Adenocarcinoma of the Gastroesophageal Junction, Advanced Unresectable Gastric Cancer, Metastatic Gastric Cancer
Conditions
Keywords
Sorafenib, Docetaxel, Cisplatin, gastric cancer, gastroesophageal junction adenocarcinoma
Brief summary
This phase II trial is studying how well giving sorafenib together with docetaxel and cisplatin works in treating patients with metastatic or locally advanced gastric or gastroesophageal junction cancer that cannot be removed by surgery. Sorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. Drugs used in chemotherapy, such as docetaxel and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving sorafenib together with docetaxel and cisplatin may kill more tumor cells.
Detailed description
PRIMARY OBJECTIVES: I. To evaluate the response rate (complete response and partial response) of the combination of BAY 43-9006 with docetaxel and cisplatin or oxaliplatin in patients with gastric and GEJ adenocarcinoma. II. To evaluate the progression-free survival (PFS) and overall survival. III. To evaluate the toxicities of BAY 43-9006 in patients with advanced and metastatic gastric or GEJ adenocarcinoma combined with docetaxel/cisplatin or docetaxel/oxaliplatin. IV. To evaluate Raf status in the tumor and to correlate response and PFS to the presence or absence of an activating mutation in B-Raf. V. To analyze the pharmacokinetic and pharmacogenetic properties of BAY 43-9006 including angiogenesis, monooxygenases, polymorphisms and multidrug-resistance (MDR). This study will be conducted via the E1Y03 mechanism. OUTLINE: This is an open-label, multicenter study. Patients are stratified according to Siewert's tumor location (I vs II vs III) and extent of disease (locally advanced unresectable vs distant metastases). Patients receive oral BAY 43-9006 twice daily on days 1-21. Patients also receive docetaxel intravenously (IV) over 1 hour and cisplatin IV over 1-2 hours on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed periodically for 3 years. An addition of an arm containing oxaliplatin was proposed after meeting the accrual goal but did not move forward and the study was closed to accrual in July, 2007 with a final accrual of 44 patients.
Interventions
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients must have measurable, histologically confirmed, advanced unresectable or metastatic gastric or GEJ adenocarcinoma; imaging studies must be conducted within 4 weeks of study entry * For patients with GEJ adenocarcinoma, the tumor location should be specified using the Siewert classification used in other NCI-sponsored Phase II studies in these disease sites * Patients must have an ECOG performance status of 0-1 * Patients may have had adjuvant chemotherapy or chemoradiation therapy, with or without 5-Fluorouracil if the treatment was performed more than 6 months before any evidence of recurrent or metastatic disease * Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately * Must have the following baseline laboratory values obtained within 2 weeks of registration: * Absolute Granulocyte Count \>= 1,500/mm\^3 * Platelet Count \>= 100,000/mm\^3 * White Blood Count \>= 3,000/mm\^3 * Serum Creatinine \<= 1.5 mg/dl * Total Bilirubin \<= 2.0 mg/dl * Aspartate aminotransferase (AST)/alanine aminotransferase (ALT)/alkaline phosphatase (Alk phos) \<= 2.5 x upper limit of normal * Patients must be able to take oral medication without crushing, dissolving or chewing tablets
Exclusion criteria
* Prior radiotherapy, chemotherapy or investigational therapies, particularly inhibitors of tyrosine Kinases, signal transduction or angiogenesis in the treatment for their recurrent and/or metastatic gastric or GEJ adenocarcinoma * Receiving any other investigational agents * Being pregnant or breast-feeding; all females of childbearing potential must have a blood or urine test within 2 weeks prior to registration to rule out pregnancy * HIV-positive patients receiving combination antiretroviral therapy are excluded from the study because of possible pharmacokinetic interactions with BAY 43-9006 * Brain metastases * History of allergic reactions attributed to compounds of similar chemical or biologic composition to BAY 43-9006 * Acute active infection with significant clinical intervention per physician's discretion * Previous or concurrent malignancies are not allowed, except: * Non-melanoma skin cancer and in situ cervical cancer * Treated cancer from which the patient has been continuously disease-free for more than five years * Other uncontrolled intercurrent illnesses including, but not limited to: uncontrolled hypertension, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia or psychiatric illness/addictive disorders that would limit compliance with study requirements * Evidence of bleeding diathesis * Concurrent cytochrome P450 enzyme-inducing anti-epileptic drugs: * Phenytoin * Carbamazepine * Phenobarbital * Rifampin * St. John's Wort
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Proportion of Patients With Objective Response (Complete Response or Partial Response) | Assessed every 6 weeks until disease progression or up to 3 years | Response was evaluated using RECIST (Response Evaluation Criteria in Solid Tumors) 1.0 criteria. Per RECIST criteria, complete response (CR) = disappearance of all target and non-target lesions. Partial response (PR)= \>=30% decrease in the sum of the longest diameters of target lesions from baseline, and persistence of one or more non-target lesion(s) and/or the maintenance of tumor marker level above the normal limits. Objective response = CR + PR. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) | Assessed every 6 weeks until disease progression or up to 3 years | Progression-free survival was defined as the shorter of: 1. The time from registration to progression. or 2. The time from registration to death without documentation of progression given that the death occurs within 4 months of the last disease assessment without progression (or registration, whichever is more recent). Therefore, cases not meeting either of the criteria for a PFS event are censored at the date of last disease assessment without progression (or registration, whichever is more recent). Progression is defined as at least 20% increase in the sum of the longest diameters of target lesions, taking as reference the smallest sum longest diameter recorded since the baseline measurements, or the appearance of one or more new lesion(s) or unequivocal progression of existing non-target lesions. |
| Overall Survival (OS) | Assessed every 3 months if patient is < 2 years from study entry; then every 6 months if patient is 2-3 years from study entry. | Overall survival was defined as the time from registration to death from any cause. |
Countries
United States
Participant flow
Recruitment details
Participants were recruited from ECOG member institutions between October 28, 2005 and July 2, 2007. The final accrual was 44 patients.
