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.

Randomized phase II adjuvant factorial study of dose-dense temozolomide alone and in combination with isotretinoin, celecoxib, and/or thalidomide for glioblastoma.

BACKGROUND: Chemoradiation, followed by adjuvant temozolomide, is the standard treatment for newly diagnosed glioblastoma. Adding other active agents may enhance treatment efficacy. METHODS: The primary objective of this factorial phase II study was to determine if one of 3 potential chemotherapy agents added to dose-dense temozolomide (ddTMZ) improves progression-free survival (PFS) for patients with newly diagnosed glioblastoma. A prior phase I trial established the safety of combining ddTMZ with isotretinoin, celecoxib, and/or thalidomide. Adults with good performance status and no evidence of progression post chemoradiation were randomized into 8 arms: ddTMZ alone (7 days on/7 days off) or doublet, triplet, and quadruplet combinations with isotretinoin, celecoxib, and thalidomide. RESULTS: The study enrolled 155 participants with a median age of 53 years (range, 18-84 y). None of the agents demonstrated improved PFS when compared with arms not containing that specific agent. There was no difference in PFS for triplet compared with doublet regimens, although a trend for improved overall survival (OS) was seen (20.1 vs 17.0 months, P = .15). Compared with ddTMZ, the ddTMZ + isotretinoin doublet had worse PFS (10.5 vs 6.5 months, P = .043) and OS (21.2 vs 11.7 months, P = .037). Trends were also seen for worse outcomes with isotretinoin-containing regimens, but there was no impact with celecoxib or thalidomide combinations. Treatment was well tolerated with expected high rates of lymphopenia. CONCLUSIONS: The results do not establish a benefit for these combinations but indicate that adding isotretinoin to ddTMZ may be detrimental. This study demonstrated the feasibility and utility of the factorial design in efficiently testing drug combinations in newly diagnosed glioblastoma. CLINICALTRIALSGOV IDENTIFIER: NCT00112502.

An algorithm for chemotherapy treatment of recurrent glioma patients after temozolomide failure in the general oncology setting.

PURPOSE: The standard therapy for newly diagnosed malignant gliomas comprises surgery, radiotherapy, and commonly temozolomide chemotherapy. For recurrent or progressive disease after temozolomide failure, there is no consensus and only limited options for chemotherapy. METHODS: We reviewed the English literature for phase II trials of therapies for recurrent malignant glioma conducted between January 2000 and September 2010. The search was supplemented by a review of articles published prior to 2000 on chemotherapy regimens that had shown activity on recurrent gliomas. RESULTS: To guide practice in the general oncology setting, an algorithm was constructed according to the activity of the reported chemotherapies at the time of writing. Some molecular studies performed on tumor tissue may help guide the selection of chemotherapy. Methylated MGMT in tumor tissue correlates with increased sensitivity to alkylating agents such as fotemustine or other nitrosoureas. Depending on MGMT status and bone marrow reserve, treatment with fotemustine, bevacizumab, bevacizumab with irinotecan, or cis-retinoic acid (cRA), might be of value. CONCLUSION: Unfortunately, progress in the development of new and more effective chemotherapy agents has been very limited and leaves the clinician treating high-grade glioma patients at relapse with few good options. The suggested algorithm is our objective evaluation of the currently existing knowledge. Hopefully, the ongoing phase II and III trials will provide us the needed chemotherapy agents in the years to come.