Nasopharyngeal CarcinomaPhase 2DernNCT03923842
Denosumab In Ebv Nasopharyngeal Carcinoma As A Model For RankMediated Immunologic Modulation Of Virus-Related Tumours
A Phase 2 study testing Denosumab Inj 120 MG/1.7ML in people with Nasopharyngeal Carcinoma and EBV Related Carcinoma, run by Gruppo Oncologico del Nord-Ovest at 2 sites in Italy.
Trial 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 Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Nasopharyngeal Carcinoma, EBV Related Carcinoma
- What is being tested?
- Denosumab Inj 120 MG/1.7ML
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 45 participants
- Where
- 2 sitesItaly
- Study dates
- 30 Jun 2019to 30 Oct 2022
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
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- 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
Who cannot join
- 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.
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- 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.
Trial locations and contacts
2 sites in 1 country.
Italy2 sites, 2 recruiting
- Recruiting
ASST degli Spedali Civili di Brescia
Brescia
Paolo Bossi, MD, paolo.bossi@unibs.it
- Not yet recruiting
Fondazione IRCCS Istituto Nazionale Tumori
Milan, 20126
Lisa Licitra, MD, 022390 2150 ext. 2150, lisa.licitra@istitutotumori.mi.it
About this study
Official title: 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
Read the 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.
- Conditions
- Nasopharyngeal Carcinoma, EBV Related Carcinoma
- Being tested
- Denosumab Inj 120 MG/1.7ML, Chemotherapy as clinical standard of care
- Keywords
- NPC, EBV
- Medical subject headings
- Nasopharyngeal Carcinoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Denosumab Inj 120 MG/1.7MLDrug
Also called 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.
Chemotherapy as clinical standard of careDrug
Also called Standard of care 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
| Study group | Role | What they receive |
|---|---|---|
| ARM A: Denosumab Treatment | Experimental | 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. Receives: Drug: Denosumab Inj 120 MG/1.7ML |
| ARM B Control Arm | Active comparator | 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 Receives: Drug: Chemotherapy as clinical standard of care |
What is being measured
The primary outcome is the main question the study is designed to answer.
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).
Measured: change in circulating EBV DNA levels from baseline (prior to the first denosumab administration on day -15 with respect to first chemotherapy administration
Secondary outcomes (1)
Progression Free Survival
PFS in patients treated or not with denosumab
Measured: 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.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 Apr 2019
- Study start30 Jun 2019
- Primary completion30 Sep 2021 (estimated)
- Study completion30 Oct 2022 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Nasopharyngeal CarcinomaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- 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)
- Enrolment
- 45 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Gruppo Oncologico del Nord-Ovest
- Sponsor type
- University, hospital or other
- Collaborators
- Mario Negri Institute for Pharmacological Research
- Responsible party
- Sponsor
- Investigators
- Paolo Bossi, Dr., Study chair, Università degli Studi di Brescia ASST degli Spedali Civili di Brescia
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03923842
- Sponsor's protocol ID
- 2017-005017-31
- Other IDs
- 2017
- Acronym
- Dern
- Status last verified
- Feb 2020
- First submitted
- 18 Apr 2019
- Last updated
- 17 Feb 2020
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Study at a glance
From the registry record, last updated by the sponsor on 17 Feb 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Denosumab In Ebv Related Nasopharyngeal Carcinoma (Npc) As A Model For Rank-Mediated Immunologic Modulation Of Virus-Related Tumours - Dern Study
- ClinicalTrials.gov ID
- NCT03923842
- Acronym / sponsor ID
- Dern / 2017-005017-31
- Conditions
- Nasopharyngeal Carcinoma, EBV Related Carcinoma
- Keywords
- NPC, EBV
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 45 participants (estimated)
- Lead sponsor
- Gruppo Oncologico del Nord-OvestUniversity, hospital or other
- Collaborators
- Mario Negri Institute for Pharmacological Research
- Study start
- 30 Jun 2019 (actual)
- Primary completion
- 30 Sep 2021 (estimated)
- Study completion
- 30 Oct 2022 (estimated)
- First posted
- 23 Apr 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
- 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.
| Arm | Type | Receives |
|---|---|---|
| ARM A: Denosumab Treatment | Experimental | Drug: Denosumab Inj 120 MG/1.7MLDenosumab 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. |
| ARM B Control Arm | Active comparator | Drug: Chemotherapy as clinical standard of careplatinum 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 |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (18 listed)
- 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
Key exclusion criteria (14 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Denosumab Inj 120 MG/1.7MLAlso: Denosumab treatmentDenosumab 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 | ARM A: Denosumab Treatment |
| Chemotherapy as clinical standard of careAlso: Standard of care treatmentplatinum 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 | Drug | ARM B Control Arm |
Primary outcome
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).
1 secondary outcome
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.
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 17 Feb 2020.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Paolo Bossi, Dr. study chair
Università degli Studi di Brescia ASST degli Spedali Civili di Brescia
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Denosumab Inj 120 MG/1.7ML in people with Nasopharyngeal Carcinoma and EBV Related Carcinoma, run by Gruppo Oncologico del Nord-Ovest at 2 sites in Italy.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 18 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 17 Feb 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Lital Hollander, manager (003939014640, lital.hollander@gmail.com), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 17 Feb 2020.