Clinical Trials /

Denosumab and Nivolumab Combination as 2d-line Therapy in Stage IV NSC Lung Cancer With Bone Metastases (DENIVOS)

NCT03669523

Description:

Bone metastases are common in Non-Small Cell Lung Cancer (NSCLC). They most often occur during disease progression. It is thought that more than half of the patients with bone metastases will have at least 1 skeletal-related event (SRE, i.e. pathological fractures, medullary compression, analgesic radiotherapy, preventive and/or analgesic surgery and hypercalcemia). Expert and medical Society guidelines, notably European Society for Medical Oncology in 2014, then in 2016, recommended using anti-resorptive agents (bisphosphonates or denosumab) to prevent SREs, attenuate pain and improve the quality of life, and decrease the medical-economic impact of this major metastatic site. Denosumab was accorded marketing authorization in France in 2011 as an anti-resorptive agent for bone metastases to delay the occurrence of SREs in lung-cancer patients. Immunotherapy, notably immune-checkpoint inhibitors, like nivolumab (anti-programed death-1), has recently become an integral part of the therapeutic arsenal against NSCLCs. Nivolumab was accorded marketing authorization based on the phase III CHECKMATE 017 (squamous cell NSCLCs) and CHECKMATE 057 (non-squamous cell NSCLCs) trials versus docetaxel, after the phase II CHECKMATE 063 trial. The denosumab-nivolumab combination is commonly used in current practice but has not been evaluated prospectively. The aim of this trial is to evaluate the combination of denosumab and nivolumab in second line of NSCLC with bone metastases.

Related Conditions:
  • Non-Small Cell Lung Carcinoma
  • Squamous Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Denosumab and Nivolumab Combination as 2d-line Therapy in Stage IV NSC Lung Cancer With Bone Metastases (DENIVOS)
  • Official Title: A Multicenter Phase II Study Evaluating Denosumab (XGEVA®) in Combination With Nivolumab (OPDIVO®) as Second-line Therapy for Patients With Stage IV Non-small-Cell Lung Cancer (Squamous and Non-squamous) With Bone Metastases: DENIVOS STUDY

Clinical Trial IDs

  • ORG STUDY ID: P_2017_007
  • SECONDARY ID: 2018-001105-85
  • NCT ID: NCT03669523

Conditions

  • Carcinoma, Non-Small-Cell Lung
  • Bone Metastases

Interventions

DrugSynonymsArms
Denosumab-nivolumab combinationDenosumab-nivolumab combination

Purpose

Bone metastases are common in Non-Small Cell Lung Cancer (NSCLC). They most often occur during disease progression. It is thought that more than half of the patients with bone metastases will have at least 1 skeletal-related event (SRE, i.e. pathological fractures, medullary compression, analgesic radiotherapy, preventive and/or analgesic surgery and hypercalcemia). Expert and medical Society guidelines, notably European Society for Medical Oncology in 2014, then in 2016, recommended using anti-resorptive agents (bisphosphonates or denosumab) to prevent SREs, attenuate pain and improve the quality of life, and decrease the medical-economic impact of this major metastatic site. Denosumab was accorded marketing authorization in France in 2011 as an anti-resorptive agent for bone metastases to delay the occurrence of SREs in lung-cancer patients. Immunotherapy, notably immune-checkpoint inhibitors, like nivolumab (anti-programed death-1), has recently become an integral part of the therapeutic arsenal against NSCLCs. Nivolumab was accorded marketing authorization based on the phase III CHECKMATE 017 (squamous cell NSCLCs) and CHECKMATE 057 (non-squamous cell NSCLCs) trials versus docetaxel, after the phase II CHECKMATE 063 trial. The denosumab-nivolumab combination is commonly used in current practice but has not been evaluated prospectively. The aim of this trial is to evaluate the combination of denosumab and nivolumab in second line of NSCLC with bone metastases.