Participants by arm
| Arm | Count |
|---|---|
| BAY 43-9006, Docetaxel, Cisplatin Patients receive oral BAY 43-9006 twice daily on days 1-21. Patients also receive docetaxel IV over 1 hour and cisplatin IV over 1-2 hours on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
BAY 43-9006: Given orally
docetaxel: Given IV
cisplatin: Given IV | 44 |
| Total | 44 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Abdominal pain due to disease | 1 |
| Overall Study | Adverse Event | 18 |
| Overall Study | Death | 2 |
| Overall Study | Disease progression | 13 |
| Overall Study | Non-protocol therapy | 1 |
| Overall Study | Physician Decision | 1 |
| Overall Study | Protocol Violation | 1 |
| Overall Study | Withdrawal by Subject | 6 |
Baseline characteristics
| Characteristic | BAY 43-9006, Docetaxel, Cisplatin |
|---|---|
| Age, Continuous | 58.4 years |
| Region of Enrollment United States | 44 participants |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 37 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 44 / 44 |
| serious Total, serious adverse events | 40 / 44 |
Outcome results
Primary
The Proportion of Patients With Objective Response (Complete Response or Partial Response)
Response was evaluated using RECIST (Response Evaluation Criteria in Solid Tumors) 1.0 criteria. Per RECIST criteria, complete response (CR) = disappearance of all target and non-target lesions. Partial response (PR)= \>=30% decrease in the sum of the longest diameters of target lesions from baseline, and persistence of one or more non-target lesion(s) and/or the maintenance of tumor marker level above the normal limits. Objective response = CR + PR.
Time frame: Assessed every 6 weeks until disease progression or up to 3 years
Population: All enrolled patients started treatment and were considered eligible and hence were all included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BAY 43-9006, Docetaxel, Cisplatin | The Proportion of Patients With Objective Response (Complete Response or Partial Response) | 0.409 Proportion of patients |
Comparison: The study was designed to distinguish a response rate of 40% from 20%, the null hypothesis. With the planned sample size of 36 eligible patients, the study has 91% power based on a 0.09 level one-sided test.p-value: 0.001290% CI: [0.284, 0.544]one-sample binomial test
Secondary
Overall Survival (OS)
Overall survival was defined as the time from registration to death from any cause.
Time frame: Assessed every 3 months if patient is < 2 years from study entry; then every 6 months if patient is 2-3 years from study entry.
Population: All enrolled patients started treatment and were considered eligible and hence were all included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BAY 43-9006, Docetaxel, Cisplatin | Overall Survival (OS) | 13.6 Months |
Secondary
Progression-free Survival (PFS)
Progression-free survival was defined as the shorter of: 1. The time from registration to progression. or 2. The time from registration to death without documentation of progression given that the death occurs within 4 months of the last disease assessment without progression (or registration, whichever is more recent). Therefore, cases not meeting either of the criteria for a PFS event are censored at the date of last disease assessment without progression (or registration, whichever is more recent). Progression is defined as at least 20% increase in the sum of the longest diameters of target lesions, taking as reference the smallest sum longest diameter recorded since the baseline measurements, or the appearance of one or more new lesion(s) or unequivocal progression of existing non-target lesions.
Time frame: Assessed every 6 weeks until disease progression or up to 3 years
Population: All enrolled patients started treatment and were considered eligible and hence were all included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BAY 43-9006, Docetaxel, Cisplatin | Progression-free Survival (PFS) | 5.8 Months |