A Phase 2 interventional study of Denosumab Inj 120 MG/1.7ML and Chemotherapy as clinical standard of care in Nasopharyngeal Carcinoma and EBV Related Carcinoma, sponsored by Gruppo Oncologico del Nord-Ovest. Status unknown at 2 sites in Italy. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2020-02-17.
Sponsored by Gruppo Oncologico del Nord-Ovest · Phase 2, Interventional, and Treatment
The aim of the present investigation is to test of the modulation obtained with denosumab as "priming" therapy before the start of chemotherapy and as concurrent therapy in a population of first line NPC recurrent/metastatic patients
Approximately 15-20% of the cancers recognize infectious agents as causal factors. Epstein Barr Virus (EBV) is considered carcinogenic to humans for haematological and solid neoplasms such as nasopharyngeal carcinoma (NPC). Oncogenic mechanisms linking EBV with NPC need to be better delineated. However, the well-defined patterns of EBV cancer cells infection, together with its encoded regulated genes in tumours offers an option for immunological therapeutic strategies.
Distant metastases, especially of the bone, occurs in up to half of patients with NPC. This underlines the importance of improving systemic disease control.
Intravenous bisphosphonates (BP) are effective treatments for skeletal-related events (SRE) in patients with bone metastases. BPs also showed antitumor properties in solid malignancies by inhibiting cancer cell proliferation, inducing apoptosis and affecting bone microenvironment, increasing progression free survival (PFS) and overall survival (OS).
In head and neck squamous cell cancer, RANKL expression has been observed and correlated with tumour differentiation and progression. RANKL expression is also found in tumour-infiltrating Tregs. Once expressed, RANKL regulates epidermal dendritic cells and increases the number of Tregs, thereby suppressing excessive response to environmental stimuli. In NPC, the role of Tregs has been described and implicated in EBV-associated carcinogenesis.
Although no direct evidence of denosumab activity in NPC cells are available, its target's effect on Tregs is at the base of an indirect effect to tackle cancer immune evasion. In this scenario, treatment with RANK and RANKL inhibitors will supposedly act as positive immunoregulator reducing bone events but also improving treatment effects.
RANK expression was confirmed on 17 metastatic relapses of NPC treated at Fondazione IRCCS Istituto Nazionale dei Tumori, Milano.
The recent introduction of denosumab, a new drug active on bone metastases, with a different mechanism of action compared to BPs, changed the scenario. Denosumab is a fully human monoclonal antibody preventing the binding of RANKL to its receptor on osteoclasts' membrane. Denosumab is formulated for SC injection and for oncology indications is administered at a dose of 120 mg Q4W. Denosumab (120 mg SC) is approved worldwide for the prevention of SREs in patients with bone metastases from solid tumors and for the treatment of adults and skeletally mature adolescents with GCTB.
The above premises warrant the investigation of the activity of denosumab - an antibody competing with RANK, enhancing increasing tumour-specific immunity through the blockade of RANKL-regulated Tregs.
824 studies on the registry are indexed under Nasopharyngeal Carcinoma; 281 are open to participants now.
This study's planned enrollment of 45 is below the median of 84 across 674 interventional studies indexed under Nasopharyngeal Carcinoma.
Browse Nasopharyngeal Carcinoma studies →Gruppo Oncologico del Nord-Ovest is the lead sponsor of 39 studies on the registry; 11 are open to participants now.
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Subject has adequate organ functions, evidenced by the following:
Exclusion Criteria:
Subject has history of prior irradiation to the mandible, specified as:
Dose constraints to the mandible: Dmax = 70 Gy, V50 = 62 Gy and V60 = 20 Gy Mandible should be contoured as whole organ, with alveolar bone, excluding teeth
Denosumab 120 mg sc on day -15, -8 and day 1, followed by Denosumab 120 mg sc q4wks + platinum based drugs q3wks + Gemcitabine 1250 mg/sm day 1,8 q3wks for 6 cycles. Denosumab 120 mg sc q4wks will continue for 12 months since chemotherapy end.
Drug: Denosumab Inj 120 MG/1.7ML
platinum based drugs q3wks + Gemcitabine 1250 mg/sm day 1,8 q3wks for 6 cycles. At the end of the 6 cycles, if the patient is not progressing, can continue treatment with Gemcitabine alone.for 12 months
Drug: Chemotherapy as clinical standard of care
Denosumab 120 mg sc on day -15, -8 and day 1, followed by Denosumab 120 mg sc q4wks + platinum based drugs q3wks + Gemcitabine 1250 mg/sm day 1,8 q3wks for 6 cycles. Denosumab 120 mg sc q4wks will continue for 12 months since chemotherapy end.
Also known as: Denosumab treatment
platinum based drugs q3wks + Gemcitabine 1250 mg/sm day 1,8 q3wks for 6 cycles. Gemcitabine will continue for 12 months if the patient will not shown disease progression
Also known as: Standard of care treatment
plasmatic EBV DNA change
Meaningful plasmatic EBV DNA change in circulating EBV DNA levels from baseline (prior to the first denosumab administration on day -15 with respect to first chemotherapy administration) to the third denosumab dose (denosumab day 16, equivalent to chemotherapy treatment day 1).
Time frame: change in circulating EBV DNA levels from baseline (prior to the first denosumab administration on day -15 with respect to first chemotherapy administration
Progression Free Survival
PFS in patients treated or not with denosumab
Time frame: PFS will be defined as the time from Chemotherapy treatment start (day1 for chemotherapy, day16 for denosumab) to disease progression or death from any cause.
Absolute change in cellular immunity to EBV
Cellular immunity will be defined blood lymphocytes activity against LMP and EBNA antigens. Absolute change will be defined as the difference in such activity from baseline (i.e. prior to first denosumab administration, chemotherapy day -15 and denosumab day 1) and the subsequent planned time point (16 days, 2 and 6 months after denosumab treatment start).
Time frame: prior to first denosumab administration, chemotherapy day -15 and denosumab day 1) and the subsequent planned time point (16 days, 2 and 6 months after denosumab treatment start
Safety profile of denosumab plus chemotherapy: NCI CTCAE v 4.03
type and frequency of treatment-emergent adverse events, graded according to NCI CTCAE v 4.03
Time frame: During study treatment anf follow up period
Absolute change in blood and salivary miRNA NPC profiles
(chosen among selected miRNAs having previously shown correlation with immune activity and with NPC), measured at each planned time point (at 16 days, 2 and 6 months after Denosumab treatment start
Time frame: at 16 days, 2 and 6 months after Denosumab treatment start
Absolute change of serum levels of RANKL and its inhibitor osteoprotegerin
Absolute change of serum levels of RANKL and its inhibitor osteoprotegerin (OPG), measured at each planned time point
Time frame: at 16 days, 2 and 6 months after treatment start
Absolute change in EBV DNA levels at each other planned time point
change in EBV DNA levels
Time frame: at 2 months after denosumab treatment start, prior to administration of 3rd denosumab treatment, and at 6 months, prior to administration of 7th denosumab treatment
Plan to share: Undecided
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Gruppo Oncologico del Nord-Ovest