Denosumab and Nivolumab Combination as 2d-line Therapy in Stage IV NSC Lung Cancer With Bone Metastases (DENIVOS) (DENIVOS)
|The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.|
|ClinicalTrials.gov Identifier: NCT03669523|
Recruitment Status : Active, not recruiting
First Posted : September 13, 2018
Last Update Posted : July 20, 2022
- Study Details
- Tabular View
- No Results Posted
- How to Read a Study Record
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.
|Condition or disease||Intervention/treatment||Phase|
|Carcinoma, Non-Small-Cell Lung Bone Metastases||Drug: Denosumab-nivolumab combination||Phase 2|
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||82 participants|
|Intervention Model:||Single Group Assignment|
|Intervention Model Description:||National (French), multicenter, prospective, open, single-arm phase II study|
|Masking:||None (Open Label)|
|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|
|Actual Study Start Date :||November 6, 2018|
|Estimated Primary Completion Date :||December 31, 2023|
|Estimated Study Completion Date :||December 31, 2024|
Experimental: Denosumab-nivolumab combination
Both drugs to be continued until progression or unacceptable toxicity and for a maximum of two years
Drug: Denosumab-nivolumab combination
- Overall Response Rate (ORR) according to the PD-L1-expression rate (threshold set at 1%) [ Time Frame: At 24 months ]
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.
- Disease-control rate (DCR) [ Time Frame: up to 24 months ]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).
- Overall survival [ Time Frame: over 24 months ]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.
- Progression-free survival [ Time Frame: over 24 months ]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.
- Overall Response Rate for the entire population [ Time Frame: At 24 months ]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.
- Overall Response Rate according to the histological type (adenocarcinoma versus squamous cell) [ Time Frame: At 24 months ]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.
- Time to the first Skeletal-Related Event in months [ Time Frame: Over 24 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.
- Incidence of adverse events, serious adverse events, deaths and biological abnormalities [ Time Frame: up to 24 months ]Scored according to NCI CTCAE V4.0 terminology
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
|Ages Eligible for Study:||18 Years and older (Adult, Older Adult)|
|Sexes Eligible for Study:||All|
|Accepts Healthy Volunteers:||No|
- 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
- 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
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03669523
|Principal Investigator:||Chantal Decroisette, MD||CH Annecy Genevois|
|Responsible Party:||Centre Hospitalier Annecy Genevois|
|Other Study ID Numbers:||
2018-001105-85 ( EudraCT Number )
|First Posted:||September 13, 2018 Key Record Dates|
|Last Update Posted:||July 20, 2022|
|Last Verified:||July 2022|
|Individual Participant Data (IPD) Sharing Statement:|
|Plan to Share IPD:||Undecided|
|Studies a U.S. FDA-regulated Drug Product:||No|
|Studies a U.S. FDA-regulated Device Product:||No|
Carcinoma, Non-Small-Cell Lung
Bone Marrow Diseases
Neoplasms by Site
Respiratory Tract Neoplasms
Respiratory Tract Diseases
Antineoplastic Agents, Immunological
Immune Checkpoint Inhibitors
Molecular Mechanisms of Pharmacological Action
Bone Density Conservation Agents
Physiological Effects of Drugs