Melanoma (Skin)Phase 1/2CRIRINNCT03949153
Cryotherapy With in Situ Immunotherapy in Melanoma Metastasis
A Phase 1/2 study testing Nivolumab 10 MG/ML Intravenous Solution [OPDIVO], Cryotherapy and Ipilimumab Injection in people with Melanoma (Skin), run by University Hospital, Strasbourg, France at 1 site in France.
Trial summary
Melanoma is the deadliest form of skin cancer and its incidence has doubled every 20 years in France, where this cancer is responsible of more than 1600 deaths each year. Patients with early diagnosis have good prognosis and can be generally cured by surgery only. Advanced melanoma however has a very bad prognosis. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Melanoma (Skin)
- What is being tested?
- Nivolumab 10 MG/ML Intravenous Solution [OPDIVO], Cryotherapy and Ipilimumab Injection
- Type of treatment
- Injection or infusion, Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 19 participants
- Where
- 1 siteFrance
- Study dates
- 16 Aug 2019to 18 Mar 2022
- Phase
- Phase 1/2
- 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
- Subject with previously treated (or unknown) primary stage IIIB/IIIC melanoma with lymph node metastases, with at least one ≥1 cm3 that is accessible to cryotherapy under interventional radiology (IR), assessed at the inclusion visit (V1).
- ECOG performance status (0 to 2) at the selection visit (V0)
- If woman or man are of reproductive age, they should have no desire to procreate for the duration of their participation in the study, agreeing to use a highly effective contraception method*, with at least one barrier method (condom or diaphragm), and for 5 months after the infusion of Nivolumab for women and 7 months for men
- Leukocytes >2000/mm3, neutrophils >1500/mm3, platelets >100,000/mm3, haemoglobin >9g/dl at the selection visit (V0)
- Total bilirubin <1.5 mg/dl except for patients with Gilbert's syndrome who may have total bilirubin <3.0 mg/dl at the selection visit (V0)
- Liver function: SGOT, SGPT, ALP <2.5 N, if liver metastases SGOT and SGPT <5 N at the selection visit (V0)
- Serum creatinine <1.5 N or creatinine clearance >40 ml/min (using the Cockcroft-Gault equation) at the selection visit (V0)
Who cannot join
- Pregnancy (women of childbearing potential : positive blood pregnancy test at the selection visit (V0) or breastfeeding
- History of hypersensitivity to ipilimumab, nivolumab or one of the excipients
- History of severe hypersensitivity to a monoclonal antibody
- History of positive tests for HIV or Acquired Immunodeficiency Syndrome (HIV assessed at the selection visit (V0))
- Positive tests for HCV or HBV indicating an acute or chronic infection at the selection visit (V0)
- Patient presenting with an active, known or suspected autoimmune disease. The following, however, may participate:
Show all 22Show fewer
- patient with type 1 diabetes or hypothyroidism requiring substitute hormone therapy only;
- patient with psoriasis, vitiligo or alopecia;
- patient with conditions that are not known to reoccur without an exogenous triggering agent.
- History of active neoplasia during the last 3 years with the exception of localised curable cancers considered to be cured, such as basal or squamous cell carcinomas, superficial bladder cancer and prostate, colon or breast carcinoma in situ.
- Active systemic infection
- Patient with a condition requiring systemic steroid treatment (at a dose >10 mg/prednisone equivalent or at unstable dose) or another immunosuppressant within/following 14 days of study drugs administration. Inhaled steroids and treatment for adrenal insufficiency, however, are permitted.
- Contraindication for the cryotherapy procedure as assessed by the radiologist (due to tumour size or proximity to a vascular or nerve structure giving the procedure an unacceptable level of risk) at the inclusion visit (V1)
- Clotting disorder that may interfere with the cryoablation, assessed at the selection visit (V0)
- Contraindication for MRI with gadolinium-based contrast media
- History of uveal melanoma
- Patient having received prior treatment for their melanoma, in particular, patient previously treated with interferon fewer than 3 months ago or with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD-137 or anti-CTLA-4 antibody. Patients who have undergone primary melanoma surgery and the excision of in-transit metastases, as well as adjuvant therapy with interferon if completed over 3 months ago are eligible.
- Contraindication for general and/or local anaesthesia
- Patient operated on under general anaesthesia, within the 4 weeks prior to the planned Nivolumab infusion.
- Patient operated on epidural anaesthesia, within the 72 h prior to the planned Nivolumab infusion.
- History of anterior organ transplantation, including allograft stem cell transplantation.
- History of interstitial lung disease
Trial locations and contacts
1 site in 1 country.
