A phase 1 study of everolimus plus docetaxel plus cisplatin as induction chemotherapy for patients with locally and/or regionally advanced head and neck cancer

Abstract

BACKGROUND: Activation of the phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is common in head and neck cancers, and it has been demonstrated that inhibition of mTOR complex 1 sensitizes cell lines to platinum and taxane chemotherapy. The authors conducted a phase 1 study to evaluate the addition of oral everolimus to cisplatin and docetaxel as induction chemotherapy for head and neck cancer. METHODS: In this single-institution phase 1 study, 3 doses of daily everolimus were explored: 5 mg daily, 7.5 mg daily (administered as 5 mg daily alternating with 10 mg daily), and 10 mg daily of each 21-day cycle. Cisplatin and docetaxel doses were fixed (both were 75 mg/m 2 on day 1 of 21-day cycle) at each dose level with pegfilgrastim support. A standard 3 þ 3 dose-escalation plan was used. After induction, patients were removed from protocol. RESULTS: Eighteen patients were enrolled (15 men, 3 women), and their median Karnofsky performance status was 90. The most common toxicities were hyperglycemia, low hemoglobin, fatigue, and thrombocytopenia. Dose-limiting toxicities (DLTs) were neutropenic fever (1 event at dose level 2, 2 events at dose level 3), and all patients recovered fully from these DLTs. The maximum tolerated dose was exceeded at dose level 3. The progression-free survival rate at 1 year was 87.5% (95% confidence interval, 56.8%-96.7%); and, at 2 years, it was 76.6% (95% confidence interval, 41.2%-92.3%). Activating PI3K catalytic subunit a (PIK3CA) gene mutations were identified in 2 human papillomavirus-associated oropharyngeal cancers. CONCLUSIONS: The phase 2 recommended dose was 7.5 mg daily for everolimus plus cisplatin and docetaxel (both at 75 mg/m 2 on day 1 of a 21-day cycle) given with pegfilgrastim support. Cancer

Temsirolimus combined with cisplatin or bevacizumab is active in osteosarcoma models

“…It is suggested that this combination can safely be used in patients based on the fact that the combination of cisplatin with other mTOR inhibitors is tolerable. 28,29 We also investigated the efficacy of temsirolimus combined with bevacizumab on osteosarcoma xenografts. Although little was known about the efficacy of this combination in osteosarcomas, rapamycin combined with bevacizumab previously demonstrated synergistic effects in hepatocellular and ovarian carcinoma xenografts.…”

State-of-the-Art and Emerging Treatment Options in the Management of Head and Neck Cancer: News from 2013

“…Fury et al [94] reported the safety of weekly everolimus combined with P and docetaxel in LA-HNSCC. The CAPRA study on weekly everolimus with carboplatin/paclitaxel as IC in LA-HNSCC reported at the recent ASCO meeting confirmed these findings.…”

RETRACTED ARTICLE: Common genetic variants in microRNA processing machinery genes are associated with risk and survival in patients with osteosarcoma

“…The genotyping was performed using the iPLEX system (Sequenom, San Diego, CA, USA) according to the published study (Fury et al 2013). Briefly, the primers were designed using Mass ARRAY Assay Design 3.1 software (Sequenom, Inc.).Then, the polymerase chain reaction amplification was conducted.…”