Detailed Description

      Bone metastases are common in Non-Small Cell Lung Cancer (NSCLC), affecting 30-65% of the
      patients, depending on the series. They most often occur during disease progression (59.7% in
      the French Lung Cancer Group trial). The frequency of skeletal-related events (SREs)
      (pathological fractures, medullary compression, analgesic radiotherapy, preventive and/or
      analgesic surgery and hypercalcemia) is high. It is thought that more than half of the
      patients with bone metastases will have at least 1 SRE, with rates ranging from 55% to 62%.

      Expert and medical Society guidelines, notably European Society for Medical Oncology in 2014,
      then in 2016, recommended using anti-resorptive agents (bisphosphonates or denosumab) to
      prevent SREs, attenuate pain and improve the quality of life, and decrease the
      medical-economic impact of this major metastatic site.

      Denosumab is a humanized monoclonal antibody. It mimics the action of osteoprotegerin (OPG),
      thereby inhibiting osteoclastogenesis by blocking the binding of the receptor activator of
      nuclear factor-kappaB (RANK) to its ligand (RANKL), and thus interrupts the vicious circle
      between tumor cells and bone. RANK is a transmembrane protein expressed on osteoclasts, and
      its ligand, RANKL, is soluble and secreted by osteoblasts. Denosumab was accorded marketing
      authorization in France in 2011 as an anti-resorptive agent for bone metastases to delay the
      occurrence of SREs in lung-cancer patients. The results of 3 phase III studies evaluating the
      place of denosumab versus zoledronic acid have been published. Lung cancers were included in
      the trial examining solid tumors (other than breast and prostate) and multiple myeloma, and
      represented 40% of the population. In a non-inferiority analysis, the primary objective was
      reached with denosumab prolonging by approximately 4 months the time to the first SRE (20.6
      versus 16.3 months, hazard ratio 0.84 [95% confidence interval 0.71-0.98] p=0.0007). In the
      lung-cancer subgroup, this difference did not reach significance (hazard ratio 0.85 [95%
      confidence interval 0.65-1.12]). In contrast, the exploratory analysis of that subgroup
      showed overall survival prolonged by 1.2 months for the denosumab arm versus zoledronic acid
      (8.9 versus 7.7 months, hazard ratio 0.8 [95% confidence interval 0.67-0.95] p=0.01).

      Immunotherapy, notably immune-checkpoint inhibitors (ICPIs), like nivolumab (anti-programed
      death-1 (PD-1)), has recently become an integral part of the therapeutic arsenal against
      NSCLCs. Nivolumab was accorded marketing authorization based on the phase III CHECKMATE 017
      (squamous cell NSCLCs) and CHECKMATE 057 (non-squamous cell NSCLCs) trials versus docetaxel,
      after the phase II CHECKMATE 063 trial. The search for a biomarker predictive of the response
      to immunotherapy is becoming more-and-more crucial, so as not to expose patients who risk
      early cancer hyper-progression. Immunohistochemical labeling of PD-1 ligand (PD-L1) on tumor
      cells (± infiltrating the stroma) is the most studied and reliable biomarker. Knowing its
      status has become indispensable in immunotherapy trials because an elevated PD-L1 has been
      correlated to a better response. Prescribing second-line nivolumab is not conditioned by the
      PD-L1 status because those trials had not foreseen stratification according to this
      criterion's status. However, post-hoc analysis of PD-L1 in the CHECKMATE 057 trial on
      non-squamous cell NSCLCs showed prolonged overall survival for patients with PD-L1-positive
      tumors, whether the positivity threshold was 1%, 5% or 10%. Thus, knowing the PD-L1 status is
      necessary to interpret the results of immunotherapy trials.

