Denosumab In Ebv Nasopharyngeal Carcinoma As A Model For RankMediated Immunologic Modulation Of Virus-Related Tumours (Dern)

February 13, 2020 updated by: Gruppo Oncologico del Nord-Ovest

Denosumab In Ebv Related Nasopharyngeal Carcinoma (Npc) As A Model For Rank-Mediated Immunologic Modulation Of Virus-Related Tumours - Dern Study

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

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Enrollment (Anticipated)

45

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • Italy
      • Brescia, Italy
        • Recruiting
        • Asst Degli Spedali Civili Di Brescia
        • Contact:
      • Milan, Italy, 20126

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  1. EBV related nasopharyngeal cancer
  2. Detectable and quantifiable plasmatic EBV DNA
  3. Recurrent and/or metastatic disease not suitable for curative treatment
  4. PS < 2
  5. Suitable for polychemotherapy
  6. Age ≥ 18 years
  7. Informed consent signed

  8. Subject has adequate organ functions, evidenced by the following:

    1. AST (SGOT), ALT (SGPT) ≤ 2.5 x upper limit of normal range (ULN), or ≤ 5 x ULN range if liver metastasis present
    2. Total bilirubin ≤ 1.5 x ULN
    3. creatinine clearance 24/h > 50 mL/min
    4. Total serum calcium > 8.8 mg/dL
    5. Absolute neutrophil count ≥ 1.5 x 10*9 cells/L
    6. Platelets ≥ 100 x 10*9 cells/L
    7. Haemoglobin ≥ 9 g/dL
  9. If of childbearing potential, willingness to use effective contraceptive method (Pearl Index < 1; e.g. oral contraceptive (pill), hormone spiral, hormone implant, transdermal patch, a combination of two barrier methods (condom and diaphragm), sterilisation, sexual abstinence) for the study duration and 5 months post-dosing.
  10. Subject understands and voluntarily signs an ICF prior to any study-related assessments/procedures are conducted.
  11. Subject is able to adhere to the study visit schedule and other protocol requirements

Exclusion Criteria:

  1. Having received 1 or more chemotherapy line for recurrent/metastatic disease
  2. Any residual CTCAE grade ≥ 2 toxicity
  3. Subject has any other malignancy within 3 years prior to randomization, with the exception of adequately treated in situ carcinoma of the cervix, uteri, or non-melanoma skin cancer (all treatment of which should have been completed 6 months prior to enrolment), in situ squamous cell carcinoma of the breast, or incidental prostate cancer T1a, Gleason < 7, PSA <10 ng/ml.
  4. Subject has had radiotherapy ≤ 4 weeks or limited field radiation for palliation ≤ 2 weeks prior to starting IP, and/or from whom ≥ 30% of the bone marrow was irradiated.
  5. Having participated in another clinical trial or having received any investigational agent in the preceding 30 days before study entry.
  6. Chronic systemic immunosuppressive therapy that cannot be interrupted during treatment study.
  7. Subject has significant active cardiac disease within the previous 6 months including unstable angina or angina requiring surgical or medical intervention, significant cardiac arrhythmia, or New York Heart Association (NYHA) class 3 or 4 congestive heart failure.
  8. Subject has a known or suspected hypersensitivity to study drugs.
  9. Subject is pregnant or breast feeding.
  10. Subject is receiving prohibited medication as per section 7.4.2 and suspension of such treatment is considered unsafe.
  11. Subject has history of prior or current osteonecrosis of the jaw (ONJ).

  12. 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

  13. Subject has any other concurrent severe and/or uncontrolled medical condition that would, in the Investigator's judgment, contraindicate subject participation in the clinical study.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: NONE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
EXPERIMENTAL: ARM A: Denosumab Treatment
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
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.
Other Names:
  • Denosumab treatment
ACTIVE_COMPARATOR: ARM B Control Arm
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
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
Other Names:
  • Standard of care treatment

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
plasmatic EBV DNA change
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
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).
change in circulating EBV DNA levels from baseline (prior to the first denosumab administration on day -15 with respect to first chemotherapy administration

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Progression Free Survival
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.
PFS in patients treated or not with denosumab
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.

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Absolute change in cellular immunity to EBV
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
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).
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
Time Frame: During study treatment anf follow up period
type and frequency of treatment-emergent adverse events, graded according to NCI CTCAE v 4.03
During study treatment anf follow up period
Absolute change in blood and salivary miRNA NPC profiles
Time Frame: at 16 days, 2 and 6 months after Denosumab treatment start
(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
at 16 days, 2 and 6 months after Denosumab treatment start
Absolute change of serum levels of RANKL and its inhibitor osteoprotegerin
Time Frame: at 16 days, 2 and 6 months after treatment start
Absolute change of serum levels of RANKL and its inhibitor osteoprotegerin (OPG), measured at each planned time point
at 16 days, 2 and 6 months after treatment start
Absolute change in EBV DNA levels at each other planned time point
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
change in EBV DNA levels
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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Gruppo Oncologico del Nord-Ovest

Collaborators

Mario Negri Institute for Pharmacological Research

Investigators

  • Study Chair: Paolo Bossi, Dr., Università degli Studi di Brescia ASST degli Spedali Civili di Brescia

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

June 30, 2019

Primary Completion (ANTICIPATED)

September 30, 2021

Study Completion (ANTICIPATED)

October 30, 2022

Study Registration Dates

First Submitted

April 18, 2019

First Submitted That Met QC Criteria

April 22, 2019

First Posted (ACTUAL)

April 23, 2019

Study Record Updates

Last Update Posted (ACTUAL)

February 17, 2020

Last Update Submitted That Met QC Criteria

February 13, 2020

Last Verified

February 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2017-005017-31

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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