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Phase II clinical study of valproic acid plus cisplatin and cetuximab in recurrent and/or metastatic squamous cell carcinoma of Head and Neck-V-CHANCE trial.

ABSTRACT: BACKGROUND:Recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN) has a poor prognosis and the combination of cisplatin and cetuximab, with or without 5-fluorouracil, is the gold standard treatment in this stage. Thus, the concomitant use of novel compounds represents a critical strategy to improve treatment results. Histone deacetylase inhibitors (HDACi) enhance the activity of several anticancer drugs including cisplatin and anti-Epidermal Growth Factor Receptor (anti-EGFR) compounds. Preclinical studies in models have shown that vorinostat is able to down regulate Epidermal Growth Factor Receptor (EGFR) expression and to revert epithelial to mesenchimal transition (EMT). Due to its histone deacetylase (HDAC) inhibiting activity and its safe use as a chronic therapy for epileptic disorders, valproic acid (VPA) has been considered a good candidate for anticancer therapy. A reasonable option may be to employ the combination of cisplatin, cetuximab and VPA in recurrent/metastatic SCCHN taking advantage of the possible positive interaction between histone deacetylase inhibitors, cisplatin and/or anti-EGFR. METHOD/DESIGN:V-CHANCE is a phase 2 clinical trial evaluating, in patients with recurrent/metastatic squamous cell carcinoma of the head and neck never treated with first-line chemotherapy, the concomitant standard administration of cisplatin (on day 1, every 3 weeks) and cetuximab (on day 1, weekly), in combination with oral VPA given daily from day -14 with a titration strategy in each patient (target serum level of 50-100 ?g/ml). Primary end point is the objective response rate measured according to Response Evaluation Criteria in Solid Tumors (RECIST). Sample size, calculated according to Simon 2 stage minimax design will include 21 patients in the first stage with upper limit for rejection being 8 responses, and 39 patients in the second stage, with upper limit for rejection being 18 responses. Secondary endpoints are time to progression, duration of response, overall survival, safety. Objectives of the translational study are the evaluation on tumor samples of markers of treatment efficacy/resistance (i.e. ?H2AX, p21/WAF, RAD51, XRCC1, EGFR, p-EGFR, Ki-67) and specific markers of VPA HDAC inhibitory activity (histones and proteins acetylation, Histone deacetylase isoforms) as well as valproate test, histones and proteins acetylation of peripheral blood mononuclear cell, tested on blood samples at baseline and at different time points during treatment. DISCUSSION:Overall, this study could provide a less toxic and more effective first-line chemotherapy regimen in patients with recurrent/metastatic squamous cell carcinoma of the head and neck by demonstrating the feasibility and efficacy of cisplatin/cetuximab plus valproic acid. Moreover, correlative studies could help to identify responder patients, and will add insights in the mechanism of the synergistic interaction between these agents. EUDRACT NUMBER:2014-001523-69 TRIAL REGISTRATION: ClinicalTrials.gov number, NCT02624128.

SUBMITTER: Caponigro F

PROVIDER: S-EPMC5123351 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Phase II clinical study of valproic acid plus cisplatin and cetuximab in recurrent and/or metastatic squamous cell carcinoma of Head and Neck-V-CHANCE trial.

Caponigro Francesco F Di Gennaro Elena E Ionna Franco F Longo Francesco F Aversa Corrado C Pavone Ettore E Maglione Maria Grazia MG Di Marzo Massimiliano M Muto Paolo P Cavalcanti Ernesta E Petrillo Antonella A Sandomenico Fabio F Maiolino Piera P D'Aniello Roberta R Botti Gerardo G De Cecio Rossella R Losito Nunzia Simona NS Scala Stefania S Trotta Annamaria A Zotti Andrea Ilaria AI Bruzzese Francesca F Daponte Antonio A Calogero Ester E Montano Massimo M Pontone Monica M De Feo Gianfranco G Perri Francesco F Budillon Alfredo A Budillon Alfredo A

BMC cancer 20161125 1

<h4>Background</h4>Recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN) has a poor prognosis and the combination of cisplatin and cetuximab, with or without 5-fluorouracil, is the gold standard treatment in this stage. Thus, the concomitant use of novel compounds represents a critical strategy to improve treatment results. Histone deacetylase inhibitors (HDACi) enhance the activity of several anticancer drugs including cisplatin and anti-Epidermal Growth Factor Receptor (ant ...[more]

PMID: 27884140

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Project description:BackgroundMET signaling is a well described mechanism of resistance to anti-EGFR therapy, and MET overexpression is common in head and neck squamous cell carcinomas (HNSCCs). In the current trial, the authors compared the oral MET inhibitor tivantinib (ARQ197) in combination with cetuximab (the TC arm) versus a control arm that received cetuximab monotherapy (C) in patients with recurrent/metastatic HNSCC.MethodsIn total, 78 evaluable patients with cetuximab-naive, platinum-refractory HNSCC were enrolled, including 40 on the TC arm and 38 on the C arm (stratified by human papillomavirus [HPV] status). Patients received oral tivantinib 360 mg twice daily and intravenous cetuximab 500 mg/m2 once every 2 weeks. The primary outcome was the response rate (according to Response Evaluation Criteria in Solid Tumors, version 1.1), and secondary outcomes included progression-free and overall survival. After patients progressed on the C arm, tivantinib monotherapy was optional.ResultsThe response rate was 7.5% in the TC arm (N = 3; 1 complete response) and 7.9% in the C arm (N = 3; not significantly different [NS]). The median progression-free survival in both arms was 4 months (NS), and the median overall survival was 8 months (NS). Both treatments were well tolerated, with a trend toward increased hematologic toxicities in the TC arm (12.5% had grade 3 leukopenia). The response rate in 31 HPV-positive/p16-positive patients was 0% in both arms, whereas the response rate in HPV-negative patients was 12.7% (12.5% in the TC arm and 13% in the C arm). Fifteen patients received tivantinib monotherapy, and no responses were observed.ConclusionsCombined tivantinib plus cetuximab does not significantly improve the response rate or survival compared with cetuximab alone but does increase toxicity in an unselected HNSCC population. Cetuximab responses appear to be limited to patients who have HPV-negative HNSCC. MET-aberration-focused trials for HNSCC and the use of higher potency, selective MET inhibitors remain of interest.