France1 site
Clinique Dermatologique/Radiologie Interventionnelle/Urologie/Gynécologie-CHU de Strasbourg/ICANS
Strasbourg, 67091
About this study
Official title: Cryotherapy Under Interventional Radiology Combined With in Situ Ipilimumab and a Flat Dose of Nivolumab in Stage IIIB/C Melanoma. Prospective Proof of Concept Study.
Melanoma is the deadliest form of skin cancer and its incidence has doubled every 20 years in France, where this cancer is responsible of more than 1600 deaths each year.
Patients with early diagnosis have good prognosis and can be generally cured by surgery only. Advanced melanoma however has a very bad prognosis.
Read more
Loco-regional lymph nodes are usually the first distant localization in metastatic melanoma. Lymph node dissection is then the recommended treatment, although it's impact on survival has never been proven.
In the same way, the benefit risk profile of interferon as adjuvant treatment after lymph node dissection is still much debated.
Recently, new treatments either with immunotherapy (ipilimumab, nivolumab) or by the targeted therapy dabrafenib/trametinib in patients with BRAF mutation have shown an impact on survival in the adjuvant setting after lymph node dissection.
But, it has not yet been established if this strategy has a benefit gain compared to starting those treatments only in the metastatic setting after watchful follow-up.
Moreover, if these novel therapies (targeted therapies: TT, immunotherapies : IT) demonstrated for the first time a real benefit in terms of survival or of responses rates in melanoma, physicians and patients had to address new problems, such as the management of unusual adverse events.
Partial and dissociated responses can also be seen with those new treatments. Some patients will have complete response in some lesions, stabilization in others and progression in a few. It is to be expected that one of the real key points of this therapy is to be found here, as this situation is commonly seen, and it would probably be a poor choice to stop a treatment that is globally effective for progression of only 1 or 2 lesions, in a patient otherwise stabilized.
That is the context in which interventional radiology (IR) should be considered as an extremely efficient option. IR is a real medical revolution in the last 2 decades.
It provides not only the opportunity to determine the characteristics of residual lesion (fibrosis, necrosis, metastasis, or sarcoidosis,…) by biopsy, but allows also their targeted destruction through different technics (cryotherapy, radiofrequency, laser,…).
The investigators are fortunate to have in their institution one of the best IR department of the world (headed by Prof. Afshin GANGI), with a technical platform unique in Europe that allows IR through ultrasound, scan, petscan and MRI.
To the best of their knowledge, Immunotherapy associated with IR has not been performed so far.
This association could in theory:
- Combine immunotherapy with tumoral necrosis, which inherently increases the effects of immunotherapy by massive tumoral leakage of danger signals and tumoral antigens;
- Allow direct injection in targeted zones, where the beneficial effect is desired, and thus increase the expected immune response;
- Reduce side effects related to immunotherapy, by reducing quantities injected; which seems particularly important in the (neo)-adjuvant setting.
That's why the investigators are willing to conduct this pilot project, the objectives of which are:
- Providing a proof of the feasibility of this association,
- Obtaining preliminary insights on the effects on non-targeted lesions,
- Adding a translational research to establish the effect on tumor antigenic expression and the immune response.
- Conditions
- Melanoma (Skin)
- Being tested
- Nivolumab 10 MG/ML Intravenous Solution [OPDIVO], Cryotherapy, Ipilimumab Injection
- Medical subject headings
- Melanoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Nivolumab 10 MG/ML Intravenous Solution [OPDIVO]Drug
Single Nivolumab 240 mg infusion at D0
CryotherapyProcedure or surgery
Cryotherapy using interventional radiology of metastatic lymphadenopathy at D1
Ipilimumab InjectionDrug
In situ injection with ipilimumab at D2.
| Study group | Role | What they receive |
|---|---|---|
| Experimental arm | Experimental | Single Nivolumab 240 mg infusion at D0, followed by cryotherapy using interventional radiology of metastatic lymphadenopathy at D1 and in situ injection with ipilimumab at D2. Receives: Drug: Nivolumab 10 MG/ML Intravenous Solution [OPDIVO]; Procedure: Cryotherapy; Drug: Ipilimumab Injection |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of failures linked to the procedure
Number of failures linked to the procedure, from all causes (unless the patient changes his/her mind = withdrawal from the study). In the context of this study, failure is defined as follows:
- Technically impossible to perform the cryoablation procedure, or
- Impossible to inject at least 2 ml of ipilimumab into the treated lymphadenopathy.
Measured: Day 1 (cryoablation) or Day 2 (ipilimumab injection)
Secondary outcomes (3)
Size of target and non-targeted lymphadenopathies
Measured: before (inclusion visit) and 4 to 7 weeks after the procedure (V5 visit).
Overall and progression-free survival
Overall and progression-free survival of this cohort with a recent historical cohort (similar patients at stages IIIB/C treated in the dermatology clinic 1 year earlier).
