MelanomaPhase 2NIRVANANCT02799901
Nivolumab Plus Radiotherapy in Advanced Melanoma
A Phase 2 study testing Nivolumab and hypofractionned radiotherapy in people with Melanoma, run by Centre Hospitalier Universitaire de Nice at 14 sites in France.
Trial summary
Combining nivolumab with conventional multisite high dose radiotherapy seems to be an interesting approach that could increase the antitumoral effect of nivolumab by increasing the diversity and quantity of tumoral antigen presentation thanks to radiotherapy. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Melanoma
- What is being tested?
- Nivolumab and hypofractionned radiotherapy
- Type of treatment
- Injection or infusion, Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 72 participants
- Where
- 14 sitesFrance
- Study dates
- 3 Mar 2017to 28 Jul 2021
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Willing and able to give written informed consent
- Men and women, ≥ 18 years of age
- Histologically confirmed Stage III (unresectable) or Stage IV melanoma. Unknown primary melanoma will be accepted.
- Measurable disease by CT per RECIST 1.1 criteria
- Indication of radiotherapy
- Patient MUST be untreated for his/her Stage III (unresectable) or Stage IV melanoma
Show all 14Show fewer
- Prior treatment with INTERFERON in the adjuvant setting is authorized.
- BRAF status must be determinate but patient will be eligible regardless the status (BRAF wildtype and BRAF V600 mutation positive patients could be included)
- A pre-treatment recent core, excision or punch biopsy must be provided for PD-L1 status determination prior to start the treatment and for exploratory biomarker analyses. The biopsy must be from an unresectable or metastatic site, and the subject must have had no intervening systemic therapy between the time of biopsy and the start of inclusion
- Patient must consent to allow the acquisition of existing formalin-fixed paraffin-embedded (FFPE) material (" archival ") (block or a minimum of 10 unstained slides) if available, for performance of correlatives studies
- Subjects must consent to allow the acquisition of blood samples: one during the week before the first nivolumab injection; the second 15 days +- 2 days after the first injection of nivolumab; the third between 15 and 30 days after the first radiotherapy session and the fourth at relapse, for performance of correlative studies,
- Eastern Cooperative Oncology Group (ECOG) Performance Status ≤1
- Within the last 2 weeks prior to study day 1 the following laboratory parameters, which should be within the ranges specified:
- Subjects affiliated to an appropriate social security system NB: Patients will be included regardless of the level of LDH.
Who cannot join
- The patient requires concomitant chronic treatment with systemic corticosteroids or any other immunosuppressive agents 7 days prior to inclusion,
- Patient with brain(s) metastase(s), symptomatic(s) or not,
- Ocular or mucosal melanoma (unknown primary melanoma will be accepted),
- The patient has concurrent severe medical problems, unrelated to the malignancy, that would significantly limit full compliance with the study or expose the patient to unacceptable risk such as but not limited to: Cardiac insufficiency (III or IV as per NYHA classification), Renal insufficiency, ongoing infection,
- Subjects with previous malignancies (except non-melanoma skin cancers, in situ bladder cancer, gastric or colon cancers, cervical cancers/dysplasia or breast carcinoma in situ) are excluded unless a complete remission was achieved at least 2 years prior to study entry and no additional therapy is required or anticipated to be required during the study period,
- Uncontrolled infectious diseases - requires negative tests for clinically suspected HIV, hepatitis B virus (HBV) and hepatitis C virus (HCV). If positive results are not indicative of true active or chronic infection, the subject may enter the study after discussion and agreement between the Investigator and the Medical Monitor,
Show all 15Show fewer
- Active Autoimmune disease: subjects with a documented history of inflammatory bowel disease, including ulcerative colitis and Crohn's disease are excluded from this study as are subjects with a history of symptomatic disease (e.g., rheumatoid arthritis, systemic progressive sclerosis [scleroderma], Systemic Lupus Erythematosus, autoimmune vasculitis [e.g., Wegener's Granulomatosis]); subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll,
- Subjects with motor neuropathy considered of autoimmune origin (e.g., Guillain Barré Syndrome) are excluded from this study,
- Previous treatment with, chemotherapy, a CTLA-4 or PD-1/PD-L1 antagonist agent, including treatment in adjuvant setting for immunotherapy,
- The patient has psychiatric or addictive disorders that may compromise his/her ability to give informed consent or to comply with the trial procedures,
- Lack of availability for clinical follow-up assessments,
- Pregnant or lactating women (a blood pregnancy test will be conducted) and effective contraception will be used throughout the treatment for women of childbearing age,
- Participation in another clinical trial protocol within 30 days prior to enrolment,
- Persons protected by a legal regime (guardianship, trusteeship),
- Vulnerable patients, patients kept in detention
Trial locations and contacts
14 sites in 1 country.
