Study Chairman: Linus Ho, MD
Study Sponsor: Schering-Plough Research Institute

Study Schedule

Patients will receive SCH66336 by mouth every day for 28 days per cycle. Gemzar will be given at the same time once per week for 3 weeks. The number of cycles will be decided by the doctor based on toxicity and tumor response.

Study Rationale (excerpted from the protocol abstract)

Mutations in the ras genes (generally L-ras) result in deregulated cell proliferation are found in 20-30% of all human tumors, including 50% of colon cancers and 90% of pancreatic cancers. All Ras proteins are produced in the cytoplasm as biologically inactive precurser molecules and must undergo three posttranslational enzymatic modifications to generate membrane-localized, mature Ras proteins. The key modification frequired for Ras protein transforming ability is farnesylation of a cysteine residue located four amino acids from the carboxy terminus of the Ras precursor protein. Farnesylation is catalyzed by the enzyme farnesyl-protein transferase (FPTase). Because FPTase activity is required for Ras function and transforming ability, a farnesyl-protein transferase inhibitor (FTI) may be efficacious in inhibiting the Ras pathway and consequent cellular proliferation.

In preclinical animal studies, oral administration of SCH66336 resulted in antitumor activity in human xenograft models in mice. The spectrum of activity includes colon, pancreatic, lung, prostate, bladder, and breast carcinomas and melanomas....When dosing was initiated after the mice had developed palpable tumors, SCH66336 induces significant tumor regression. When combined wiht a variety of cytotoxic agents, SCH66336 demonstrated additive or possibly synergistic efficacy in animal models.

Patient Eligibility

Inclusion:

Patients may either have recently diagnosed or recurrent metastatic pancreatic cancer. Cancer must be verified by biopsy.

Patients may have had surgery or have been treated wtih 5-fluorouracil (5FU) and/or radiation for locally-advanced disease or as an adjuvant to surgery.

Patients must be at least 18 years old with measuable metastatic disease (outside of the pancreas) on CT. Ascites is not measurable. Must have normal blood counts and chemistry. If indicated, patients may have a stent (internal or external) to normalize bilirubin.

Exclusion:

Patients must NOT have clinical evidence of malabsorption (ie, steatorrhea), prior therapy with farnesyl transferase inhibitors, chemotherapy (except as noted above), biologic therapy, concurrent treatment, radiation, immunotherapy or hormonal therapy (except Megace for appetite stimulation).

Patients must not have brain or other central nervous system metastases.

Patients must be otherwise medically stable (no active infection, heart abnormalities) HIV positivity, or other cancer) Patients must be recovered fully from any prior treatment.

Female patients must not be pregnant or breast feeding. All patients must practice effective contraception, if fertile.