Measured: All along the study, until the end of study visit (6 months after the procedure)
Incidence of Treatment-Emergent Adverse Events
Number, nature and severity of adverse events and serious adverse events (according to NCI CTCAE) related to immune therapy and cryoablation
Measured: From Day 0 to the end of study visit (6 months after the procedure)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted14 May 2019
- Study start16 Aug 2019
- Primary completion20 Oct 2021
- Study completion18 Mar 2022
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 Melanoma (Skin)Studies of the same condition, open and under way.
- More trials run by University Hospital, Strasbourg, FranceThe 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 1/2
- Primary purpose
- Other
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 19 participants (actual)
Sponsor and investigators
- Lead sponsor
- University Hospital, Strasbourg, France
- Sponsor type
- University, hospital or other
- Collaborators
- Bristol-Myers Squibb
- Responsible party
- Sponsor
- Investigators
- Dan LIPSKER, MD PhD, Principal investigator, CHU de Strasbourg
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03949153
- Sponsor's protocol ID
- 7102
- Other IDs
- 2018-003521-28, 2018
- Acronym
- CRIRIN
- Status last verified
- Jun 2026
- First submitted
- 11 Apr 2019
- Last updated
- 5 Jun 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Braud A, Auloge P, Meyer N, Bouvrais C, Gharbi M, Lang H, Gangi A, Lipsker D. Neoadjuvant in Situ and Systemic Immunotherapy with Lymph Node Cryoablation in Resectable Stage III Melanoma Metastasis: a Proof-of-Concept Study. Cardiovasc Intervent Radiol. 2024 May;47(5):567-572. doi: 10.1007/s00270-024-03699-9. Epub 2024 Apr 3.
PubMed 38570342
Study at a glance
From the registry record, last updated by the sponsor on 5 Jun 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Cryotherapy Under Interventional Radiology Combined With in Situ Ipilimumab and a Flat Dose of Nivolumab in Stage IIIB/C Melanoma. Prospective Proof of Concept Study.
- ClinicalTrials.gov ID
- NCT03949153
- Acronym / sponsor ID
- CRIRIN / 7102
- Conditions
- Melanoma (Skin)
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 19 participants (actual)
- Lead sponsor
- University Hospital, Strasbourg, FranceUniversity, hospital or other
- Collaborators
- Bristol-Myers Squibb
- Study start
- 16 Aug 2019 (actual)
- Primary completion
- 20 Oct 2021 (actual)
- Study completion
- 18 Mar 2022 (actual)
- First posted
- 14 May 2019 (actual)
- 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.
Melanoma is the deadliest form of skin cancer and its incidence has doubled every 20 years in France, where this cancer is responsible of more than 1600 deaths each year.
Patients with early diagnosis have good prognosis and can be generally cured by surgery only. Advanced melanoma however has a very bad prognosis.
Loco-regional lymph nodes are usually the first distant localization in metastatic melanoma. Lymph node dissection is then the recommended treatment, although it's impact on survival has never been proven.
In the same way, the benefit risk profile of interferon as adjuvant treatment after lymph node dissection is still much debated.
Recently, new treatments either with immunotherapy (ipilimumab, nivolumab) or by the targeted therapy dabrafenib/trametinib in patients with BRAF mutation have shown an impact on survival in the adjuvant setting after lymph node dissection.
But, it has not yet been established if this strategy has a benefit gain compared to starting those treatments only in the metastatic setting after watchful follow-up.
Moreover, if these novel therapies (targeted therapies: TT, immunotherapies : IT) demonstrated for the first time a real benefit in terms of survival or of responses rates in melanoma, physicians and patients had to address new problems, such as the management of unusual adverse events.
Partial and dissociated responses can also be seen with those new treatments. Some patients will have complete response in some lesions, stabilization in others and progression in a few. It is to be expected that one of the real key points of this therapy is to be found here, as this situation is commonly seen, and it would probably be a poor choice to stop a treatment that is globally effective for progression of only 1 or 2 lesions, in a patient otherwise stabilized.
That is the context in which interventional radiology (IR) should be considered as an extremely efficient option. IR is a real medical revolution in the last 2 decades.
It provides not only the opportunity to determine the characteristics of residual lesion (fibrosis, necrosis, metastasis, or sarcoidosis,…) by biopsy, but allows also their targeted destruction through different technics (cryotherapy, radiofrequency, laser,…).
The investigators are fortunate to have in their institution one of the best IR department of the world (headed by Prof. Afshin GANGI), with a technical platform unique in Europe that allows IR through ultrasound, scan, petscan and MRI.
To the best of their knowledge, Immunotherapy associated with IR has not been performed so far.