14 sites in 1 country
France14 sites
CHU d'Amiens
Amiens
CH d'Annecy
Annecy
CHRU de Besançon
Besançon
Hôpital Ambroise Paré
Boulogne-Billancourt
Hôpital Avicenne
Boulogne-Billancourt
CHU Hôpital Clemenceau
Caen
CHU de Clermont Ferrand
Clermont-Ferrand
CHRU de Lille
Lille
Hôpital Dupuytren
Limoges
Hospices civiles de Lyon
Lyon
CHU La Timone
Marseille
CHU de NIce
Nice, 06200
Hôpital St Louis
Paris
CHU de Rouen
Rouen
About this study
Official title: Nivolumab in Combination With High Dose Radiotherapy at Varied Tumor Sites in Advanced Melanoma and no Prior Antitumoral Treatment
Combining nivolumab with conventional multisite high dose radiotherapy seems to be an interesting approach that could increase the antitumoral effect of nivolumab by increasing the diversity and quantity of tumoral antigen presentation thanks to radiotherapy. Multifractionated high dose radiotherapy (HR) targeting various tumor sites could also increase occurrence of tumor mutations and the diversity of the T-cell receptor repertoire of intratumoral T cells.
The purpose of this study is to combine nivolumab with 3 fractions of HR of one metastasis for each tumor site (defined as skin/muscle, thoracic, abdomen, bone, other).
The investigators hypothesize that combining nivolumab with multisite, multifractionated HR increases the overall survival rate at 1 year compared to published data with nivolumab alone.
Read the detailed description
Recent progress has been made in advanced melanoma with drug targeting immune system such as ipilimumab targeting CTLA-4 and nivolumab targeting PD-1. Some case reports and preclinical data suggested that the antitumoral immune response of these immune check point inhibitors (ipilimumab and nivolumab as well) could be enhanced if associated with massive tumoral antigen release in the blood stream, due to local treatment such as high dose radiotherapy (HR). The first rigorous scientific demonstration of this phenomenon was done by Demaria et al. They showed that irradiation of xenograft tumor could induce decrease of tumoral growth of a non-irradiated other xenograt tumor. This effect was due to immune response to irradiation but it only occured when immune system was modulated by CTLA-4 inhibition. In that experiences CTLA4 and radiation actions were synergistic.
Dovedi et al. also reported that targeting PD-1/PD-L1 pathway have greater anti-tumor efficacy if concomitant radiotherapy was given and especially if radiotherapy was multifractionated.
Very interestingly the fractionated radiotherapy also induced huge increase of tumoral PD-L1 expression by three times 5 days after beginning of radiotherapy. This could explain the synergistic impact of this strategy.
At least eight clinical studies are ongoing, testing the combination of CTLA-4 blockade with radiotherapy in metastatic melanoma or other tumors, with various treatment schedules either for ipilimumab (3 or 10 mg/kg) or radiotherapy (before or after ipilimumab, fractions of 6 to 8 Gy; total body irradiation or treatment of only one metastasis).
One study (NCT01565837) is a phase II study that analyses the efficacy of 10mg/kg ipilimumab (every 3 weeks) associated with HR for all metastatic sites but only for oligometastatic patients (< 6 metastasis), which reflects only a minority of metastatic melanoma patients.