Project description:BackgroundAngiogenesis is a hallmark of head and neck squamous cell carcinoma (HNSCC), and a mechanism of resistance to EGFR inhibition. We investigated the safety and potential activity of pazopanib, an angiogenesis inhibitor, plus cetuximab, an EGFR inhibitor, in patients with recurrent or metastatic HNSCC.MethodsWe did an open-label, single-centre, dose-escalation phase 1b trial using a standard 3 + 3 design, followed by an expansion cohort phase. Eligible participants were patients with histologically or cytologically confirmed recurrent or metastatic HNSCC, aged at least 18 years, had measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, and an Eastern Cooperative Oncology Group performance status of 0-1. During dose escalation, pazopanib oral suspension was administered daily in 8-week cycles at doses of 200 mg/day, 400 mg/day, 600 mg/day, or 800 mg/day, with cetuximab given intravenously once per week (400 mg/m2 first dose and 250 mg/m2 in consecutive cycles). The primary endpoint was to determine the maximum tolerated dose or recommended phase 2 dose of pazopanib in combination with cetuximab. Analyses were done per protocol. This trial is registered with ClinicalTrials.gov, number NCT01716416, and it is ongoing but closed to accrual.FindingsBetween June 5, 2013, and April 4, 2017, we enrolled 22 patients into the phase 1b, dose-escalation phase of the trial. A maximum tolerated dose of pazopanib in combination with cetuximab was not reached. Single dose-limiting toxic events (all grade 3) during dose escalation occurred with pazopanib 400 mg/day (neutropenia with infection), 600 mg/day (proteinuria), and 800 mg/day (fatigue). The established recommended phase 2 dose for the combination was 800 mg/day of pazopanib during cycles of 8 weeks each, plus cetuximab 400 mg/m2 on day 1 of cycle 1, then cetuximab 250 mg/m2 weekly. A further nine patients were enrolled into the expansion cohort and treated with the established recommended phase 2 dose. The most common (grade 3-4) adverse events for all patients were hypertension (ten [32%] of 31), lymphocyte count decrease (seven [23%]), and dysphagia (seven [23%]). There were no treatment-related deaths. 11 (35%; 95% CI 19·2-54·6) of 31 patients achieved an overall response, as assessed by the investigator; two (6%) had a complete response and nine (29%) a partial response. Tumour responses were also observed in six (55%) of 11 patients with platinum-naive and cetuximab-naive disease, three (25%) of 12 patients with cetuximab-resistant disease, and five (28%) of 18 patients with platinum-resistant disease.InterpretationPazopanib oral suspension at a dose of 800 mg/day was feasible to administer in combination with standard weekly cetuximab for patients with recurrent or metastatic HNSCC. Encouraging preliminary antitumour activity was observed with this combination therapy and warrants further validation in randomised trials.FundingGlaxoSmithKline and Novartis.

Project description:Cetuximab remains to date the only targeted therapy approved for the treatment of head and neck squamous cell carcinoma (HNSCC). The EGFR pathway plays a key role in the tumorigenesis and progression of this disease as well as in the resistance to radiotherapy (RT). While several anti-EGFR agents have been tested in HNSCC, cetuximab, an IgG1 subclass monoclonal antibody against EGFR, is the only drug with proven efficacy for the treatment of both locoregionally-advanced (LA) and recurrent/metastatic (R/M) disease. The addition of cetuximab to radiotherapy is a validated treatment option in LA-HNSCC. However, its use has been limited to patients who are considered unfit for standard of care chemoradiotherapy (CRT) with single agent cisplatin given the lack of direct comparison of these two regimens in randomized phase III trials and the inferiority suggested by metanalysis and phase II studies. The current use of cetuximab in HNSCC is about to change given the recent results from randomized prospective clinical trials in both the LA and R/M setting. Two phase III studies evaluating RT-cetuximab vs. CRT in Human Papillomavirus (HPV)-positive LA oropharyngeal squamous cell carcinoma (De-ESCALaTE and RTOG 1016) showed inferior overall survival and progression-free survival for RT-cetuximab combination, and therefore CRT with cisplatin remains the standard of care in this disease. In the R/M HNSCC, the EXTREME regimen has been the standard of care as first-line treatment for the past 10 years. However, the results from the KEYNOTE-048 study will likely position the anti-PD-1 agent pembrolizumab as the new first line treatment either alone or in combination with chemotherapy in this setting based on PD-L1 status. Interestingly, cetuximab-mediated immunogenicity through antibody dependent cell cytotoxicity (ADCC) has encouraged the evaluation of combined approaches with immune-checkpoint inhibitors in both LA and R/M-HNSCC settings. This article reviews the accumulated evidence on the role of cetuximab in HNSCC in the past decade, offering an overview of its current impact in the treatment of LA and R/M-HNSCC disease and its potential use in the era of immunotherapy.

Dataset Information

Phase II clinical study of valproic acid plus cisplatin and cetuximab in recurrent and/or metastatic squamous cell carcinoma of Head and Neck-V-CHANCE trial.

Publications

Phase II clinical study of valproic acid plus cisplatin and cetuximab in recurrent and/or metastatic squamous cell carcinoma of Head and Neck-V-CHANCE trial.

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