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

  • STATUS
    Recruiting
  • End date
    Jul 25, 2023
  • participants needed
    86
  • sponsor
    Centre Hospitalier Annecy Genevois
Updated on 25 January 2021
ct scan
renal function
cancer
carcinoma
growth factor
squamous cell carcinoma
x-rays
BRAF
metastasis
neutrophil count
liver metastasis
tumor cells
epidermal growth factor receptor
EGFR
brain metastases
docetaxel
bone scan
nivolumab
cancer chemotherapy
bisphosphonate
epidermal growth factor
stage iv non-small cell lung cancer
kidney function test
lung carcinoma
secondary malignant neoplasm of liver

Summary

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.

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.

Details
Condition Non-Small Cell Lung Cancer, Bone Metastases, Bone Metastasis
Treatment Denosumab-nivolumab combination
Clinical Study IdentifierNCT03669523
SponsorCentre Hospitalier Annecy Genevois
Last Modified on25 January 2021

Eligibility

Yes No Not Sure

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 known 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 1.5109/L and/or platelets 100109/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
Patient with asymptomatic brain metastases (treated or not) OR symptomatic brain metastases but adequately treated and controlled at the time of enrolment (without or with corticotherapy 10mg/day), can be included. 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 immunotherapy
Patients with symptomatic cerebral metastases not treated and not controlled
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
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