First-line Treatment for Patients With Non-resectable Gastric Cancer or Cancer of the Esophagus or
Conditions
Keywords
Gastric cancer, Cancer of the esophagus, Oxaliplatin, Docetaxel, S1
Brief summary
The purpose of this study is to determine maximal tolerable dose (MTD) of the combination of docetaxel, oxaliplatin and S1 (DOS) to patients with gastric cancer.
Detailed description
The primary aim of this dose-finding study is to determine the maximum tolerated doses of docetaxel, oxaliplatin and S1 given every second (DOS2w) or third (DOS3w) week as first-line treatment in patients with advanced gastro-esophageal cancer. Secondary end points are to evaluate toxicities according to NCI-CTCAE v. 4, response rate, progression-free survival and overall survival Primary Outcome Measure: To determine maximum tolerated dose (MTD) for the the combination regimes (DOS2w) and (DOS3w). The investigators have planned to examine 4 dose levels of (DOS2w) and 3 dose levels of (DOS3w). Methods: This dose-finding study is planned to include a total of 24 patients with advanced gastro-esophageal cancer, adenocarcinoma. 12 patients will be included in (DOS2w) at four at progressively higher dose levels. Chemotherapy will be repeated day 1 every second week to a maximum of nine courses. 12 patients will be included in (DOS3w) at three progressively higher dose levels. Chemotherapy will be repeated day 1 every third week to a maximum of six courses. In both (DOS2w) and (DOS3w) dose-limiting toxicity (DLT) will be evaluated after the first course. In case of DLT among one of the three patients during the first course of treatment additional three patients will be added at the respective dose level. Dose escalation is continues if 0/3 or 1/6 patients experience DLT. Patients will be evaluated with a ct-scan at baseline and after every three or four cycles to exclude progression and evaluate response. Response is assessed by the investigator according to RECIST version 1.1.
Interventions
DRUGDOS2w Dose level 1A
Docetaxel (30 mg/m2), Oxaliplatin (70 mg/m2) and S1 (60 mg/2) will be given every 2 weeks. In total there is 5 dose levels and if no patients experience DLT on a given level, next dose level will be administered.
DRUGDOS2w Dose level 2A
Docetaxel (30 mg/m2), Oxaliplatin (70 mg/m2) and S1 (70 mg/2) will be given every 2 weeks. In total there is 5 dose levels and if no patients experience DLT on a given level, next dose level will be administered.
DRUGDOS2w Dose level 3A
Docetaxel (40 mg/m2), Oxaliplatin (70 mg/m2) and S1 (70 mg/2) will be given every 2 weeks. In total there is 5 dose levels and if no patients experience DLT on a given level, next dose level will be administered.
DRUGDOS2w Dose level 4A
Docetaxel (50 mg/m2), Oxaliplatin (70 mg/m2) and S1 (70 mg/2) will be given every 2 weeks. In total there is 5 dose levels and if no patients experience DLT on a given level, next dose level will be administered.
DRUGDOS3w Dose level 1B
Docetaxel (40 mg/m2), Oxaliplatin (100 mg/m2) and S1 (50 mg/2) will be given every 3 weeks. In total there is 5 dose levels and if no patients experience DLT on a given level, next dose level will be administered.
DRUGDOS3w Dose level 2B
Docetaxel (50 mg/m2), Oxaliplatin (100 mg/m2) and S1 (50 mg/2) will be given every 3 weeks. In total there is 5 dose levels and if no patients experience DLT on a given level, next dose level will be administered.
DRUGDOS3w Dose level 3B
Docetaxel (60 mg/m2), Oxaliplatin (100 mg/m2) and S1 (50 mg/2) will be given every 3 weeks. In total there is 5 dose levels and if no patients experience DLT on a given level, next dose level will be administered.
Sponsors
Per Pfeiffer
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Two parallel phase 1/2a studies with 3+3 design with either DOS given every second week or every third week in Caucasian patients (Table 1). Patients were included into DOS2w and DOS3w in sequence. In the DOS2w group: Patients received escalating doses of Docetaxel (30-50 mg/m2 on Day 1), fixed doses of O (70 mg/ m2 on Day 1) and S-1 (30-35 mg/m2/day twice daily orally on Days 1-7) every two weeks. In the DOS3w group: Patients received escalating doses of docetaxel (40-60 mg/m2 on Day 1), fixed doses of O (100 mg/ m2 on Day 1) and S-1 (25 mg/m2/day twice daily orally on Days 1-14) every three weeks.
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
1. Histological proven adenocarcinoma of the esophagus or the ventricle (ECV), and which cannot be treated curatively. 2. Age ≥ 18 years. 3. WHO performance status 0-1. 4. Neutrophils ≥ 1,5 x 109/L and platelets ≥ 100 x 109/L. 5. Bilirubin ≤ 1,5 x UNL (Upper Normal Limit) and ASAT and/or ALAT ≤ 3 x UNL. 6. Creatinine-clearance ≥ 60 ml/min. 7. Planned first day of treatment within 8 days after inclusion in the study. 8. Signed consent form.