This association could in theory:
- Combine immunotherapy with tumoral necrosis, which inherently increases the effects of immunotherapy by massive tumoral leakage of danger signals and tumoral antigens;
- Allow direct injection in targeted zones, where the beneficial effect is desired, and thus increase the expected immune response;
- Reduce side effects related to immunotherapy, by reducing quantities injected; which seems particularly important in the (neo)-adjuvant setting.
That's why the investigators are willing to conduct this pilot project, the objectives of which are:
- Providing a proof of the feasibility of this association,
- Obtaining preliminary insights on the effects on non-targeted lesions,
- Adding a translational research to establish the effect on tumor antigenic expression and the immune response.
Study design
- Primary purpose
- Other
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Experimental arm | Experimental | Drug: Nivolumab 10 MG/ML Intravenous Solution [OPDIVO], Procedure: Cryotherapy, Drug: Ipilimumab InjectionSingle Nivolumab 240 mg infusion at D0, followed by cryotherapy using interventional radiology of metastatic lymphadenopathy at D1 and in situ injection with ipilimumab at D2. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- Subject with previously treated (or unknown) primary stage IIIB/IIIC melanoma with lymph node metastases, with at least one ≥1 cm3 that is accessible to cryotherapy under interventional radiology (IR), assessed at the inclusion visit (V1).
- ECOG performance status (0 to 2) at the selection visit (V0)
- If woman or man are of reproductive age, they should have no desire to procreate for the duration of their participation in the study, agreeing to use a highly effective contraception method*, with at least one barrier method (condom or diaphragm), and for 5 months after the infusion of Nivolumab for women and 7 months for men
- Leukocytes >2000/mm3, neutrophils >1500/mm3, platelets >100,000/mm3, haemoglobin >9g/dl at the selection visit (V0)
- Total bilirubin <1.5 mg/dl except for patients with Gilbert's syndrome who may have total bilirubin <3.0 mg/dl at the selection visit (V0)
Key exclusion criteria (22 listed)
- Pregnancy (women of childbearing potential : positive blood pregnancy test at the selection visit (V0) or breastfeeding
- History of hypersensitivity to ipilimumab, nivolumab or one of the excipients
- History of severe hypersensitivity to a monoclonal antibody
- History of positive tests for HIV or Acquired Immunodeficiency Syndrome (HIV assessed at the selection visit (V0))
- Positive tests for HCV or HBV indicating an acute or chronic infection at the selection visit (V0)
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 |
|---|---|---|
| Nivolumab 10 MG/ML Intravenous Solution [OPDIVO]Single Nivolumab 240 mg infusion at D0 | Drug | Experimental arm |
| CryotherapyCryotherapy using interventional radiology of metastatic lymphadenopathy at D1 | Procedure or surgery | Experimental arm |
| Ipilimumab InjectionIn situ injection with ipilimumab at D2. | Drug | Experimental arm |
Primary outcome
Number of failures linked to the procedure
Time frame: Day 1 (cryoablation) or Day 2 (ipilimumab injection)
Number of failures linked to the procedure, from all causes (unless the patient changes his/her mind = withdrawal from the study). In the context of this study, failure is defined as follows: * Technically impossible to perform the cryoablation procedure, or * Impossible to inject at least 2 ml of ipilimumab into the treated lymphadenopathy.
3 secondary outcomes
Size of target and non-targeted lymphadenopathies
Time frame: before (inclusion visit) and 4 to 7 weeks after the procedure (V5 visit).
Overall and progression-free survival
Time frame: All along the study, until the end of study visit (6 months after the procedure)
Incidence of Treatment-Emergent Adverse Events
Time frame: From Day 0 to the end of study visit (6 months after the procedure)
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 5 Jun 2026.
- Results publication: PubMed 38570342Braud A, Auloge P, Meyer N, Bouvrais C, Gharbi M, Lang H, Gangi A, Lipsker D. Neoadjuvant in Situ and Systemic Immunotherapy with Lymph Node Cryoablation in Resectable Stage III Melanoma Metastasis: a Proof-of-Concept Study. Cardiovasc Intervent Radiol. 2024 May;47(5):567-572. doi: 10.1007/s00270-024-03699-9. Epub 2024 Apr 3.
- Individual participant dataSharing planned: No
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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.
Dan LIPSKER, MD PhD principal investigator
CHU de Strasbourg
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Nivolumab 10 MG/ML Intravenous Solution [OPDIVO], Cryotherapy and Ipilimumab Injection in people with Melanoma (Skin), run by University Hospital, Strasbourg, France at 1 site 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 7 inclusion and 22 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 5 Jun 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site 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 combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
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?
Number of failures linked to the procedure (time frame: Day 1 (cryoablation) or Day 2 (ipilimumab injection)). 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 NCT03949153, 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 5 Jun 2026.