Phase I study of sorafenib and tipifarnib for recurrent glioblastoma: NABTC 05-02.

Recurrent glioblastoma (GBM) has a very low 6-month progression free survival (PFS) with currently available treatments. Combination chemotherapy to target multiple cell signaling pathways is currently being investigated in order to improve prognosis for recurrent disease. The purpose of this phase I study was to determine the maximum tolerated dose (MTD) for the combination of tipifarnib and sorafenib for the treatment of recurrent GBM. Patients with pathologically proven WHO grade IV GBM and radiographically proven tumor recurrence were eligible for this study. Treatments included sorafenib at twice daily and escalating dosages of tipifarnib. Dose-limiting toxicity (DLT) was determined over the first 28-days of treatments, and the MTD was determined in a 3 + 3 study design. We enrolled 24 patients, and 21 patients completed the MTD period. The study was stopped early with no MTD determination for excessive toxicities. The last dose level reached was sorafenib at 200 mg twice a day and tipifarnib 100 mg twice a day on an alternating week schedule. The DLTs included diarrhea, lipase elevation, hypophosphatemia, and arthralgia. The combination of sorafenib and tipifarnib has excessive toxicities and full single agent dosages could not be achieved in combination.

Phase I study of the combination of sorafenib and temsirolimus in patients with metastatic melanoma.

PURPOSE: This phase I clinical trial was conducted to determine the safety, efficacy, and molecular effects of sorafenib with temsirolimus in patients with advanced melanoma. PATIENTS AND METHODS: Patients with stage IV or unresectable or recurrent stage III melanoma and Eastern Cooperative Oncology Group performance status of 0 to 1 were eligible. Sorafenib was given orally once or twice daily and temsirolimus was given i.v. weekly, both starting on day 1, with a 4-week cycle. Responses were assessed every 2 cycles per Response Evaluation Criteria in Solid Tumors criteria. Consenting patients with accessible tumors underwent optional tumor biopsies before treatment and after the second infusion of temsirolimus. Tumor biopsies were analyzed for activating mutations in BRAF and NRAS, and for expression of P-extracellular signal-regulated kinase (P-ERK) and P-S6 proteins. RESULTS: A total of 25 patients were accrued to the study. The maximum tolerated doses were sorafenib 400 mg every morning and 200 mg every evening and temsirolimus 25 mg i.v. weekly. Dose-limiting toxicities included thrombocytopenia, hand-foot syndrome, serum transaminase elevation, and hypertriglyceridemia. There were no complete or partial responses with the combination; 10 patients achieved stabilization of disease as their best response. The median progression-free survival was 2.1 months. Matching pretreatment and day 15 tumor biopsies showed marked inhibition of P-S6 with treatment in 3 of 4 evaluable patients, but minimal inhibition of P-ERK. CONCLUSIONS: Combination therapy with sorafenib and temsirolimus resulted in significant toxicity at higher dose levels, failed to achieve any clinical responses in genetically unselected patient population, and did not inhibit P-ERK.

Ridaforolimus: a promising drug in the treatment of soft-tissue sarcoma and other malignancies.

Ridaforolimus (deforolimus; AP23573; MK-8669) is a novel sirolimus derivative manufactured by ARIAD Pharmaceuticals and acquired by Merck. It is a small-molecule kinase inhibitor of the mTOR in clinical development for the treatment of cancer. Both intravenous and oral formulations of the agent are being tested in cancer clinical trials. In preclinical and clinical studies, ridaforolimus exhibited significant antitumor activity with acceptable safety and tolerability. With single-agent ridaforolimus, mucositis and myelosuppression were dose-limiting toxicities. In advanced soft-tissue sarcoma, single-agent ridaforolimus was associated with a 29% clinical benefit rate and 2% partial response rate. A Phase III trial has recently been reported to have met its primary end point.

Evaluating temsirolimus activity in multiple tumors: a review of clinical trials.

Activation of mammalian target of rapamycin (mTOR) signaling occurs in a wide variety of human tumors and can lead to increased susceptibility to mTOR inhibitors. Temsirolimus, a novel analog of rapamycin, has shown promising preclinical and early clinical anti-tumor activity in various solid and hematologic tumor types, either alone or in combination with chemotherapy or other targeted agents. Randomized phase III trials have already demonstrated significant clinical benefits of treatment with single-agent temsirolimus in advanced renal cell carcinoma and relapsed and/or refractory mantle cell lymphoma. Other malignancies studied in the phase I and II trial settings include glioblastoma, breast cancer, endometrial cancer, non-Hodgkin lymphomas, and multiple myeloma. This article reviews a comprehensive collection of the clinical trial results reported to date for temsirolimus in various solid and hematologic malignancies, as well as current strategies being tested in ongoing trials. The findings with temsirolimus in multiple tumors provide a valuable framework for future development of temsirolimus and other mTOR inhibitors.

Accuracy of recorded tumor, node, and metastasis stage in a comprehensive cancer center.

PURPOSE: The benefits of recording the tumor, node, and metastasis (TNM) stages of cancer patients are well accepted, but little is known about how accurately this is performed. An audit was performed to determine the accuracy of recorded stage and to act as a baseline before the implementation of an education program. PATIENTS AND METHODS: All new patient referrals to Princess Margaret Hospital between July 1 and August 31, 1997, were reviewed. An audit panel composed of five health record technicians (HRTs) and 10 doctors was assembled. Each auditor reviewed 10% of the health record. If there was a discrepancy between the stage in the health record and the auditor stage, then the final stage was determined by the audit committee. Analysis of the agreement between the health record, the physician auditor, the HRT auditor, and the final stage was performed. RESULTS: A total of 855 patients were referred with a new diagnosis of a malignancy for which there was a TNM stage system; 833 patients (97.4%) had a stage assigned. There was agreement between the health record stage and final stage in 80% (95% confidence interval [CI], 77% to 82%) of cases for clinical stage, compared with 90% (95% CI, 87% to 92%) for pathologic stage. Of the major site groups, lung was the least accurately recorded. The most common major discrepancies were due to the recording of X when a definite category could be assigned. CONCLUSION: This audit demonstrates the importance of staging and provides impetus to develop staging guidelines and education programs.