Such strategy is of high interest because it takes into account the putative tumoral heterogeneity which could lead to failure of the association of nivolumab with the irradiation of only one tumor site.
The investigators propose to combine nivolumab with 3 fractions of HR of one metastasis for each tumor site (defined as skin/muscle, thoracic, abdomen, bone, other).They have chosen 3 fractions instead of only 1 for each tumor site because of preclinical data in mice showing that one fraction is less efficient than several fractions to stimulate the immune system and kill tumoral cells. The increase of the number of fractions could also lead to an increase of the diversity of tumoral antigens released in the blood stream which could also favors diversity of the T-cell receptor repertoire of intratumoral T cells.
In our protocol dose constraint for each tissue type can be easily achieved with the 3 X 6 Gy schedule without excess of toxicity.
In conclusion the present protocol aims to increase the quantity and diversity of released tumoral antigens by providing multisite, multifractionated HR during nivolumab treatment in advanced untreated melanoma patients.
The investigators hypothesize that combining nivolumab with multisite, multifractionated HR increases the overall survival rate at 1 year compared to published data with nivolumab alone.
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
NivolumabBiological
Injection of nivolumab
hypofractionned radiotherapyRadiation
radiation
| Study group | Role | What they receive |
|---|---|---|
| Patient | Experimental | patient with Advanced melanoma Receives: Biological: Nivolumab; Radiation: hypofractionned radiotherapy |
What is being measured
The primary outcome is the main question the study is designed to answer.
overall survival
to increase the overall survival rate at 1 year with the combination of nivolumab and radiotherapy compared to nivolumab alone for patients with advanced melanoma
Measured: 1 year
Secondary outcomes (12)
the rate of progression-free survival
Measured: at 6 months
the rate of progression-free survival
Measured: at 1 year
the rate of progression-free survival
Measured: at 2 years
Global progression free survival (PFS) rate
Measured: at 6 months
Global progression free survival (PFS) rate
Measured: at 1 year
Global progression free survival (PFS) rate
Measured: at 2 years
global PFS rate
Measured: at 6 months
global PFS rate
Measured: at 1 year
global PFS rate
Measured: at 2 year
overall survival
Measured: at 2 years
disease control rate (DCR)
Measured: at 2 years
predictive factors for response
Measured: at 2 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted15 Jun 2016 (estimated)
- Study start3 Mar 2017
- Primary completion28 Jul 2021
- Study completion28 Jul 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for MelanomaStudies of the same condition, open and under way.
- More trials run by Centre Hospitalier Universitaire de NiceThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 72 participants (actual)
Sponsor and investigators
- Lead sponsor
- Centre Hospitalier Universitaire de Nice
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Henri MONTAUDIE, PH, Principal investigator, Centre Hospitalier Universitaire de Nice
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02799901
- Sponsor's protocol ID
- 16-PP-02
- Acronym
- NIRVANA
- Status last verified
- Nov 2023
- First submitted
- 30 May 2016
- Last updated
- 15 Nov 2023
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Gerard A, Doyen J, Cremoni M, Bailly L, Zorzi K, Ruetsch-Chelli C, Brglez V, Picard-Gauci A, Troin L, Esnault VLM, Passeron T, Montaudie H, Seitz-Polski B. Baseline and early functional immune response is associated with subsequent clinical outcomes of PD-1 inhibition therapy in metastatic melanoma patients. J Immunother Cancer. 2021 Jun;9(6):e002512. doi: 10.1136/jitc-2021-002512.