      The RANK-RANKL system was studied in preclinical osteoimmunology models. It is expressed by
      certain cells, notably antigen-presenting cells, such as dendritic cells or lymphocytes,
      essential for the adaptive immunity function solicited by immunotherapy. It is part of the
      tumor necrosis factor receptor (TNF-R) family and is implicated in the interactions between
      dendritic cells and lymphocytes. The RANK-RANKL role in the development and function of
      regulatory T cells (Tregs) remains poorly elucidated. Information on the interaction of the
      RANK-RANKL system and adaptive immunity obtained with the preclinical models is discordant
      and rare. A case report on a patient with melanoma bone metastases treated with denosumab and
      ipilimumab (ICPI of the anti-cytotoxic T-lymphocyte antigen 4 type) obtained a promising
      carcinological outcome, without any sign of deleterious interaction.

      The aim of this trial is to evaluate the combination of denosumab and nivolumab in second
      line of NSCLC with bone metastases.
    

Trial Arms

NameTypeDescriptionInterventions
Denosumab-nivolumab combinationExperimentalBoth drugs to be continued until progression or unacceptable toxicity and for a maximum of two years
  • Denosumab-nivolumab combination

Eligibility Criteria

        Inclusion Criteria:

          -  Cytologically or histologically proven stage IV NSCLC

          -  Patients who had received first-line platin salt-based chemotherapy and will be given
             second-line nivolumab;

          -  Patients with bone metastases, symptomatic or not, confirmed by X-rays, CT scan, MRI,
             PET-CT scan or technetium bone scintigraphy

          -  Presence of at least 1 measurable target lesion, according to RECIST criteria 1.1, in
             a non-irradiated site

          -  For non-squamous cell NSCLC, patients without activating epidermal growth factor
             receptor mutation, anaplastic lymphoma kinase (ALK) or reactive oxygen species (ROS)-1
             translocation, or B‐Raf proto‐oncogene, serine/threonine kinase (BRAF V600) mutation

          -  PD-L1 status known and expressed as a percentage of tumor cells; assessed at the
             diagnosis or the more recent PD-L1 expression status available.

          -  Eastern Cooperative Oncology Group Performance Status 0/1

          -  Estimated life-expectancy ≥12 weeks

          -  No prior malignant tumor during the previous 5 years, except for in situ carcinomas of
             the cervix or basal or squamous cell carcinomas of the skin adequately treated;

          -  Adequate organ function determined by laboratory analyses less than 7 days before
             inclusion:

               -  Normal hepatic function: bilirubin < 1.5× normal (N), alanine aminotransferase
                  and aspartate aminotransferase <2.5× N or <5× N if hepatic metastases are present

               -  Renal function (renal clearance of creatinine at least ≥45 mL/min)

               -  Hematological function: absolute number of neutrophils ≥1.5×109/L and/or
                  platelets ≥100×109/L, hemoglobin ≥8 g/dL

          -  Women of child-bearing age must use an effective contraceptive method and mechanical
             contraception during and up to 6 months after the end of treatment;

          -  Men must use effective contraception during and up to 6 months after the treatment
             period

          -  Subjects with cerebral metastases may be enrolled, provided that all lesions are
             controlled, and adequately treated by radiotherapy (stereotactic or not), craniotomy,
             or gamma knife therapy, with no evidence of progression, and have not required
             steroids for at least 2 months prior to enrolment. Carcinomatous meningitis is
             excluded regardless of clinical stability

          -  Subjects must have signed and dated an approved written informed consent form in
             accordance with regulatory and institutional guidelines. This must be obtained before
             the performance of any protocol related procedures that are not part of normal subject
             care

          -  Patient affiliated or benefitting from the French national health insurance program

        Exclusion Criteria:

          -  Patients previously treated with bisphosphonates and/or denosumab

          -  Patients previously treated with immunotherapy

          -  Patients with symptomatic cerebral metastases

          -  Contraindication to nivolumab use:

               -  Prior autoimmune disease(s), define as disease required systemic treatment in the
                  past (i.e. with use of disease modifying agents, corticosteroids or
                  immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or
                  physiologic corticosteroid replacement therapy for adrenal or pituitary
                  insufficiency, etc.) is not considered a form of systemic treatment

