Study Summary
This protocol is a phase I, single arm, open-label study of escalating doses of combination Tomudex and gemcitabine. The design of the study will be a dose-seeking type to determine a recommended dose of Tomudex combined with gemcitabine that can be given together in a 21 day schedule.

In the treatment of cancer, it has been shown that a combination of chemotherapeutic agents is more effective than treatment with a single agent. Agents that have minimal overlapping toxicity profiles can be given in combination more easily. In selecting agents for combination treatment, consideration is given to the level of drug activity against a particular type of tumour, the toxicity profile of each drug and the specific class that the drug belongs to.

The mechanism of action of Tomudex is via inhibition of DNA synthesis. Tomudex was found to be highly cytotoxic in all wild-type tumour cell lines and it produced significant growth delays, superior to 5-fluorouracil (5-FU) and methotrexate (MTX), in human tumour xenografts. The mechanism of action of gemcitabine is via inhibition of DNA and RNA synthesis. Gemcitabine is active in a variety of murine solid tumours and leukemias, as well as several human xenografts. Both of these drugs have been approved for use in the clinic and each has been shown to have some efficacy against a variety of tumor types.

Patients with advanced cancer, having received one or no prior treatment with chemotherapy will be given a dose of Tomudex ranging from 2.0 mg/m2 to 3.5 mg/m2 on day 1 and an 800 mg/m2 or 1 000 mg/m2 dose of gemcitabine on days 1 and 8 of each cycle. Cycles will be repeated every 21 days until disease progression, unacceptable toxicity, or patient's refusal. Dose escalation will not be carried in individual patients. Each individual patient will receive the dose assigned to his/her cohort on entry to the study.

The primary objective of the study is to determine the maximum tolerated dose (MTD) and recommended phase II dose of Tomudex when given in combination with gemcitabine to patients with advanced cancer in this combination schedule. The secondary objective is to determine the toxicity profile of the combination of gemcitabine plus Tomudex in patients with advanced cancer.

References:

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2. Jackman AL, Calvert AH. Folate-based thymidylate synthase inhibitors as anticancer drugs (Review). Ann Oncol 1995; 6(9): 871-81.
3. Hertel LW, Kroin JS, Misner JW et al: Synthesis of 2-deoxy-2', 2' difluoro-D-ribose and 2-deoxy-2', 2' difluoro-D ribofuranosyl nucleosides. L. Org. Chem. 1988; 53:2406-2409.

Lay Summary
This study is designed to find the optimal doses for combining the use of two newly approved chemotherapy drugs, gemcitabine and tomudex. Patients are entered at a certain dose, and observed for side effects, as well as the size of tumors. If there are no very serious side effects amongst three patients treated at a given dose, the subsequent group of three receive a slightly higher dose. Any patient who suffers from a tumor that is not responding to standard therapy, or for which there is no proven effective therapy may be eligible. You must be fully ambulatory, and blood tests must show good liver and kidney function.

The key here is the very close surveillance that the patients receive. We do not know whether this will be effective, and we are closely monitoring the risks from side effects.

• Have histologically or cytologically confirmed solid tumour.
• Have documented evidence of incurable or inoperable, advanced cancer.
• Presence of evaluable or measurable disease. Disease sites used to evaluate tumour response may have received prior radiation treatment provided that there was demonstrated of progression at that site following radiation.
• ECOG performance status of 0, 1, or 2, and life expectancy of 12 or more weeks.
• Age >= years and <= 80 years.
• Previous therapy:
  Chemotherapy: No more than 1 prior course of chemotherapy. At least 4 weeks must have elapsed between the last dose of chemotherapy and entry into the protocol. Patients must have recovered from all acute toxic effects of chemotherapy.
• Radiotherapy: Curative and palliative radiotherapy is allowed provided that no more than 25% of bone marrow producing skeleton was irradiated, and that at least 4 weeks have elapsed between the end of radiotherapy and entry into the protocol (exceptions will be made, however, for low dose non-myelosuppressive radiotherapy). Patients must have recovered from the acute toxic effect of radiotherapy.
  
• Laboratory requirements: Hematology: ANC³1.5 x 10/9/L; Platelets³ 100 x 10/9/L Chemistry: Bilirubin>= UNL; AST or ALT<=2 x UNL;<=3 x UNL if documented liver metastases Creatinine: <=UNL unless creatinine clearance >65 ml/min
  
• Patient consent must be obtained according to local Institutional and /or University Human Experimentation Committee requirements. It will be the responsibility of the local participating investigators to obtain the necessary local clearance, and to indicate in writing to Zeneca Pharmaceuticals that such clearance has been obtained, before the trial can commence in that centre.
• Patients must be accessible for treatment and follow-up. Patients registered on this trial must be treated and followed at the participating centre.