RATIONALE: Drugs used in chemotherapy, such as docetaxel, oxaliplatin, and fluorouracil, work
in different ways to stop the growth of tumor cells, either by killing the cells or by
stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill
more tumor cells.
PURPOSE: This phase I/II trial is studying the side effects and best dose of docetaxel when
given with oxaliplatin and fluorouracil and to see how well they work in treating patients
with metastatic or unresectable stomach cancer, gastroesophageal junction cancer, or other
- To establish the maximum tolerated dose of docetaxel when administered with oxaliplatin
and fluorouracil in patients with metastatic or unresectable solid tumors. (Phase I)
- To determine the response rate in patients with metastatic or unresectable
adenocarcinoma of the stomach or gastroesophageal junction treated with this regimen.
- To determine the dose limiting toxicity of this regimen in these patients.
- To evaluate the frequency of CYP3A4, CYP3A5, and MDR polymorphisms and their impact on
toxicity of docetaxel.
- To evaluate the frequency of XRCC1 and ERCC2 polymorphisms and their impact on the
toxicity of oxaliplatin.
- To evaluate the frequency of DPD and TSER polymorphisms and their impact on the toxicity
- To characterize the toxicity profile of this regimen in these patients.
OUTLINE: This is a dose-escalation study of docetaxel.
Patients receive docetaxel IV over 1 hour and oxaliplatin IV over 2 hours on day 1 and
fluorouracil IV continuously over 46 hours on days 1 and 2. Treatment repeats every 14 days
for at least 2 courses in the absence of disease progression, symptomatic tumor progression,
or unacceptable toxicity.
Patients undergo blood sample collection periodically for pharmacokinetic and pharmacogenomic
correlative studies. Plasma concentrations of docetaxel are analyzed by reverse-phase high
performance liquid chromatography and tandem mass spectrometry. Polymorphisms in CYP3A4/5,
MDR, and other genes are analyzed by PCR.
After completion of study therapy, patients are followed every 3 months.
PROJECTED ACCRUAL: A total of 73 patients (30 for phase I and 43 for phase II) will be
accrued for this study.
- Histologically confirmed metastatic or surgically unresectable solid tumor meeting 1
of the following criteria:
- Any solid tumor (Phase I)
- Adenocarcinoma of the stomach or gastroesophageal junction (Phase II)
- Unidimensionally measurable disease by CT scan or MRI
- No uncontrolled brain metastasis
- ECOG performance status 0-1
- ANC ≥ 1,500/mm³
- Platelet count ≥ 100,000/mm³
- Hemoglobin ≥ 8.0 g/dL
- Creatinine ≤ 1.5 times upper limit of normal (ULN)
- Total bilirubin normal
- Meets 1 of the following criteria:
- Alkaline phosphatase (AP) normal AND AST or ALT ≤ 5 times ULN
- AP ≤ 2.5 times ULN AND AST or ALT ≤ 1.5 times ULN
- AP ≤ 5 times ULN AND AST or ALT normal
- Not pregnant or nursing
- Negative pregnancy test
- Fertile patients must use effective contraception during and for ≥ 3 months after
completion of study therapy
- No preexisting neuropathy
- No concurrent uncontrolled illness or other condition that would preclude study
- No history of severe hypersensitivity reaction to docetaxel or to other drugs
formulated with polysorbate 80
- No history of allergic reactions attributed to compounds of similar chemical or
biologic composition to agents used in this study
PRIOR CONCURRENT THERAPY:
- Recovered from prior therapy
- More than 4 weeks since prior therapy (Phase I)
- No prior oxaliplatin or taxanes (Phase I)
- More than 4 weeks since prior radiotherapy (Phase I)
- No more than two prior therapies for metastatic disease (Phase I)
- No prior therapy for metastatic disease (Phase II)
- At least 6 months since prior adjuvant therapy (given prior to the occurrence of
metastatic disease) (Phase II)
- Prior fluorouracil and concurrent radiotherapy for palliation of the primary tumor
allowed provided metastatic disease is present outside the radiotherapy field (Phase
- No prior radiotherapy to ≥ 30% of bone marrow
- No other concurrent investigational agents