Stomach Neoplasms
Conditions
Brief summary
This phase II study addressed the use of docetaxel in combination with oxaliplatin with or without 5-FU or capecitabine in metastatic or locally recurrent gastric cancer previously untreated with chemotherapy for advanced disease. Prior to this study a pilot phase I (part I) determined the optimal dose by assessing the safety and tolerability of 2 dose levels in each arm. The optimal dose was administered in the Part II study. Participants who received the optimal dose in each treatment arm in Part I were included in the Part II analysis population. Primary objective: * To assess the time to progression (TTP) of Docetaxel in combination with Oxaliplatin with or without 5-Fluorouracil (5-FU) or Capecitabine in metastatic or locally recurrent gastric cancer previously untreated with chemotherapy for advanced disease (part II). Secondary objectives: * To establish the safety profile. * To assess the Overall Response Rate (ORR) based on the World Health Organization (WHO) criteria * To assess the Overall Survival (OS)
Detailed description
The purpose of this study (Part II) was to evaluate the time to progression in the 3 arms at an optimal dose level of docetaxel and oxaliplatin defined during a prior pilot (Part I) phase study. The estimated duration of treatment was to be 6 months. Treatment was to be administered up to progression, unacceptable toxicities, or withdrawal of consent. The reason and date of removal of all participants was documented on the case report form. Participants who ended treatment but had not yet progressed (e.g. unacceptable toxicities or withdrawal of consent) were be followed every 8 weeks with a complete tumor assessment until documented progression or further anti-tumor therapy. Then, they would be followed every 3 months after progression for survival status; date of death or progression were reported. Participants who ended treatment for progression, were to be followed every 3 months until death. Date of death was reported. The planned duration of the study was 30 months.
Interventions
DRUGDocetaxel + Oxaliplatin
Dose level 1 (non-optimal dose): Docetaxel 75 mg/m² as an 1-hour intravenous (IV) infusion on day 1 followed by Oxaliplatin 100 mg/m² as a two to six-hour IV infusion on day 1 Dose level 2 (optimal dose): Docetaxel 75 mg/m² as an 1-hour IV infusion on day 1 followed by Oxaliplatin 130 mg/m² as a two to six-hour IV infusion on day 1
DRUGDocetaxel + Oxaliplatin + 5-FU
Dose level 1 (non-optimal dose): Docetaxel 40 mg/m² as a 1-hour intravenous (IV) infusion day 1; Oxaliplatin 85 mg/m² simultaneously with folinic acid 400 mg/m² as a 2-hour IV infusion, followed by 5-FU 2400 mg/m2 as a 46-hour continuous infusion day 1. Dose level 2 (optimal dose): Docetaxel 50 mg/m² as a 1-hour IV infusion day 1; Oxaliplatin 85 mg/m² simultaneously with folinic acid 400 mg/m² as a 2-hour IV infusion, followed by 5-FU 2400 mg/m² as a 46-hour continuous infusion day 1.
DRUGDocetaxel + Oxaliplatin + Capecitabine
Dose level 1 (optimal dose): Docetaxel 50 mg/m² as a 1-hour intravenous (IV) infusion on day 1, Oxaliplatin 100 mg/m² as a two to six-hour IV infusion on day 1, Capecitabine 625 mg/m2 two times a day continuously. Dose level 2 (non-optimal dose): Docetaxel 65 mg/m² as a 1-hour IV infusion on day 1, Oxaliplatin 100 mg/m² as a two to six-hour IV infusion on day 1, Capecitabine 625 mg/m² two times a day continuously.
