Trial was terminated due to halt in funding.

This phase II trial evaluated the impact of Oxaliplatin and Gemcitabine in patients with recurrent or advanced transitional cell carcinoma of the bladder. The combination of Oxaliplatin and Gemcitabine is considered investigational and this study will help in determining if their activity and toxicity profiles are comparable or better than the standard regimens.

The combination of Oxaliplatin and Gemcitabine has synergistic effects on a variety of human cancer cell lines in vitro. Clinically, it has demonstrated activity in other malignancies including lung, and pancreas. In the former study, poor prognosis advanced non-small cell lung cancer patients received Gemcitabine 1000mg/m2 and Oxaliplatin 65mg/m2 both on days 1 and 8. The overall response rate was 16%, with no reports of neutropenic fever. In the latter study, locally advanced and metastatic pancreatic cancer patients received Gemcitabine 1000mg/m2 on day 1 and Oxaliplatin 100mg/m2 on day 2 every 2 weeks. The overall response rate was 31%. The toxicity profile included grades 3 to 4 neutropenia and thrombocytopenia in 11%, 14% for nausea or vomiting, 6.2% for diarrhea, and 11% for peripheral neuropathy, with no toxic deaths

There has been one feasibility study evaluating the combination of Oxaliplatin and Gemcitabine in advanced transitional cell carcinoma (TCC) of the urothelium. Twenty patients with advanced urothelial carcinomas who were treated with Gemcitabine and Oxaliplatin at 1500mg/m2 and 85mg/m2 IV respectively, both on day 1 of a 14 day cycle. The median number of cycles was 5 and ranged from 1 to 7. A total of 90 cycles were delivered with 87 assessable for toxicity in 19 patients. No neutropenic fever occurred and G-CSF was not used although allowed as needed. Grades 3 to 4 neutropenia and thrombocytopenia were observed in 9 (10%) and 3 (3%) of the courses given respectively. Grades 1 to 2 neuropathy was noted to be common with only one patient suffering grade 3 neuropathy. Non-hematologic adverse effects were found to be mild. Response rates were not provided.

In summary, there is favorable evidence of antitumor activity in vitro and in clinical studies for a variety of cancers. Furthermore, the toxicity profile of this combination is also favorable. It is therefore logical to evaluate the effectiveness and tolerability of this combination in advanced urothelial carcinoma.

Inclusion Criteria:

• All patients must have histologically or cytologically confirmed diagnosis of transitional cell carcinoma of the bladder.
• Patients must have metastatic or locally recurrent transitional cell carcinoma of the bladder. Patients with locoregional disease must be considered incurable by means of locoregional therapy.
• All sites of disease must be assessed and designated as measurable or non- measurable disease as documented by CT, MRI, X-ray physical exam or nuclear exam. All measurable disease must be assessed within 28 days prior to registration. All non-measurable disease must be assessed within 42 days prior to registration.
• Patients must not have more than one prior chemotherapy regimen for recurrent/metastatic disease. Patients with initial locally advanced but nonmetastatic disease are allowed to have one prior chemotherapy regimen as part of the primary curative therapy. All chemotherapy must be completed 4 weeks prior to registration. Any number of prior biologic therapies (e.g. chimeric antibodies or kinase inhibitors) is permitted as part of the chemotherapy regimen.
• Patients may have received prior radiotherapy if there has been complete recovery from all radiation-induced toxicities. At least 4 weeks must have elapsed from the completion of radiation therapy to the time of registration. If lesions within the radiation port are to be used to assess response to therapy, those lesions must have demonstrated clear progression by the criteria outlined in Section 10.1.2V following completion of radiation therapy.
• Patients must not have a surgical procedure for bladder cancer within 4 weeks prior to registration. Patients must have completely recovered from all surgery prior to registration.
• Patients must have adequate bone marrow reserve as evidenced by ANC > 1,500 μl and platelets > 100,000/ μl obtained within 14 days prior to registration.
• Patients must have adequate hepatic function as evidenced by serum bilirubin <1.5x the institutional upper limit of normal. Serum transaminase (SGOT or SGPT) be must < 1.5 x the institutional upper limit of normal serum unless the liver is involved with tumor, in which case serum transaminase (SGOT or SGPT) must be < 5 x the institutional limit of normal. These tests must be obtained within 14 days prior to registration.
• Patients must have a creatinine < 2 x the institutional upper limit of normal obtained within 14 days prior to registration.
• All patients must be 18 years of age or older.
• Patients must have a Zubrod performance of 0-2.
• Patients must not have prior therapy with Oxaliplatin or Gemcitabine.

Exclusion Criteria

• Patients with severe psychiatric disorder are not eligible.
• Patients with known brain metastasis are not eligible. However, brain imaging studies are not required for eligibility if the patient has no neurological signs or symptoms. If brain imaging studies are performed, they must be negative for disease.
• No other prior malignancy is allowed except for adequately treated basal cell or squamous cell carcinoma, in situ cervical cancer, or adequately treated Stage I and II cancer from which the patient is in complete remission, or any other malignancy from which the patient has been disease-free for 5 years.
• Patients with any evidence of active or uncontrolled infection, recent myocardial infarction, unstable angina, or life-threatening arrhythmia are not eligible.
• Patients with any evidence of active or uncontrolled infection, recent myocardial infarction, unstable angina, or life-threatening arrhythmia are not eligible.
• Patients with severe psychiatric disorder are not eligible.
• Patients with known brain metastasis are not eligible. However, brain imaging studies are not required for eligibility if the patient has no neurological signs or symptoms. If brain imaging studies are performed, they must be negative for disease.
• No other prior malignancy is allowed except for adequately treated basal cell or squamous cell carcinoma, in situ cervical cancer, or adequately treated Stage I and II cancer from which the patient is in complete remission, or any other malignancy from which the patient has been disease-free for 5 years.

Eighteen patients were enrolled into the trial. There were 17 subjects that underwent treatment, with one dropping out before starting chemotherapy.

From date of registration until treatment completion, disease progression or other reasons for removal from protocol treatments, whichever came first, an average of 1 year.

Toxicity was graded according to National Cancer Institute Common Terminology Criteria of Adverse Events, version 3.0. Safety was assessed through adverse event monitoring, physical examinations, vital signs and clinical laboratory tests before each dosing.

The main limitation for our study was the small sample size.