Feasibility Study of Adjuvant Treatment With S-1 and Oxaliplatin in Patients With Resectable Esophageal Cancer (SOX)

In this prospective single arm study the investigators will assess the feasibility of S-1 and Oxaliplatin as adjuvant treatment in patients with esophageal cancer.

The primary objective is to assess the feasibility of administering adjuvant S-1 and Oxaliplatin (SOX) in patients with esophageal cancer after neoadjuvant chemoradiotherapy with paclitaxel and carboplatin and esophagectomy. Primary end point is the percentage of patients completing the preplanned number of 6 cycles of SOX.

Study Overview

• Status: Completed
• Conditions: Esophageal Cancer
• Intervention / Treatment: Drug: S-1 and Oxaliplatin

Detailed Description

Since the outcome of patients with esophageal cancer treated with neoadjuvant chemoradiation and surgery is still poor, strategies to improve survival should be explored. The benefit of adjuvant chemotherapy after neoadjuvant chemoradiotherapy followed by surgery is unknown. Preferably, such adjuvant chemotherapy regimen should consist of a non-cross resistant, well-tolerated schedule. For this purpose, the combination of S-1, an oral fluoropyrimidine, with oxaliplatin, may be of benefit, as each of these compounds have shown efficacy in gastroesophageal cancer. Also, importantly, the combination of S-1 with oxaliplatin (SOX) in advanced gastric cancer was well-tolerated. Nevertheless, it should be acknowledged that after major surgery for esophageal cancer, adjuvant treatment with combination chemotherapy may be hard to accomplish as was shown in the MAGIC trial for gastric cancer where less than half of all patients completed adjuvant therapy.

Therefore the investigators want to assess the feasibility of an adjuvant treatment scheme with S-1 and Oxaliplatin. When the proposed treatment scheme is feasible the potential benefit on survival will be evaluated in further studies. Feasibility is defined ≥50% of patients completing the pre-planned number of cycles

Study Objectives Primary Objective To assess the feasibility of administering adjuvant SOX in patients with esophageal cancer after neoadjuvant chemoradiotherapy with paclitaxel and carboplatin and esophagectomy

Secondary Objectives

1. Percentage of patients completing 6 cycles of S-1 (with or without oxaliplatin).
2. Dose modifications (ie, delays, dose reductions, or interruptions) for S-1.
3. Dose modifications (ie, delays, dose reductions, or interruptions) for oxaliplatin.
4. Dose intensity of S-1.
5. Dose intensity of oxaliplatin.
6. Toxicity.
7. Disease free survival.

Exploratory Objectives

1. Assessment of pharmacokinetics of S1 as predictive factors for efficacy and toxicity.
2. Potential biomarker development based on assessment of archived tumor tissue and blood samples and the proposed mechanism of action of study drugs.

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 1

Contacts and Locations

Study Locations

• Netherlands
  • Amsterdam, Netherlands, 1100 DD
    • Academic Medical Center, Medical Oncology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Radically resected adenocarcinoma of the esophagus
• Completed neoadjuvant treatment with paclitaxel 50 mg/m2 and carboplatin Area Under Curve (AUC) = 2 on days 1, 8, 15, 22 and 29 and radiotherapy to a total dose of 41.4 Gy in 23 fractions of 1.8 Gy, 5 fractions per week.
• Age ≥ 18 years
• WHO performance status 0-1
• Adequate bone marrow function (Hb ≥ 6.0 mmol/L, absolute neutrophil count ≥1.0 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 Upper Limit Normal (ULN), serum transaminases ≤ 3 x).
• Negative pregnancy test in women with childbearing potential.
• Expected adequacy of follow-up.
• Written informed consent.

Exclusion Criteria:

• Any history or clinical signs of metastasis
• History of a second malignancy <5 years with the exception of adequately treated carcinoma of cervix or basal/squamous cell carcinoma of skin.
• Known dihydropyrimidine dehydrogenase (DPD) deficiency or treatment within 4 weeks with DPD inhibitors, including sorivudine or its chemically related analogues such as brivudine.
• Significant cardiovascular disease < 1 yr before start of the study (symptomatic congestive heart failure, myocardial ischemia or infarction, unstable angina pectoris, serious uncontrolled cardiac arrhythmia, arterial thrombosis, cerebrovascular event, pulmonary embolism).
• Chronic active infection.
• Any other concurrent severe or uncontrolled disease preventing the safe administration of study drugs.
• Any impairment of gastrointestinal function or -disease that may significantly impair the absorption of oral drugs (i.e. uncontrolled nausea, vomiting, diarrhoea (defined as CTC grade 2 or higher), malabsorption syndrome, bowel obstruction, or inability to swallow tablets).
• Concomitant treatments: concomitant (or within 4 weeks before start of the study) administration of any other experimental drug under investigation; concurrent treatment with any other anti-cancer therapy.
• Continuous use of systemic immunosuppressive agents (except the use of corticosteroids as anti-emetic prophylaxis/treatment).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Adjuvant S-1 and Oxaliplatin; Adjuvant treatment with s-1 and oxaliplatin after neoadjuvant chemoradiation and esophagectomy in patients with resectable esophageal cancer	Drug: S-1 and Oxaliplatin; Six courses of oxaliplatin (130 mg/m2) intravenously on day 1 and S-1 (25 mg/m2 b.i.d.) orally from day 1 to 14 every 3 weeks, starting within 12 weeks after esophagectomy; Other Names: Teysuno

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
The percentage of patients completing the preplanned number of 6 cycles of SOX.	24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of patients completing 6 cycles of S-1 (with or without oxaliplatin)		24 months
Dose modifications for S-1	in terms of delay of treatment in weeks	24 months
Dose modifications for S-1	in terms of dose reduction in percentage of orginal dose	24 months
Dose modifications for S-1	in terms of number of interruptions of treatment	24 months
Dose modifications for Oxaliplatin	in terms of delay of treatment in weeks	24 months
Dose modifications for Oxaliplatin	in terms of dose reduction in percentage of orginal dose	24 months
Dose modifications for Oxaliplatin	in terms of number of interruptions of treatment	24 months
Dose intensity for S-1	total received dose of S-1 in mg/m2 per week	24 months
Dose intensity for Oxaliplatin	total received dose of oxaliplatin in mg/m2 per week	24 months
Toxicity	in terms of CTCAE v4.0 criteria	24 months
Disease free survival	in months	24 months
Overall survival	in months	24 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
AUC of S-1	assessment of pharmacokinetics (Cmax/T1/2) in relation to toxicity in terms of CTCAE criteria and efficacy in terms of disease free survival	24 months

Collaborators and Investigators

• Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Collaborators: Celgene Corporation
• Investigators: Principal Investigator: H WM van Laarhoven, MD,PHD,PHD, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2014
• Primary Completion (Actual): November 1, 2019
• Study Completion (Actual): November 1, 2019

Study Registration Dates

• First Submitted: December 16, 2014
• First Submitted That Met QC Criteria: January 22, 2015
• First Posted (Estimate): January 28, 2015

Study Record Updates

• Last Update Posted (Actual): November 18, 2019
• Last Update Submitted That Met QC Criteria: November 15, 2019
• Last Verified: November 1, 2019

More Information

Terms related to this study

• Keywords: Feasibility; S-1; Esophageal cancer; Oxaliplatin; Adjuvant treatment
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Head and Neck Neoplasms; Esophageal Diseases; Esophageal Neoplasms; Antineoplastic Agents; Oxaliplatin
• Other Study ID Numbers: NL49889.018.14