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

NCT03669523 | Completed Phase 2 DMC

• 2 other identifiers: P_2017_0072018-001105-85
• Study Type: interventional
• Target: 82
• Locations: 1 country
• Sites: 27

Brief 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.

Conditions

Carcinoma, Non-Small-Cell Lung; Bone Metastases

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (7)

• Disease-control rate (DCR)

  up to 24 months

• Overall survival

  over 24 months

• Progression-free survival

  over 24 months

• Overall Response Rate for the entire population

  At 24 months

• Overall Response Rate according to the histological type (adenocarcinoma versus squamous cell)

  At 24 months

Study Arms (1)

Denosumab-nivolumab combination

EXPERIMENTAL

Both drugs to be continued until progression or unacceptable toxicity and for a maximum of two years

Drug: Denosumab-nivolumab combination

Interventions

Denosumab-nivolumab combination DRUG

* Denosumab: 120 mg every 4 weeks subcutaneously * Nivolumab: 240mg intravenously on day 1 every 2 weeks

Denosumab-nivolumab combination

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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;
• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Centre Hospitalier Annecy Genevois: lead
• French Lung Cancer Group: collaborator

Study Sites (27)

CH du Pays d'Aix

Aix-en-Provence, 13616, France

Location

Chu Angers

Angers, 49033, France

Location

Centre Hospitalier de Beauvais

Beauvais, 60021, France

Location

Centre Hospitalier Fleyriat

Bourg-en-Bresse, 01012, France

Location

CHU Morvan - Institut de Cancérologie et d'Hématologie

Brest, 29609, France

Location

CH Intercommunal

Créteil, 94010, France

Location

Ch Intercommunal Elbeuf Louvier Val de Reuil

Elbeuf, 76503, France

Location

CH Intercommunal des Alpes du Sud

Gap, 05000, France

Location

Hôpital Robert Boulin

Libourne, 33505, France

Location

Chu Dupuytren

Limoges, 87042, France

Location

CH Marne La Vallée

Marne La Vallée, 77600, France

Location

Hopital Européen

Marseille, 13003, France

Location

Hopital Nord APHM

Marseille, 13915, France

Location

CH Meaux

Meaux, 77108, France

Location

Centre Catalan d'Oncologie

Perpignan, 66000, France

Location

CH Annecy-Genevois

Pringy, 74374, France

Location

CHU Hôpital Pontchailloux

Rennes, 35033, France

Location

CHU Rouen

Rouen, 76031, France

Location

CHU La Réunion - Site de Bellepierre

Saint-Denis, 97411, France

Location

Groupe Hospitalier Sud Réunion - CHU de la Réunion

Saint-Pierre, 97410, France

Location

Institut de Cancérologie de la Loire

Saint-Priest-en-Jarez, 42271, France

Location

CLCC Paul Strauss

Strasbourg, 67000, France

Location

Centre Hospitalier de Bigorre

Tarbes, 65013, France

Location

Hôpital d'Instruction des Armées Saint-Anne

Toulon, 83041, France

Location

CHITS Toulon Sainte-Musse

Toulon, 83056, France

Location

Hôpital André Mignot Centre Hospitalier de Versailles

Versailles, 78157, France

Location

CH Villefranche sur Saone

Villefranche-sur-Saône, 69655, France

Location

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases

Study Officials

• Chantal Decroisette, MD

  CH Annecy Genevois

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: National (French), multicenter, prospective, open, single-arm phase II study

Study Record Dates

• First Submitted: September 5, 2018
• First Posted: September 13, 2018
• Study Start: November 6, 2018
• Primary Completion: October 19, 2023
• Study Completion: October 19, 2023
• Last Updated: February 13, 2025

Record last verified: 2025-02

Locations

FR (27)