A prospective, phase 1/2 study of everolimus and temozolomide in patients with advanced pancreatic neuroendocrine tumor

Abstract

Background Both everolimus and temozolomide are associated with single-agent activity in patients with pancreatic neuroendocrine tumor (NET). We performed a phase I/II study to evaluate the safety and efficacy of temozolomide in combination with everolimus in patients with advanced pancreatic NET. Methods Patients were treated with temozolomide 150 mg/m2 per day on days 1–7 and days 15–21 in combination with everolimus daily in each 28-day cycle. In cohort 1, temozolomide was administered together with everolimus 5 mg daily. Following demonstration of safety in this cohort, subsequent patients in cohort 2 were treated with temozolomide with everolimus 10 mg daily. The duration of temozolomide treatment was limited to 6 months. Patients were followed for toxicity, radiologic and biochemical response, and survival. Results A total of 43 patients were enrolled, including 7 in cohort 1 and 36 in cohort 2. Treatment was associated with known toxicities of each drug; no synergistic toxicities were observed. Among 40 evaluable patients, 16 (40%) experienced a partial response. The median progression-free survival duration was 15.4 months. Median overall survival was not reached. Conclusions Temozolomide and everolimus can be safely administered together in patients with advanced pancreatic NET, and the combination is associated with encouraging antitumor activity. Future studies evaluating the efficacy of combination therapy compared to treatment with either agent alone are warranted.

Streptozocin and 5-Fluorouracil for the Treatment of Pancreatic Neuroendocrine Tumors: Efficacy, Prognostic Factors and Toxicity

“…The toxicity of the treatment was evident but was not a major concern, with fewer grade-3 to -4 adverse advents than with other therapies [18,19,20,21,22] and no treatment-related deaths. The patient who experienced the most serious toxicity had a VIP-producing tumor and developed a hormonal crisis that caused dehydration and required intensive care as previously described [36].…”

“…Furthermore, molecular targeted therapies, such as everolimus [19,20] and sunitinib [21], have been shown active in pNETs. Everolimus has also been tested in combination with temozolomide [22]. …”

Systemic Therapy in Incurable Gastroenteropancreatic Neuroendocrine Tumours: A Clinical Practice Guideline

“…The search uncovered eleven relevant randomized prospective studies [9][10][11][12][13][14][15][16][17][18][19] , sixteen nonrandomized prospective studies [20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] , and thirteen retrospective studies [36][37][38][39][40][41][42][43][44][45][46][47][48] . Where multiple reports and abstracts were published for a single trial or study, only the most recent full publication was included, unless other reports contained data that were not available in the most recent publication.…”

Temozolomide in Advanced Neuroendocrine Neoplasms: Pharmacological and Clinical Aspects

“…Forty-three patients with pNEN were treated with TMZ at a dose of 150 mg/m 2 per day on days 1-7 and days 15-21 in combination with everolimus at 10 mg daily in each 28-day cycle for 6 months. Among 40 evaluable patients, 16 (40%) experienced a PR; PFS was 15.4 months, although OS was not reached at the time of analysis [51] .…”

“…Prophylactic antibiotics were included in this study, and only 1 patient developed an opportunistic infection [47] . A third study of TMZ in combination with everolimus also used the dose-intense schedule of TMZ at 150 mg/m 2 for 7 days every other week [51] . Due to concerns regarding toxicity, TMZ was administered for a maximum of 6 months.…”