Sponsors
Sanofi
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically proven gastric adenocarcinoma, including adenocarcinoma of the gastro-oesophageal junction * Metastatic or locally recurrent disease * Prior adjuvant (and/or neo-adjuvant) chemotherapy with 5-Fluorouracil, Cisplatin, epirubicin is allowed provided that the patient has relapsed \> 12 months after the end of the chemotherapy * Performance status Karnofsky index \> 70 * Hematology within 7 days before randomization:Hemoglobin ≥10g/dl, Absolute Neutrophil Count ≥2.0 10\^9/L, platelets ≥100 x 10\^9/L * Blood chemistry within 7 days before randomization:Total bilirubin ≤1x Upper Normal Limit(UNL), Aspartate Aminotransferase (AST) Serum Glutamic Oxaloacetic Transaminase SGOT) and Alanine Aminotransferase (ALT)Serum Glutamate Pyruvate Transaminase(SGPT) ≤2.5xUNL, alkaline phosphatase ≤ 5x UNL, provided that AST or ALT \> 1.5 x UNL is not associated with alkaline phosphatase \> 2.5 x UNL; creatinine ≤1.25x UNL or 1.25x UNL \< creatinine ≤1.5x UNL and calculated/measured creatinine clearance ≥60 ml/min) * Measurable and/or evaluable metastatic disease
Exclusion criteria
* Any prior palliative chemotherapy * Neurosensory symptoms National Cancer Institute Common Toxicity Criteria for Adverse Events grade≥2 The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Progression | every 8 weeks up to a maximum of 36 months | The number of months measured from the day of randomization to the first tumor progression according to World Health Organization (WHO) criteria evaluation of cancer response, or death from any cause. WHO Criteria for Progressive Disease: ≥ 25% increase in the size of at least one bidimensionally or unidimensionally measurable lesion. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Best Overall Response Rate (ORR) | every 8 weeks up to a maximum of 36 months | Percentage of partial and complete responses, according to WHO criteria: Complete Response: Disappearance of all known disease, determined by 2 observations not less than 4 weeks apart. Partial Response: Decrease by at least 50% of the diameters of all measurable lesions, determined by 2 observations not less than 4 weeks apart. |
| Overall Survival (OS) | up to a maximum of 36 months | The number of months measured from the date of randomization to the date of death due to any cause. |
Countries
Belgium, France, Germany, Hungary, Italy, Portugal, Russia, Spain, Switzerland, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
A total 275 participants from 12 countries were randomized in the part I/II study. 64 participants were enrolled in Part I. 211 new participants were enrolled specifically for Part II.
Pre-assignment details
The intent-to-treat (ITT) population, included 254 participants randomized to the optimal dose of study medication from Parts I (43) and II (211), and excluded 21 participants administered the non-optimal dose in Part I.
Participants by arm
| Arm | Count |
|---|---|
| (TE) Taxotere and Eloxatin Participants administered Docetaxel (Taxotere) 75 mg/m² as an 1-hour IV infusion on day 1 followed by Oxaliplatin (Eloxatin) 130 mg/m² as a two to six-hour IV infusion on day 1 per chemotherapy cycle. | 79 |
| (TEF) Taxotere, Eloxatin and 5-fluorouracil Participants administed with Docetaxel (Taxotere) 50 mg/m² as a 1-hour IV infusion day 1; Oxaliplatin (Eloxatin) 85 mg/m² simultaneously with folinic acid 400 mg/m² as a 2-hour IV infusion, followed by 5-FU 2400 mg/m² as a 46-hour continuous infusion day 1 per chemotherapy cycle. | 89 |
| (TEX) Taxotere, Eloxatin and Xeloda Participants administered Docetaxel (Taxotere) 50 mg/m² as a 1-hour intravenous (IV) infusion on day 1, Oxaliplatin (Eloxatin) 100 mg/m² as a two to six-hour IV infusion on day 1, Capecitabine (Xeloda) 625 mg/m2 two times a day continuously per chemotherapy cycle. | 86 |
| Total | 254 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 21 | 23 | 15 |
| Overall Study | Clinically progressive disease | 0 | 1 | 0 |
| Overall Study | Death | 0 | 1 | 2 |
| Overall Study | Discontinued at end of study | 0 | 1 | 2 |
| Overall Study | Good prognosis | 0 | 1 | 0 |
| Overall Study | Investigator/Clinical decision | 5 | 6 | 6 |
| Overall Study | Patient did not receive study medication | 1 | 1 | 4 |
| Overall Study | Progressive disease | 37 | 28 | 38 |
| Overall Study | Protocol Violation | 2 | 5 | 1 |
| Overall Study | Surgery | 1 | 1 | 4 |
| Overall Study | Withdrawal by Subject | 11 | 20 | 12 |
