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

Carcinoma, Non-Small-Cell Lung Clinical Trial

— 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 Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03669523
• Other study ID #: P_2017_007
• Secondary ID: 2018-001105-85
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: November 6, 2018
• Est. completion date: December 31, 2024

Study information

• Verified date: July 2022
• Source: Centre Hospitalier Annecy Genevois
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 82
• Est. completion date: December 31, 2024
• Est. primary completion date: December 31, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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 =1.5×109/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

• 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

Related Conditions & MeSH terms

• Bone Marrow Diseases
• Bone Metastases
• Bone Neoplasms
• Carcinoma, Non-Small-Cell Lung
• Neoplasm Metastasis

Intervention

Drug:
• Denosumab-nivolumab combination
Denosumab: 120 mg every 4 weeks subcutaneously Nivolumab: 240mg intravenously on day 1 every 2 weeks

Locations

Country	Name	City	State
France	CH du Pays d'Aix	Aix-en-Provence
France	Chu Angers	Angers
France	Centre Hospitalier de Beauvais	Beauvais
France	Centre Hospitalier Fleyriat	Bourg-en-Bresse
France	CHU Morvan - Institut de Cancérologie et d'Hématologie	Brest
France	CH Intercommunal	Créteil
France	Ch Intercommunal Elbeuf Louvier Val de Reuil	Elbeuf
France	CH Intercommunal des Alpes du Sud	Gap
France	Hôpital Robert Boulin	Libourne
France	Chu Dupuytren	Limoges
France	CH Marne La Vallée	Marne-La-Vallée
France	Hopital Européen	Marseille
France	Hopital Nord APHM	Marseille
France	CH Meaux	Meaux
France	Centre Catalan d'Oncologie	Perpignan
France	CH Annecy-Genevois	Pringy
France	CHU Hôpital Pontchailloux	Rennes
France	CHU Rouen	Rouen
France	CHU La Réunion - Site de Bellepierre	Saint-Denis
France	Groupe Hospitalier Sud Réunion - CHU de la Réunion	Saint-Pierre
France	Institut de Cancérologie de la Loire	Saint-Priest-en-Jarez
France	CLCC Paul Strauss	Strasbourg
France	Centre Hospitalier de Bigorre	Tarbes
France	CHITS Toulon Sainte-Musse	Toulon
France	Hôpital d'Instruction des Armées Saint-Anne	Toulon
France	Hôpital André Mignot Centre Hospitalier de Versailles	Versailles
France	CH Villefranche sur Saone	Villefranche-sur-Saône

Sponsors (2)

Lead Sponsor	Collaborator
Centre Hospitalier Annecy Genevois	French Lung Cancer Group

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall Response Rate (ORR) according to the PD-L1-expression rate (threshold set at 1%)	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.	At 24 months
Secondary	Disease-control rate (DCR)	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).	up to 24 months
Secondary	Overall survival	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.	over 24 months
Secondary	Progression-free survival	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.	over 24 months
Secondary	Overall Response Rate for the entire population	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.	At 24 months
Secondary	Overall Response Rate according to the histological type (adenocarcinoma versus squamous cell)	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.	At 24 months
Secondary	Time to the first Skeletal-Related Event in months	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.	Over 24 months
Secondary	Incidence of adverse events, serious adverse events, deaths and biological abnormalities	Scored according to NCI CTCAE V4.0 terminology	up to 24 months