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

• Status: Recruiting
• Trial end date: 2023-12-31
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Centre Hospitalier Annecy Genevois; Centre Hospitalier de la Région d'Annecy
• Collaborator: French Lung Cancer Group
• Treatments: Antibodies, Monoclonal; Denosumab; Nivolumab

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 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