| Overall Study | Withdrew consent | 1 | 1 | 2 |
Baseline characteristics
| Characteristic | (TE) Taxotere and Eloxatin | Total | (TEX) Taxotere, Eloxatin and Xeloda | (TEF) Taxotere, Eloxatin and 5-fluorouracil |
|---|---|---|---|---|
| Age Continuous | 59.2 years STANDARD_DEVIATION 11.4 | 58.7 years STANDARD_DEVIATION 11.1 | 59.0 years STANDARD_DEVIATION 11 | 57.9 years STANDARD_DEVIATION 11.1 |
| Karnofsky Performance Status (KPS) 100% Normal, no complaints: no evidence of disease | 19 participants | 66 participants | 19 participants | 28 participants |
| Karnofsky Performance Status (KPS) 70% Cares for self but unable to work | 1 participants | 6 participants | 3 participants | 2 participants |
| Karnofsky Performance Status (KPS) <70% Requires assistance | 1 participants | 1 participants | 0 participants | 0 participants |
| Karnofsky Performance Status (KPS) 80% Normal activity with effort, some signs | 31 participants | 88 participants | 33 participants | 24 participants |
| Karnofsky Performance Status (KPS) 90% Able to carry on normal activity; minor signs | 26 participants | 92 participants | 31 participants | 35 participants |
| Karnofsky Performance Status (KPS) Missing | 1 participants | 1 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Asian/Oriental | 0 participants | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Black | 1 participants | 1 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Unknown or Not Reported | 1 participants | 4 participants | 2 participants | 1 participants |
| Race/Ethnicity, Customized White | 77 participants | 248 participants | 84 participants | 87 participants |
| Sex: Female, Male Female | 28 Participants | 78 Participants | 22 Participants | 28 Participants |
| Sex: Female, Male Male | 51 Participants | 176 Participants | 64 Participants | 61 Participants |
| Weight loss during last 3 months greater than 5% | 39 participants | 122 participants | 41 participants | 42 participants |
| Weight loss during last 3 months less than or equal to 5% | 39 participants | 130 participants | 44 participants | 47 participants |
| Weight loss during last 3 months Missing | 1 participants | 2 participants | 1 participants | 0 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 75 / 78 | 87 / 88 | 77 / 82 |
| serious Total, serious adverse events | 35 / 78 | 24 / 88 | 36 / 82 |
Outcome results
Primary
Time to Progression
The number of months measured from the day of randomization to the first tumor progression according to World Health Organization (WHO) criteria evaluation of cancer response, or death from any cause. WHO Criteria for Progressive Disease: ≥ 25% increase in the size of at least one bidimensionally or unidimensionally measurable lesion.
Time frame: every 8 weeks up to a maximum of 36 months
Population: 248 participants in the full analysis population (FAP).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| (TE) Taxotere and Eloxatin | Time to Progression | 4.50 Months |
| (TEF) Taxotere, Eloxatin and 5-fluorouracil | Time to Progression | 7.66 Months |
| (TEX) Taxotere, Eloxatin and Xeloda | Time to Progression | 5.55 Months |
Secondary
Best Overall Response Rate (ORR)
Percentage of partial and complete responses, according to WHO criteria: Complete Response: Disappearance of all known disease, determined by 2 observations not less than 4 weeks apart. Partial Response: Decrease by at least 50% of the diameters of all measurable lesions, determined by 2 observations not less than 4 weeks apart.
Time frame: every 8 weeks up to a maximum of 36 months
Population: 248 participants in the full analysis population (FAP).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| (TE) Taxotere and Eloxatin | Best Overall Response Rate (ORR) | 23.1 percentage of participants |
| (TEF) Taxotere, Eloxatin and 5-fluorouracil | Best Overall Response Rate (ORR) | 46.6 percentage of participants |
| (TEX) Taxotere, Eloxatin and Xeloda | Best Overall Response Rate (ORR) | 25.6 percentage of participants |
Secondary
Overall Survival (OS)
The number of months measured from the date of randomization to the date of death due to any cause.
Time frame: up to a maximum of 36 months
Population: 248 participants in the full analysis population (FAP).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| (TE) Taxotere and Eloxatin | Overall Survival (OS) | 8.97 months |
| (TEF) Taxotere, Eloxatin and 5-fluorouracil | Overall Survival (OS) | 14.59 months |
| (TEX) Taxotere, Eloxatin and Xeloda | Overall Survival (OS) | 11.30 months |