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S-1 Versus Capecitabine in the First Line Treatment of MCC Patients. (SALTO)

Primary Purpose

Colorectal Cancer, Metastases

Status
Completed
Phase
Phase 3
Locations
Netherlands
Study Type
Interventional
Intervention
Capecitabine
Teysuno
Bevacizumab
Sponsored by
Dutch Colorectal Cancer Group
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Colorectal Cancer focused on measuring Hand-foot syndrome, Toxicity, Fluoropyrimidine, Capecitabine, Teysuno, S1

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Medisch Centrum Alkmaar
  • Meander Medisch Centrum
  • Nederlands Kanker Instituut/Antoni van Leeuwenhoek Ziekenhuis
  • Academic Medical Centre
  • OLVG
  • VUMC
  • Wilhelmina Ziekenhuis
  • Ziekenhuis Lievensberg
  • Amphia Ziekenhuis
  • Slingeland Ziekenhuis
  • Catherina Ziekenhuis
  • Medisch Spectrum Twente
  • St Jansdal
  • Spaarne Ziekenhuis
  • Medisch Centrum Leeuwarden
  • Antonius Ziekenhuis
  • Waterland Ziekenhuis
  • Sint Franciscus Gasthuis
  • Vlietland Ziekenhuis
  • Orbis Medisch Centrum
  • Tweesteden Ziekenhuis
  • University Medical Centre Utrecht
  • VieCuri Medisch Centrum
  • Zaans Medisch Centrum

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Experimental

Arm Label

Capecitabine

S1

Arm Description

Capecitabine 1250 mg/m2 for patients < 70 years of age, and 1000 mg/m2 for patients ≥ 70 years of age, orally b.i.d. day 1-14 with or without bevacizumab 7.5 mg/kg i.v. day 1.

S-1 30 mg/m2 orally b.i.d. irrespective of age, day 1-14 with or without bevacizumab 7.5 mg/kg i.v. day 1.

Outcomes

Primary Outcome Measures

Incidence of HFS in first line treatment
To determine the incidence of HFS in first line treatment with S-1 compared to capecitabine in patients with metastatic colorectal cancer.

Secondary Outcome Measures

Grade 3 HFS
Incidence of grade 3 hand-foot syndrome, according to CTC 4.0.
Progression-free survival
Time from randomisation until progression or death whichever comes first
Overall toxicity
Adverse events graded accoording to the NCI CTCAE version 4
Overall survival
From date of randomisation to death or last known to be alive
Response rate
Response acccording to RECIST 1.1

Full Information

First Posted
June 24, 2013
Last Updated
March 13, 2018
Sponsor
Dutch Colorectal Cancer Group
Collaborators
Nordic Pharma SAS
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1. Study Identification

Unique Protocol Identification Number
NCT01918852
Brief Title
S-1 Versus Capecitabine in the First Line Treatment of MCC Patients.
Acronym
SALTO
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

2. Study Status

Record Verification Date
March 2018
Overall Recruitment Status
Completed
Study Start Date
December 2013 (undefined)
Primary Completion Date
December 2015 (Actual)
Study Completion Date
March 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Dutch Colorectal Cancer Group
Collaborators
Nordic Pharma SAS

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Colorectal Cancer, Metastases
Keywords
Hand-foot syndrome, Toxicity, Fluoropyrimidine, Capecitabine, Teysuno, S1

