Phase 1 and pharmacokinetic study of everolimus in combination with cetuximab and carboplatin for recurrent/metastatic squamous cell carcinoma of the head and neck

Abstract

BACKGROUND Platinum‐based therapy combined with cetuximab is standard first‐line therapy for recurrent or metastatic squamous cell carcinoma of the head and neck (RMSCCHN). Preclinical studies have suggested that mammalian target of rapamycin inhibitors may overcome resistance to epidermal growth factor receptor blockers and may augment cetuximab antitumor activity. We conducted a phase 1b trial of carboplatin, cetuximab, and everolimus for untreated RMSCCHN. METHODS Patients received carboplatin (area under the curve = 2 mg/ml/min; 3 weeks on, 1 week off), cetuximab (with a loading dose of 400 mg/m2 and then 250 mg/m2 weekly), and dose‐escalating everolimus (2.5, 5.0, 7.5, and 10 mg/day) with a 3+3 design. After 4 cycles, patients without progression continued cetuximab/everolimus until progression or intolerable toxicity. Patients (age ≥ 18 years) had previously untreated, unresectable RMSCCHN not amenable to radiotherapy and an Eastern Cooperative Oncology Group performance status of 0 to 2. RESULTS The study enrolled 20 patients (male/female = 18/2) with RMSCCHN; the median age was 65 years (44‐75 years). Thirteen patients received everolimus (male/female = 92%). Two of 6 patients receiving 2.5 mg/day experienced dose‐limiting toxicity (DLT) with grade 3 hyponatremia and nausea. In 7 patients receiving de‐escalated everolimus (2.5 mg every other day), grade 3 hyperglycemia produced DLT in 1 of 6 patients. The objective response rate (RR) was 61.5% (all partial responses). Progression‐free survival (PFS) was 8.15 months. The pharmacokinetics of everolimus was described with a 2‐compartment mixed‐effects model. There was a significant correlation between tumor p‐p44/42 staining and response (P = .044) and a marginally significant correlation between phosphorylated mammalian target of rapamycin and overall survival. CONCLUSIONS The maximum tolerated dose of everolimus with cetuximab and carboplatin was 2.5 mg every other day. The regimen was associated with an encouraging RR and PFS, and this suggested possible clinical efficacy in a select group of patients with squamous cell carcinoma of the head and neck. Cancer 2014;120:3940–3951. © 2014 American Cancer Society.

Phase II trial of everolimus in patients with previously treated recurrent or metastatic head and neck squamous cell carcinoma

“…The toxicities associated with this class of drug remain a challenge in clinical trials in HNSCC. Although a phase I study of everolimus in combination with cetuximab and carboplatin in recurrent or metastatic HNSCC met its accrual target of 20 patients, the maximum tolerated dose occurred after deescalation for dose‐limiting toxicity, including hyponatremia, nausea, and hyperglycemia . A phase I/II trial using everolimus in combination with cetuximab and cisplatin in the recurrent or metastatic setting was terminated because of toxicity (NCT01009346).…”

“…The use of mTOR inhibitors in the neoadjuvant setting or in frontline metastatic setting may yield more promising responses. Saba et al studied everolimus in combination with cetuximab and carboplatin as frontline treatment in recurrent or metastatic HNSCC with an objective response rate of 60%. Although there is currently limited evidence to support the use of everolimus monotherapy in the setting of recurrent or metastatic HNSCC, the study of this drug may be more promising in a biomarker‐enrichment trial design earlier in the treatment of patients with HNSCC.…”

The mTOR Complexes in Cancer Cell Metabolism

“…Thus, rapalogues in combination with chemotherapeutic agents are undergoing clinical trials for a number of different cancers. Phase I clinical trials have been conducted for use of everolimus with conventional chemotherapeutic agents for the treatment of advanced/metastatic pancreatic cancer [78], recurrent/metastatic squamous cell carcinoma of the head and neck [124], cholangiocarcinoma [25]. Phase II clinical trials of everolimus with carboplatin for the treatment of patients with triple negative breast cancer demonstrated efficacy [141].…”

Luteolin Impacts on the DNA Damage Pathway in Oral Squamous Cell Carcinoma

“…While these regimens do improve patients' tumor-free survival, they also produce deleterious side effects, such as oral mucositis, osteonecrosis, radiation caries, and hyposalivation (5)(6)(7). Based on increased knowledge of the involved molecular mechanisms and translational applications to personalized medicine, targeted therapies against epidermal growth factor receptor (EGFR) and mammalian target of rapamycin (mTOR) had recently been proposed and proven to have some success (8)(9)(10). However, it is also believed that such chemotherapies exacerbate the development of tumor resistance (11).…”