Clinical trial NCT01918852: S-1 Versus Capecitabine in the First Line Treatment of MCC Patients.
Official title: S1 Versus Capecitabine in the First Line Treatment of Metastatic Colorectal Cancer Patients, the SALTO Randomised Phase III Study of the Dutch Colorectal Cancer Group. A Safety Evaluation of Oral Fluoropyrimidines
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Colorectal Cancer
Metastases
Keywords: Hand-foot syndrome
Toxicity
Fluoropyrimidine
Capecitabine
Teysuno
S1
Lead sponsor: Dutch Colorectal Cancer Group
Sponsor class: OTHER
Collaborators: name: Nordic Pharma SAS
First posted: 2013-08-08
Enrollment: 161
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The study is a two-arm randomised phase III trial. Patients will be randomised to receive capecitabine (arm A) or S-1 (arm B). Bevacizumab may be added according to the choice of the investigator. Patients will be followed 3-weekly at the outpatient clinic, toxicity will be assessed according to study protocol guidelines. Patients will be evaluated every 3 cycles for response. Upon disease progression patients will be treated according to the local investigators

Detailed description: Capecitabine, an oral fluoropyrimidine, has shown a comparable efficacy but a better tolerability compared to bolus 5-FU/LV. However, capecitabine has a higher incidence of hand-foot syndrome (HFS). HFS is characterized by erythema, dysesthesia and/or paresthesia of the palms of the hands or soles of feet. In advanced stage, desquamation, ulceration and blistering can occur. Although HFS is not life threatening, it can cause significant discomfort and impairment of function, especially in elderly patients. This adverse event is becoming particularly relevant since many patients may require the administration of capecitabine over prolonged periods of time.

S-1 (Teysuno®) is an oral fluoropyrimidine that has shown comparable efficacy to 5FU and capecitabine in gastrointestinal cancers but is associated with a much lower incidence of HFS. Studies on S-1 have mainly been performed in Asian patients,which population has known differences in tumour biology and toxicity compared to Western population. S-1 has shown comparable efficacy to other fluoropyrimidines as monotherapy or in combination chemotherapy schedules in several gastrointestinal tumors. However, given the lack of data from prospective studies on S-1 as monochemotherapy in metastatic colorectal cancer in Western patients, this study is designed to compare S-1 and capecitabine monotherapy in terms of safety, with particular interest in HFS, in metastatic colorectal cancer patients.

Eligibility criteria: Inclusion Criteria:

* Histological proof of colorectal cancer.
* Distant metastases (patients with only local recurrence are not eligible).
* Unidimensionally measurable disease (≥1 cm on spiral CT scan or ≥2 cm on chest X-ray; liver ultrasound is not allowed). Serum CEA may not be used as a parameter for disease evaluation.
* In case of previous radiotherapy, at least one measurable lesion should be located outside the irradiated field.
* Age ≥ 18 years
* Planned treatment with fluoropyrimidine monotherapy with or without bevacizumab.
* WHO performance status 0-2 (Karnofsky PS ≥70%)
* Adequate bone marrow function (Hb ≥ 6.0 mmol/L, absolute neutrophil count ≥1.5 x 109/L, platelets ≥ 100 x 109/L), renal function (serum creatinine ≤ 1.5x ULN and creatinine clearance, Cockroft formula, ≥30 ml/min), liver function (serum bilirubin ≤ 2 x ULN, serum transaminases ≤ 3 x ULN without presence of liver metastases or ≤ 5x ULN with presence of liver metastases).
* Life expectancy \> 12 weeks.
* Negative pregnancy test in women with childbearing potential.
* Expected adequacy of follow-up.
* Institutional Review Board approval.
* Written informed consent.

Exclusion Criteria:

* Prior adjuvant treatment for stage II/III colorectal cancer completed within 6 months prior to randomisation.
* Any prior adjuvant treatment after resection of distant metastases.
* Any previous systemic treatment for metastatic disease.
* History or clinical signs/symptoms of CNS metastases.
* History of a second malignancy \<5 years with the exception of adequately treated carcinoma of cervix or basal/squamous cell carcinoma of skin.
* Previous intolerance of capecitabine.
* Known dihydropyrimidine dehydrogenase (DPD) deficiency or treatment within 4 weeks with DPD inhibitors, including sorivudine or its chemically related analogues such as brivudine.
* Planned radical resection of metastases after downsizing by systemic treatment.
* Significant cardiovascular disease \< 1 yr before randomisation (symptomatic congestive heart failure, myocardial ischemia or infarction, unstable angina pectoris, serious uncontrolled cardiac arrhythmia, arterial thrombosis, cerebrovascular event, pulmonary embolism).
* Any significant cardiovascular events during previous fluoropyrimidine therapy.