               -  Prior diffuse interstitial pneumopathy

               -  Systemic immunosuppressive therapy; define as steroid medication at a dose
                  greater than prednisone 10 mg/day or equivalent. For patients with mismatch
                  repair-deficient high-grade gliomas, concurrent steroid medication at a dose
                  greater than prednisone 20mg/day or equivalent

          -  Contraindication for denosumab use:

               -  Poor dental status requiring immediate specialized management, like oral surgery

               -  Prior or current signs of osteonecrosis of the jaw/osteomyelitis

               -  Invasive dental intervention schedule during the study or not yet healed

          -  Patient with known sensitivity to any of the products to be administered during the
             study

          -  Concomitant administration of bisphosphonates

          -  Hypocalcemia or severe uncorrected hypercalcemia

          -  Medical or psychological condition preventing informed consent

          -  Pregnant or breastfeeding woman

          -  PD-L1-status results unavailable

          -  Simultaneous participation of the patient in another clinical research trial
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall Response Rate (ORR) according to the PD-L1-expression rate (threshold set at 1%)
Time Frame:At 24 months
Safety Issue:
Description:ORR (Complete and Partial Responses) will be expressed as number, percentage and 95% confidence interval, calculated with the exact method. The evaluation of ORR, according to PD-L1-expression rate, using RECIST criteria 1.1, will be performed by the investigator in each center. A panel of French Lung Cancer Group investigators meeting 3 times/year will then validate it by a second reading.

Secondary Outcome Measures

Measure:Disease-control rate (DCR)
Time Frame:up to 24 months
Safety Issue:
Description:The DCR (complete and partial responses + stabilized disease using RECIST criteria 1.1) will be expressed as number, percentage and 95% confidence interval, calculated with the exact method, for the entire population, then by subgroups according to the PD-L1-expression rate, and histological type (adenocarcinoma versus squamous-cell).
Measure:Overall survival
Time Frame:over 24 months
Safety Issue:
Description:Overall survival over 24 months will be described using the Kaplan-Meier method. Log-rank tests will be used to analyze subgroups according to PD-L1-expression rate, then histological type (adenocarcinoma versus squamous-cell). Survival medians, in the overall population and according to PD-L1-expression rate, then histological type (adenocarcinoma versus squamous-cell) will be calculated.
Measure:Progression-free survival
Time Frame:over 24 months
Safety Issue:
Description:Progression-free survival over 24 months will be described with the Kaplan-Meier method. Log-rank tests will be used to analyze subgroups according to PD-L1-expression rate, then histological type (adenocarcinoma versus squamous-cell). Progression-free survival medians, in the overall population and according to PD-L1-expression rate, then histological type (adenocarcinoma versus squamous-cell) will be calculated.
Measure:Overall Response Rate for the entire population
Time Frame:At 24 months
Safety Issue:
Description:The 24-month Overall Response Rate (Complete and Partial Responses using RECIST criteria 1.1) for the entire population, then according to histological type (adenocarcinoma versus squamous-cell) will be expressed as number, percentage and 95% confidence interval, calculated with the exact method.
Measure:Overall Response Rate according to the histological type (adenocarcinoma versus squamous cell)
Time Frame:At 24 months
Safety Issue:
Description:The 24-month Overall Response Rate (Complete and Partial Responses using RECIST criteria 1.1) for the entire population, then according to histological type (adenocarcinoma versus squamous-cell) will be expressed as number, percentage and 95% confidence interval, calculated with the exact method.
Measure:Time to the first Skeletal-Related Event in months
Time Frame:Over 24 months
Safety Issue:
Description:The time to an Skeletal-Related Event will be estimated with the Kaplan-Meier method over 24 months of follow-up. Skeletal-Related Event are defined as pathological fractures, medullary compression, analgesic radiotherapy, preventive and/or analgesic surgery and hypercalcemia.
Measure:Incidence of adverse events, serious adverse events, deaths and biological abnormalities
Time Frame:up to 24 months
Safety Issue:
Description:Scored according to NCI CTCAE V4.0 terminology

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Centre Hospitalier de la Région d'Annecy

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