Rao, Ravi D.

8043 Background: Mammalian target of rapamycin (mTOR) is a serine-threonine kinase that regulates the production vascular endothelial growth factor (VEGF) and cell growth and proliferation. Inhibitors of mTOR have anti-mitotic and anti-angiogenic effects in various cancers (including melanoma). Everolimus (RAD-001), an orally administered inhibitor of mTOR, is well tolerated at a dose of 30 mg/week. We conducted a phase II study to evaluate the role of RAD-001 in treating patients with metastatic melanoma (MM). Methods: A 2 stage, phase II multi-institutional trial was conducted in patients with MM to assess progression free survival (PFS) rate at 16 weeks was at least 50% against the alternative it was at most 30%. Data about expected baseline PFS were derived from historical controls. Each cycle was 8 weeks in duration. Inclusion criteria: measurable disease, ECOG performance score (PS) of 0–2. Exclusion criteria: presence of intracranial metastases, concurrent use of inducers of cytochrome 3A4 and abnormal hepatic, renal or bone marrow function. Correlative studies included changes pharmacodynamic endpoints to evaluate effect of therapy on signaling pathways. Results: 24 patients with MM were enrolled. Median age was 56 years (33–79), 21 (88%) had at 2 or more sites of metastatic disease. Most (75%) had stage M1c, with 13% each having 1a and 1b disease. PS was 0, 1 and 2 in 58, 38% and 4%, resp. All but 9 had received previous therapy for MM. Planned interim analysis was done after 20 patients were enrolled. Of these, 7 (i.e., 35%) were PF at 16 weeks, which exceeded the decision rule for restarting accrual. No patient had an objective response; all 7 had stable disease. There were no grade 3 toxicities. Grade 2 toxic events (at least possibly related to therapy) were: fatigue (17%), diarrhea (8%) and anemia (8%). Patients had a clinically relevant benefit, with the median PFS for all 24 patients of 3 months. Median overall survival was not reached. Three patients continue on therapy. RAD-001 treatment resulted in changes in serum VEGF levels. Conclusion: Interim analysis after enrollment of 20 patients suggests that RAD-001 is well tolerated and has sufficient anti-tumor activity in MM to warrant the opening of enrollment to the second stage of this trial. Further accrual is planned. No significant financial relationships to disclose.

Abstract Purpose: The mammalian target of rapamycin (mTOR) functions within the phosphoinositide 3-kinase/Akt signaling pathway as a critical modulator of cell survival. Methods: The mTOR inhibitor temsirolimus (CCI-779) was combined with chemoradiotherapy in glioblastoma multiforme (GBM) patients in a dose-escalation phase I trial. The first 12 patients were treated with CCI-779 combined with radiation/temozolomide and adjuvant temozolomide. A second cohort of 13 patients was treated with concurrent CCI-779/radiation/temozolomide followed by adjuvant temozolomide monotherapy. Results: Concomitant and adjuvant CCI-779 was associated with a high rate (3 of 12 patients) of grade 4/5 infections. By limiting CCI-779 treatment to the radiation/temozolomide phase and using antibiotic prophylaxis, the rate of infections was reduced, although 2 of 13 patients developed exacerbation of pre-existing fungal or viral infections. Dose-limiting toxicities were observed in 2 of 13 patients with this modified schedule. Weekly CCI-779 (50 mg/week) combined with radiation/temozolomide is the recommended phase II dose and schedule. The immune profile of patients in the second cohort was assessed before, during, and after CCI-779 therapy. There was robust suppression of helper and cytotoxic T cells, B cells, natural killer, cells and elevation of regulatory T cells during CCI-779/radiation/temozolomide therapy with recovery to baseline levels during adjuvant temozolomide of cytotoxic T cells, natural killer cells, and regulatory T cells. Conclusions: The increased infection rate observed with CCI-779 combined with chemoradiotherapy in GBM was reduced with antibiotic prophylaxis and by limiting the duration of CCI-779 therapy. The combined suppressive effects of CCI-779 and temozolomide therapy on discrete immune compartments likely contributed to the increased infectious risks observed. Clin Cancer Res; 16(22); 5573–80. ©2010 AACR.

Oligodendroglioma frequently (≥ 70%) responds to radiation and chemotherapy, and is the first CNS neoplasm in which a genetic signature (1p and 19q deletion) has been associated with outcome within the context of large clinical trials. Current translational investigations focus on deletions or mutations of potential tumor suppressor genes, epigenetic alterations, amplification or mutation of growth factor and regulatory genes, and characterization of signaling events and regulatory protein expression. The most compelling data has involved 1p and 19q loss, which is observed in over 50% of anaplastic oligodendrogliomas. In two randomized phase III trials (Radiation Therapy Oncology Group 9402 and European Organisation for Research and Treatment of Cancer 26951), the addition of neoadjuvant or adjuvant procarbazine, lomustine, and vincristine (PCV; respectively) to radiotherapy did not produce superior survival as compared with radiotherapy alone. A modest increase in progression-free survival was observed with the addition of PCV, but at the cost of increased toxicity. Combined 1p and 19q loss identified a favorable prognostic group in both studies, which appeared to be independent of treatment arms. However, it is unclear whether these deletions represent surrogate markers of a favorable biologic tumor behavior, or are predictive of outcome after specific treatment. Currently, there is insufficient data to allow therapeutic decisions to be made solely on the basis of 1p and 19q gene deletion status. Future phase III trials are evaluating other chemotherapeutic and targeted agents, including temozolomide, and include correlative investigations of aberrant molecular events in these neoplasms, which may lead to future therapeutic strategies that are based on specific molecular signatures.