Primary outcomes:
measure: Incidence of HFS in first line treatment
timeFrame: HFS will be assessed every 3 weeks up to 6 months average.
Secondary outcomes:
measure: Grade 3 HFS
timeFrame: HFS will be assessed every 3 weeks, up to 6 months average
measure: Progression-free survival
timeFrame: Every 9 weeks, for 6 months (average)
measure: Overall toxicity
timeFrame: Every 3 weeks, for 6 months (average)
measure: Overall survival
timeFrame: 2 years
measure: Response rate
timeFrame: Response will be assessed every 9 weeks, up to 6 months average.
Other outcomes:
Locations:
city: Alkmaar
country: Netherlands
facility: Medisch Centrum Alkmaar
city: Amersfoort
country: Netherlands
facility: Meander Medisch Centrum
city: Amsterdam
country: Netherlands
facility: Nederlands Kanker Instituut/Antoni van Leeuwenhoek Ziekenhuis
city: Amsterdam
country: Netherlands
facility: Academic Medical Centre
city: Amsterdam
country: Netherlands
facility: OLVG
city: Amsterdam
country: Netherlands
facility: VUMC
city: Assen
country: Netherlands
facility: Wilhelmina Ziekenhuis
city: Bergen op Zoom
country: Netherlands
facility: Ziekenhuis Lievensberg
city: Breda
country: Netherlands
facility: Amphia Ziekenhuis
city: Doetinchem
country: Netherlands
facility: Slingeland Ziekenhuis
city: Eindhoven
country: Netherlands
facility: Catherina Ziekenhuis
city: Enschede
country: Netherlands
facility: Medisch Spectrum Twente
city: Harderwijk
country: Netherlands
facility: St Jansdal
city: Hoofddorp
country: Netherlands
facility: Spaarne Ziekenhuis
city: Leeuwarden
country: Netherlands
facility: Medisch Centrum Leeuwarden
city: Nieuwegein
country: Netherlands
facility: Antonius Ziekenhuis
city: Purmerend
country: Netherlands
facility: Waterland Ziekenhuis
city: Rotterdam
country: Netherlands
facility: Sint Franciscus Gasthuis
city: Schiedam
country: Netherlands
facility: Vlietland Ziekenhuis
city: Sittard
country: Netherlands
facility: Orbis Medisch Centrum
city: Tilburg
country: Netherlands
facility: Tweesteden Ziekenhuis
city: Utrecht
country: Netherlands
facility: University Medical Centre Utrecht
city: Venlo
country: Netherlands
facility: VieCuri Medisch Centrum
city: Zaandam
country: Netherlands
facility: Zaans Medisch Centrum
Study officials:
affiliation: Amsterdam Medical Centre
name: Cornelis JA Punt, Prof MD PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Kwakman JJM, van Werkhoven E, Simkens LHJ, van Rooijen JM, van de Wouw YAJ, Tije AJT, Creemers GM, Hendriks MP, Los M, van Alphen RJ, Polee MB, Muller EW, van der Velden AMT, van Voorthuizen T, Koopman M, Mol L, Punt CJA. Updated Survival Analysis of the Randomized Phase III Trial of S-1 Versus Capecitabine in the First-Line Treatment of Metastatic Colorectal Cancer by the Dutch Colorectal Cancer Group. Clin Colorectal Cancer. 2019 Jun;18(2):e229-e230. doi: 10.1016/j.clcc.2019.01.002. Epub 2019 Jan 29. No abstract available.
citation: Kwakman JJM, Simkens LHJ, van Rooijen JM, van de Wouw AJ, Ten Tije AJ, Creemers GJM, Hendriks MP, Los M, van Alphen RJ, Polee MB, Muller EW, van der Velden AMT, van Voorthuizen T, Koopman M, Mol L, van Werkhoven E, Punt CJA. Randomized phase III trial of S-1 versus capecitabine in the first-line treatment of metastatic colorectal cancer: SALTO study by the Dutch Colorectal Cancer Group. Ann Oncol. 2017 Jun 1;28(6):1288-1293. doi: 10.1093/annonc/mdx122.