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

• ClinicalTrials.gov Identifier: NCT03923842
• Recruitment Status: Unknown
• First Posted: April 23, 2019
• Last Update Posted: February 17, 2020
• Sponsor: Gruppo Oncologico del Nord-Ovest
• Collaborator: Mario Negri Institute for Pharmacological Research
• Information provided by (Responsible Party): Gruppo Oncologico del Nord-Ovest

Tracking Information

• First Submitted Date: April 18, 2019
• First Posted Date: April 23, 2019
• Last Update Posted Date: February 17, 2020
• Actual Study Start Date: June 30, 2019
• Estimated Primary Completion Date: September 30, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 7, 2019)

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).

Original Primary Outcome Measures (submitted: April 22, 2019)

plasmatic EBV DNA reduction [ 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 reduction. 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).

Current Secondary Outcome Measures (submitted: April 22, 2019)

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

• Original Secondary Outcome Measures: Same as current

Current Other Pre-specified Outcome Measures (submitted: May 7, 2019)

• 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).
• 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
• 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
• 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
• 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

Original Other Pre-specified Outcome Measures (submitted: April 22, 2019)

• 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
• 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).
• 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
• 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
• 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

Descriptive Information

• 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 Type: Interventional
• Study Phase: Phase 2

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention 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:

NN

Primary Purpose: Treatment

Condition

• Nasopharyngeal Carcinoma
• EBV Related Carcinoma

Intervention

• 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 Name: Denosumab treatment
• 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 Name: Standard of care treatment

Study Arms

• 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.
  Intervention: Drug: Denosumab Inj 120 MG/1.7ML
• 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
  Intervention: Drug: Chemotherapy as clinical standard of care

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Unknown status
• Estimated Enrollment (submitted: April 22, 2019): 45
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: October 30, 2022
• Estimated Primary Completion Date: September 30, 2021 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Italy

Administrative Information

• NCT Number: NCT03923842
• Other Study ID Numbers: 2017-005017-31
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Undecided

• Current Responsible Party: Gruppo Oncologico del Nord-Ovest
• Original Responsible Party: Same as current
• Current Study Sponsor: Gruppo Oncologico del Nord-Ovest
• Original Study Sponsor: Same as current
• Collaborators: Mario Negri Institute for Pharmacological Research

Investigators

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

• PRS Account: Gruppo Oncologico del Nord-Ovest
• Verification Date: February 2020