A phase II trial of farnesyl protein transferase inhibitor SCH 66336, given by twice-daily oral administration, in patients with metastatic colorectal cancer refractory to 5-fluorouracil and irinotecan Journal Article
| Authors: | Zhu, Y.; Sharma, S.; Saltz, L. B.; Kemeny, N.; Kelsen, D. P.; Ilson, D.; O'reilly, E.; Zaknoen, S.; Baum, C.; Statkevich, P.; Hollywood, E. |
| Article Title: | A phase II trial of farnesyl protein transferase inhibitor SCH 66336, given by twice-daily oral administration, in patients with metastatic colorectal cancer refractory to 5-fluorouracil and irinotecan |
| Abstract: | Background: ras genes encode Ras proteins that are important for signal transduction in cancer cells. Farnesyl protein transferase (FPTase) is an enzyme that is responsible for a critical post-translational modification of Ras. Patients and methods: We report the results of a phase II trial of SCH 66336, an FPTase inhibitor, in patients with metastatic colorectal cancer. This is the first reported experience of an FPTase inhibitor in this disease. All patients were considered refractory to first- and second-line therapy. A total of 21 evaluable patients were treated with a starting dose of 200 mg b.i.d. given continuously. Results: The major side-effects were fatigue (grade 1 in 42%, grade 2 in 42% and grade 3 in 14%), diarrhea (grade 1 in 23% and grade 3 in 42%) and nausea (grade 2 in 16%). Elevations in serum creatinine (grade 2 or 3) were observed in 19% of patients and appeared to be related to dehydration induced by diarrhea. Significant hematological toxicity was not observed (only grade 1 thrombocytopenia in 19% and grade 2 or 3 anemia in 28%). Pharmacological studies revealed adequate mean pre-dose plasma concentrations in this group of patients on day 15 of therapy. No objective responses were observed, although stable disease was seen in three patients for several months. Administration of SCH 66336 was accompanied by gastrointestinal toxicity. Conclusions: Future development of this compound cannot be recommended as monotherapy in this disease. |
| Keywords: | signal transduction; survival; adult; controlled study; treatment outcome; aged; aged, 80 and over; middle aged; survival analysis; unclassified drug; clinical trial; fatigue; fluorouracil; diarrhea; dose response; drug efficacy; liver neoplasms; pyridines; cancer radiotherapy; cancer staging; follow up; follow-up studies; neoplasm staging; colorectal cancer; metastasis; controlled clinical trial; phase 2 clinical trial; breast cancer; anemia; thrombocytopenia; lung neoplasms; dehydration; drug administration schedule; creatinine; creatinine blood level; drug resistance; pathology; dose-response relationship, drug; drug resistance, neoplasm; enzyme inhibitor; irinotecan; colorectal neoplasms; lung tumor; gastrointestinal toxicity; protein processing; enzyme inhibitors; biopsy, needle; colorectal tumor; colon cancer; cancer cell; liver tumor; needle biopsy; protein farnesyltransferase inhibitor; tipifarnib; ras protein; piperidines; loperamide; drug blood level; drug administration; administration, oral; ras; pyridine derivative; oral drug administration; middle age; piperidine derivative; lonafarnib; humans; human; male; female; priority journal; article; oral rehydration therapy; protein farnesyltransferase; farnesyl protein; r 11577 |
| Journal Title: | Annals of Oncology |
| Volume: | 13 |
| Issue: | 7 |
| ISSN: | 0923-7534 |
| Publisher: | Oxford University Press |
| Date Published: | 2002-07-01 |
| Start Page: | 1067 |
| End Page: | 1071 |
| Language: | English |
| DOI: | 10.1093/annonc/mdf173 |
| PUBMED: | 12176785 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Export Date: 14 November 2014 -- Source: Scopus |
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