifier: NCT04166604    
Other Study ID Numbers: LONGBOARD C19-01
First Posted: November 18, 2019    Key Record Dates
Last Update Posted: July 13, 2020
Last Verified: October 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by GERCOR - Multidisciplinary Oncology Cooperative Group:
trifluridine/ tipiracil
G-CSF
neutropenia
Additional relevant MeSH terms:
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Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Trifluridine
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antiviral Agents
Anti-Infective Agents