PubMed 34088741
Study at a glance
From the registry record, last updated by the sponsor on 15 Nov 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Nivolumab in Combination With High Dose Radiotherapy at Varied Tumor Sites in Advanced Melanoma and no Prior Antitumoral Treatment
- ClinicalTrials.gov ID
- NCT02799901
- Acronym / sponsor ID
- NIRVANA / 16-PP-02
- Conditions
- Melanoma
- Keywords
- advanced melanoma, high dose radiotherapy, Nivolumab
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 72 participants (actual)
- Lead sponsor
- Centre Hospitalier Universitaire de NiceUniversity, hospital or other
- Study start
- 3 Mar 2017 (actual)
- Primary completion
- 28 Jul 2021 (actual)
- Study completion
- 28 Jul 2021 (actual)
- First posted
- 15 Jun 2016 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Combining nivolumab with conventional multisite high dose radiotherapy seems to be an interesting approach that could increase the antitumoral effect of nivolumab by increasing the diversity and quantity of tumoral antigen presentation thanks to radiotherapy. Multifractionated high dose radiotherapy (HR) targeting various tumor sites could also increase occurrence of tumor mutations and the diversity of the T-cell receptor repertoire of intratumoral T cells.
The purpose of this study is to combine nivolumab with 3 fractions of HR of one metastasis for each tumor site (defined as skin/muscle, thoracic, abdomen, bone, other).
The investigators hypothesize that combining nivolumab with multisite, multifractionated HR increases the overall survival rate at 1 year compared to published data with nivolumab alone.
Detailed description
Recent progress has been made in advanced melanoma with drug targeting immune system such as ipilimumab targeting CTLA-4 and nivolumab targeting PD-1. Some case reports and preclinical data suggested that the antitumoral immune response of these immune check point inhibitors (ipilimumab and nivolumab as well) could be enhanced if associated with massive tumoral antigen release in the blood stream, due to local treatment such as high dose radiotherapy (HR). The first rigorous scientific demonstration of this phenomenon was done by Demaria et al. They showed that irradiation of xenograft tumor could induce decrease of tumoral growth of a non-irradiated other xenograt tumor. This effect was due to immune response to irradiation but it only occured when immune system was modulated by CTLA-4 inhibition. In that experiences CTLA4 and radiation actions were synergistic.
Dovedi et al. also reported that targeting PD-1/PD-L1 pathway have greater anti-tumor efficacy if concomitant radiotherapy was given and especially if radiotherapy was multifractionated.
Very interestingly the fractionated radiotherapy also induced huge increase of tumoral PD-L1 expression by three times 5 days after beginning of radiotherapy. This could explain the synergistic impact of this strategy.
At least eight clinical studies are ongoing, testing the combination of CTLA-4 blockade with radiotherapy in metastatic melanoma or other tumors, with various treatment schedules either for ipilimumab (3 or 10 mg/kg) or radiotherapy (before or after ipilimumab, fractions of 6 to 8 Gy; total body irradiation or treatment of only one metastasis).
One study (NCT01565837) is a phase II study that analyses the efficacy of 10mg/kg ipilimumab (every 3 weeks) associated with HR for all metastatic sites but only for oligometastatic patients (< 6 metastasis), which reflects only a minority of metastatic melanoma patients.
Such strategy is of high interest because it takes into account the putative tumoral heterogeneity which could lead to failure of the association of nivolumab with the irradiation of only one tumor site.
The investigators propose to combine nivolumab with 3 fractions of HR of one metastasis for each tumor site (defined as skin/muscle, thoracic, abdomen, bone, other).They have chosen 3 fractions instead of only 1 for each tumor site because of preclinical data in mice showing that one fraction is less efficient than several fractions to stimulate the immune system and kill tumoral cells. The increase of the number of fractions could also lead to an increase of the diversity of tumoral antigens released in the blood stream which could also favors diversity of the T-cell receptor repertoire of intratumoral T cells.
In our protocol dose constraint for each tissue type can be easily achieved with the 3 X 6 Gy schedule without excess of toxicity.
In conclusion the present protocol aims to increase the quantity and diversity of released tumoral antigens by providing multisite, multifractionated HR during nivolumab treatment in advanced untreated melanoma patients.
The investigators hypothesize that combining nivolumab with multisite, multifractionated HR increases the overall survival rate at 1 year compared to published data with nivolumab alone.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Patient | Experimental | Biological: Nivolumab, Radiation: hypofractionned radiotherapypatient with Advanced melanoma |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (14 listed)
- Willing and able to give written informed consent
- Men and women, ≥ 18 years of age
- Histologically confirmed Stage III (unresectable) or Stage IV melanoma. Unknown primary melanoma will be accepted.
