Back to results

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

Primary Purpose

Nasopharyngeal Carcinoma, EBV Related Carcinoma

Status

Unknown status

Phase

Phase 2

Locations

Italy

Study Type

Interventional

Intervention

Denosumab Inj 120 MG/1.7ML

Chemotherapy as clinical standard of care

About this trial

This is an interventional treatment trial for Nasopharyngeal Carcinoma focused on measuring NPC, EBV

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

EBV related nasopharyngeal cancer
Detectable and quantifiable plasmatic EBV DNA
Recurrent and/or metastatic disease not suitable for curative treatment
PS < 2
Suitable for polychemotherapy
Age ≥ 18 years
Informed consent signed
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
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.
Subject understands and voluntarily signs an ICF prior to any study-related assessments/procedures are conducted.
Subject is able to adhere to the study visit schedule and other protocol requirements

Exclusion Criteria:

Having received 1 or more chemotherapy line for recurrent/metastatic disease
Any residual CTCAE grade ≥ 2 toxicity
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.
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.
Having participated in another clinical trial or having received any investigational agent in the preceding 30 days before study entry.
Chronic systemic immunosuppressive therapy that cannot be interrupted during treatment study.
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.
Subject has a known or suspected hypersensitivity to study drugs.
Subject is pregnant or breast feeding.
Subject is receiving prohibited medication as per section 7.4.2 and suspension of such treatment is considered unsafe.
Subject has history of prior or current osteonecrosis of the jaw (ONJ).
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
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.

Sites / Locations

ASST degli Spedali Civili di BresciaRecruiting
Fondazione IRCCS Istituto Nazionale Tumori

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

ARM A: Denosumab Treatment

ARM B Control Arm

Arm Description

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.

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

Outcomes

Primary Outcome Measures

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).

Secondary Outcome Measures

Progression Free Survival

PFS in patients treated or not with denosumab

Full Information

NCT ID

NCT03923842

First Posted

April 18, 2019

Last Updated

February 13, 2020

Sponsor

Gruppo Oncologico del Nord-Ovest

Collaborators

Mario Negri Institute for Pharmacological Research

1. Study Identification

Unique Protocol Identification Number

NCT03923842

Brief Title

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

Acronym

Dern

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

February 2020

Overall Recruitment Status

Unknown status

Study Start Date

June 30, 2019 (Actual)

Primary Completion Date

September 30, 2021 (Anticipated)

Study Completion Date

October 30, 2022 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Gruppo Oncologico del Nord-Ovest

Collaborators

Mario Negri Institute for Pharmacological Research

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

Brief Summary

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

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Nasopharyngeal Carcinoma, EBV Related Carcinoma

Keywords

NPC, EBV

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Model Description

This is a phase II, 2:1 randomized, open label, and multicentre proof of principle trial with denosumab in patients with recurrent/metastatic (RM) NPC at first line systemic therapy.

Masking

None (Open Label)

Masking Description

Allocation

Randomized

Enrollment

45 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

ARM A: Denosumab Treatment

Arm Type

Experimental

Arm Description

Arm Title

ARM B Control Arm

Arm Type

Active Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

Denosumab Inj 120 MG/1.7ML

Other Intervention Name(s)

Denosumab treatment

Intervention Description

Intervention Type

Drug

Intervention Name(s)

Chemotherapy as clinical standard of care

Other Intervention Name(s)

Standard of care treatment

Intervention Description

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

Primary Outcome Measure Information:

Title

plasmatic EBV DNA change

Description

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

Secondary Outcome Measure Information:

Title

Progression Free Survival

Description

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.

Other Pre-specified Outcome Measures:

Title

Absolute change in cellular immunity to EBV

Description

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

Title

Safety profile of denosumab plus chemotherapy: NCI CTCAE v 4.03

Description

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

Title

Absolute change in blood and salivary miRNA NPC profiles

Description

(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

Title

Absolute change of serum levels of RANKL and its inhibitor osteoprotegerin

Description

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

Title

Absolute change in EBV DNA levels at each other planned time point

Description

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

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: EBV related nasopharyngeal cancer Detectable and quantifiable plasmatic EBV DNA Recurrent and/or metastatic disease not suitable for curative treatment PS < 2 Suitable for polychemotherapy Age ≥ 18 years Informed consent signed Subject has adequate organ functions, evidenced by the following: AST (SGOT), ALT (SGPT) ≤ 2.5 x upper limit of normal range (ULN), or ≤ 5 x ULN range if liver metastasis present Total bilirubin ≤ 1.5 x ULN creatinine clearance 24/h > 50 mL/min Total serum calcium > 8.8 mg/dL Absolute neutrophil count ≥ 1.5 x 10*9 cells/L Platelets ≥ 100 x 10*9 cells/L Haemoglobin ≥ 9 g/dL 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. Subject understands and voluntarily signs an ICF prior to any study-related assessments/procedures are conducted. Subject is able to adhere to the study visit schedule and other protocol requirements Exclusion Criteria: Having received 1 or more chemotherapy line for recurrent/metastatic disease Any residual CTCAE grade ≥ 2 toxicity 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. 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. Having participated in another clinical trial or having received any investigational agent in the preceding 30 days before study entry. Chronic systemic immunosuppressive therapy that cannot be interrupted during treatment study. 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. Subject has a known or suspected hypersensitivity to study drugs. Subject is pregnant or breast feeding. Subject is receiving prohibited medication as per section 7.4.2 and suspension of such treatment is considered unsafe. Subject has history of prior or current osteonecrosis of the jaw (ONJ). 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 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.

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Lital Hollander, manager

Phone

003939014640

lital.hollander@gmail.com

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Paolo Bossi, Dr.

Organizational Affiliation

Università degli Studi di Brescia ASST degli Spedali Civili di Brescia

Official's Role

Study Chair

Facility Information:

Facility Name

ASST degli Spedali Civili di Brescia

City

Brescia

Country

Italy

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Paolo Bossi, MD

paolo.bossi@unibs.it

Facility Name

Fondazione IRCCS Istituto Nazionale Tumori

City

Milan

ZIP/Postal Code

20126

Country

Italy

Individual Site Status

Not yet recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Lisa Licitra, MD

Phone

022390 2150

Ext

2150

lisa.licitra@istitutotumori.mi.it

12. IPD Sharing Statement

Plan to Share IPD

Undecided

Learn more about this trial

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

We'll reach out to this number within 24 hrs