Brief Title
Denosumab In Ebv Nasopharyngeal Carcinoma As A Model For RankMediated Immunologic Modulation Of Virus-Related Tumours
Official Title
Denosumab In Ebv Related Nasopharyngeal Carcinoma (Npc) As A Model For Rank-Mediated Immunologic Modulation Of Virus-Related Tumours - Dern Study
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.
Study Phase
Phase 2
Study Type
Interventional
Primary Outcome
plasmatic EBV DNA change
Secondary Outcome
Progression Free Survival
Condition
Nasopharyngeal Carcinoma
Intervention
Denosumab Inj 120 MG/1.7ML
Study Arms / Comparison Groups
ARM A: Denosumab Treatment
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.
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status
Drug
Estimated Enrollment
45
Start Date
June 30, 2019
Completion Date
October 30, 2022
Primary Completion Date
September 30, 2021
Eligibility Criteria
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.
Gender
All
Ages
18 Years - N/A
Accepts Healthy Volunteers
No
Contacts
Paolo Bossi, Dr., 003939014640, [email protected]
Location Countries
Italy
Location Countries
Italy
Administrative Informations
NCT ID
NCT03923842
Organization ID
2017-005017-31
Responsible Party
Sponsor
Study Sponsor
Gruppo Oncologico del Nord-Ovest
Collaborators
Mario Negri Institute for Pharmacological Research
Study Sponsor
Paolo Bossi, Dr., Study Chair, Università degli Studi di Brescia ASST degli Spedali Civili di Brescia
Verification Date
February 2020