Exclusion criteria
1. No previous treatment with chemotherapy, except for (neo)-adjuvant chemotherapy for adenocarcinoma - treatment should have been completed at least 6 months before entrance in this study. 2. No sensory neuropathy. 3. No previously treatment with docetaxel, oxaliplatin or S1. 4. No clinical suspicion of brain metastases. 5. No cytotoxic treatment or other experimental treatment within 2 weeks of inclusion in the study. 6. Other serious disease (i.e. heart disease, AMI within 1 year or ongoing infection). 7. No pregnant women or women who are lactating. Patients who are not using contraception. 8. No known DPD-deficiency or known allergy to taxanes or platinum. 9. No signs of physical or mental illness that would prevent absorption of oral treatment.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Median Overall Survival | Up to 2 years after first administration of DOS |
Countries
Denmark
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| DOS2W Dose Level 1A Treatment with Docetaxel, Oxaliplatin and S1. Treatment is given every 2nd week.
DOS2W: Docetaxel (30 mg/m2), Oxaliplatin (70 mg/m2) and S1 (60 mg/m2) will be given every 2nd week. In total there is 5 dose levels and if no patients experience DLT on a given level, next dose level will be administered. | 3 |
| DOS3W Dose Level 1B Treatment with Docetaxel, Oxaliplatin and S1. Treatment is given every 3rd week.
DOS3W: Docetaxel (40 mg/m2), Oxaliplatin (100 mg/m2) and S1 (50 mg/2) will be given every 3rd week. In total there is 5 dose levels and if no patients experience DLT on a given level, next dose level will be administered. | 3 |
| DOS2W Dose Level 2A Treatment with Docetaxel, Oxaliplatin and S1. Treatment is given every 2nd week.
DOS2W: Docetaxel (30 mg/m2), Oxaliplatin (70 mg/m2) and S1 (70 mg/2) will be given every 2nd week. In total there is 5 dose levels and if no patients experience DLT on a given level, next dose level will be administered. | 3 |
| DOS2W Dose Level 3A Treatment with Docetaxel, Oxaliplatin and S1. Treatment is given every 2nd week.
DOS2W: Docetaxel (40 mg/m2), Oxaliplatin (70 mg/m2) and S1 (70 mg/2) will be given every 2nd week. In total there is 5 dose levels and if no patients experience DLT on a given level, next dose level will be administered. | 6 |
| DOS2W Dose Level 4A Treatment with Docetaxel, Oxaliplatin and S1. Treatment is given every 2nd week.
DOS2W: Docetaxel (50 mg/m2), Oxaliplatin (70 mg/m2) and S1 (70 mg/2) will be given every 2nd week. In total there is 5 dose levels and if no patients experience DLT on a given level, next dose level will be administered. | 6 |
| DOS3W Dose Level 2B Treatment with Docetaxel, Oxaliplatin and S1. Treatment is given every 3rd week.
DOS3W: Docetaxel (50 mg/m2), Oxaliplatin (100 mg/m2) and S1 (50 mg/2) will be given every 3rd week. In total there is 5 dose levels and if no patients experience DLT on a given level, next dose level will be administered. | 8 |
| DOS3W Dose Level 3B Treatment with Docetaxel, Oxaliplatin and S1. Treatment is given every 3rd week.
DOS3W: Docetaxel (60 mg/m2), Oxaliplatin (100 mg/m2) and S1 (50 mg/2) will be given every 3rd week. In total there is 5 dose levels and if no patients experience DLT on a given level, next dose level will be administered. | 5 |
| Total | 34 |
Baseline characteristics
| Characteristic | DOS2W Dose Level 3A | DOS2W Dose Level 4A | DOS3W Dose Level 2B | DOS3W Dose Level 3B | Total | DOS2W Dose Level 1A | DOS3W Dose Level 1B | DOS2W Dose Level 2A |
|---|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 4 Participants | 5 Participants | 2 Participants | 17 Participants | 1 Participants | 2 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants | 2 Participants | 3 Participants | 3 Participants | 17 Participants | 2 Participants | 1 Participants | 2 Participants |
| Region of Enrollment Denmark | 6 participants | 6 participants | 8 participants | 5 participants | 34 participants | 3 participants | 3 participants | 3 participants |
| Sex: Female, Male Female | 5 Participants | 3 Participants | 1 Participants | 3 Participants | 12 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 1 Participants | 3 Participants | 7 Participants | 2 Participants | 22 Participants | 3 Participants | 3 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 3 | 3 / 3 | 3 / 6 | 3 / 6 | 3 / 3 | 6 / 8 | 4 / 5 |
| other Total, other adverse events | 0 / 3 | 0 / 3 | 4 / 6 | 0 / 6 | 0 / 3 | 1 / 8 | 3 / 5 |
| serious Total, serious adverse events | 0 / 3 | 0 / 3 | 2 / 6 | 2 / 6 | 0 / 3 | 1 / 8 | 2 / 5 |
Outcome results
Primary
Median Overall Survival
Time frame: Up to 2 years after first administration of DOS
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| DOS2W 1A | Median Overall Survival | 4.3 Months |
| DOS2W 2A | Median Overall Survival | 13.8 Months |
| DOS2W 3A | Median Overall Survival | 14.6 Months |
| DOS2W 4A | Median Overall Survival | 15.2 Months |
| DOS3W 1B | Median Overall Survival | 8.3 Months |
| DOS3W 2B | Median Overall Survival | 16.4 Months |
| DOS3W 3B | Median Overall Survival | 7.8 Months |