- Measurable disease by CT per RECIST 1.1 criteria
- Indication of radiotherapy
Key exclusion criteria (15 listed)
- The patient requires concomitant chronic treatment with systemic corticosteroids or any other immunosuppressive agents 7 days prior to inclusion,
- Patient with brain(s) metastase(s), symptomatic(s) or not,
- Ocular or mucosal melanoma (unknown primary melanoma will be accepted),
- The patient has concurrent severe medical problems, unrelated to the malignancy, that would significantly limit full compliance with the study or expose the patient to unacceptable risk such as but not limited to: Cardiac insufficiency (III or IV as per NYHA classification), Renal insufficiency, ongoing infection,
- Subjects with previous malignancies (except non-melanoma skin cancers, in situ bladder cancer, gastric or colon cancers, cervical cancers/dysplasia or breast carcinoma in situ) are excluded unless a complete remission was achieved at least 2 years prior to study entry and no additional therapy is required or anticipated to be required during the study period,
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| NivolumabInjection of nivolumab | Biological | Patient |
| hypofractionned radiotherapyradiation | Radiation | Patient |
Primary outcome
overall survival
Time frame: 1 year
to increase the overall survival rate at 1 year with the combination of nivolumab and radiotherapy compared to nivolumab alone for patients with advanced melanoma
12 secondary outcomes
the rate of progression-free survival
Time frame: at 6 months
the rate of progression-free survival
Time frame: at 1 year
the rate of progression-free survival
Time frame: at 2 years
Global progression free survival (PFS) rate
Time frame: at 6 months
Global progression free survival (PFS) rate
Time frame: at 1 year
Global progression free survival (PFS) rate
Time frame: at 2 years
global PFS rate
Time frame: at 6 months
global PFS rate
Time frame: at 1 year
global PFS rate
Time frame: at 2 year
overall survival
Time frame: at 2 years
disease control rate (DCR)
Time frame: at 2 years
predictive factors for response
Time frame: at 2 years
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 15 Nov 2023.
- Derived from this study: PubMed 34088741Gerard A, Doyen J, Cremoni M, Bailly L, Zorzi K, Ruetsch-Chelli C, Brglez V, Picard-Gauci A, Troin L, Esnault VLM, Passeron T, Montaudie H, Seitz-Polski B. Baseline and early functional immune response is associated with subsequent clinical outcomes of PD-1 inhibition therapy in metastatic melanoma patients. J Immunother Cancer. 2021 Jun;9(6):e002512. doi: 10.1136/jitc-2021-002512.
- Individual participant dataSharing planned: No
Related trials for Melanoma
RecruitingPhase 1/2
Study of INBRX-106 and INBRX-106 in Combination With Pembrolizumab (Keytruda®) in Subjects With Locally Advanced or Metastatic Solid Tumors (Hexavalent OX40 Agonist)
Solid Tumor, Non-Small Cell Lung Cancer
RecruitingPhase 1
IL-17 Blockade to Decrease irAEs (REPLAY)
Metastatic Melanoma
Enrolling by invitationObservational study
Natural History Study of Early Life Exposures in Agriculture (ELEA)
Prostate Cancer, Leukemia
RecruitingPhase 1
A Feasibility Study Utilizing Immune Recall to Increase Response to Checkpoint Therapy
Melanoma
Active, not recruitingPhase 1/2
A Study of Dapansutrile Plus Pembrolizumab in Patients With PD-1 Refractory Advanced Melanoma
Melanoma
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Henri MONTAUDIE, PH principal investigator
Centre Hospitalier Universitaire de Nice
14 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Nivolumab and hypofractionned radiotherapy in people with Melanoma, run by Centre Hospitalier Universitaire de Nice at 14 sites in France.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 14 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 15 Nov 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 14 sites in France. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
overall survival (time frame: 1 year). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02799901, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 15 Nov 2023.