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
161 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Capecitabine
Arm Type
Active Comparator
Arm Description
Capecitabine 1250 mg/m2 for patients < 70 years of age, and 1000 mg/m2 for patients ≥ 70 years of age, orally b.i.d. day 1-14 with or without bevacizumab 7.5 mg/kg i.v. day 1.
Arm Title
S1
Arm Type
Experimental
Arm Description
S-1 30 mg/m2 orally b.i.d. irrespective of age, day 1-14 with or without bevacizumab 7.5 mg/kg i.v. day 1.
Intervention Type
Drug
Intervention Name(s)
Capecitabine
Other Intervention Name(s)
Xeloda
Intervention Type
Drug
Intervention Name(s)
Teysuno
Other Intervention Name(s)
S1
Intervention Type
Drug
Intervention Name(s)
Bevacizumab
Other Intervention Name(s)
Avastin
Primary Outcome Measure Information:
Title
Incidence of HFS in first line treatment
Description
To determine the incidence of HFS in first line treatment with S-1 compared to capecitabine in patients with metastatic colorectal cancer.
Time Frame
HFS will be assessed every 3 weeks up to 6 months average.
Secondary Outcome Measure Information:
Title
Grade 3 HFS
Description
Incidence of grade 3 hand-foot syndrome, according to CTC 4.0.
Time Frame
HFS will be assessed every 3 weeks, up to 6 months average
Title
Progression-free survival
Description
Time from randomisation until progression or death whichever comes first
Time Frame
Every 9 weeks, for 6 months (average)
Title
Overall toxicity
Description
Adverse events graded accoording to the NCI CTCAE version 4
Time Frame
Every 3 weeks, for 6 months (average)
Title
Overall survival
Description
From date of randomisation to death or last known to be alive
Time Frame
2 years
Title
Response rate
Description
Response acccording to RECIST 1.1
Time Frame
Response will be assessed every 9 weeks, up to 6 months average.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Cornelis JA Punt, Prof MD PhD
Organizational Affiliation
Amsterdam Medical Centre
Official's Role
Principal Investigator
Facility Information:
Facility Name
Medisch Centrum Alkmaar
City
Alkmaar
Country
Netherlands
Facility Name
Meander Medisch Centrum
City
Amersfoort
Country
Netherlands
Facility Name
Nederlands Kanker Instituut/Antoni van Leeuwenhoek Ziekenhuis
City
Amsterdam
ZIP/Postal Code
1066 CX
Country
Netherlands
Facility Name
Academic Medical Centre
City
Amsterdam
Country
Netherlands
Facility Name
OLVG
City
Amsterdam
Country
Netherlands
Facility Name
VUMC
City
Amsterdam
Country
Netherlands
Facility Name
Wilhelmina Ziekenhuis
City
Assen
Country
Netherlands
Facility Name
Ziekenhuis Lievensberg
City
Bergen op Zoom
Country
Netherlands
Facility Name
Amphia Ziekenhuis
City
Breda
Country
Netherlands
Facility Name
Slingeland Ziekenhuis
City
Doetinchem
Country
Netherlands
Facility Name
Catherina Ziekenhuis
City
Eindhoven
Country
Netherlands
Facility Name
Medisch Spectrum Twente
City
Enschede
Country
Netherlands
Facility Name
St Jansdal
City
Harderwijk
Country
Netherlands
Facility Name
Spaarne Ziekenhuis
City
Hoofddorp
Country
Netherlands
Facility Name
Medisch Centrum Leeuwarden
City
Leeuwarden
Country
Netherlands
Facility Name
Antonius Ziekenhuis
City
Nieuwegein
Country
Netherlands
Facility Name
Waterland Ziekenhuis
City
Purmerend
Country
Netherlands
Facility Name
Sint Franciscus Gasthuis
City
Rotterdam
Country
Netherlands
Facility Name
Vlietland Ziekenhuis
City
Schiedam
Country
Netherlands
Facility Name
Orbis Medisch Centrum
City
Sittard
Country
Netherlands
Facility Name
Tweesteden Ziekenhuis
City
Tilburg
Country
Netherlands
Facility Name
University Medical Centre Utrecht
City
Utrecht
Country
Netherlands
Facility Name
VieCuri Medisch Centrum
City
Venlo
Country
Netherlands
Facility Name
Zaans Medisch Centrum
City
Zaandam
Country
Netherlands

12. IPD Sharing Statement

Plan to Share IPD
Undecided
Citations:
PubMed Identifier
30782413
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.
Results Reference
derived
PubMed Identifier
28383633
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.
Results Reference
derived
Links:
URL
http://www.dccg.nl
Description
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S-1 Versus Capecitabine in the First Line Treatment of MCC Patients.

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