Cryotherapy With in Situ Immunotherapy in Melanoma Metastasis (CRIRIN)
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|ClinicalTrials.gov Identifier: NCT03949153|
Recruitment Status : Recruiting
First Posted : May 14, 2019
Last Update Posted : September 6, 2019
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.
|Condition or disease||Intervention/treatment||Phase|
|Melanoma (Skin)||Drug: Nivolumab 10 MG/ML Intravenous Solution [OPDIVO] Procedure: Cryotherapy Drug: Ipilimumab Injection||Phase 1 Phase 2|
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||15 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|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.|
|Actual Study Start Date :||August 16, 2019|
|Estimated Primary Completion Date :||August 2021|
|Estimated Study Completion Date :||February 2022|
Experimental: Experimental arm
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.
Drug: Nivolumab 10 MG/ML Intravenous Solution [OPDIVO]
Single Nivolumab 240 mg infusion at D0
Cryotherapy using interventional radiology of metastatic lymphadenopathy at D1
Drug: Ipilimumab Injection
In situ injection with ipilimumab at D2.
- 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.
- 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) ]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).
- Incidence of Treatment-Emergent Adverse Events [ Time Frame: From Day 0 to the end of study visit (6 months after the procedure) ]Number, nature and severity of adverse events and serious adverse events (according to NCI CTCAE) related to immune therapy and cryoablation
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): NCT03949153
|Contact: Dan LIPSKER, MD PhD||+33 3 88 11 61 email@example.com|
|Clinique Dermatologique/Radiologie Interventionnelle/Urologie/Gynécologie-Hôpitaux Universitaires de Strasbourg||Recruiting|
|Strasbourg, France, 67091|
|Contact: Dan LIPSKER, MD, PhD +33 3 88 11 61 79 firstname.lastname@example.org|
|Sub-Investigator: Cédric LENORMAND|
|Sub-Investigator: Jean-Nicolas SCRIVENER|
|Sub-Investigator: Guillaume HAZEMANN|
|Sub-Investigator: Afshin GANGI|
|Sub-Investigator: Julien GARNON|
|Sub-Investigator: Jean CAUDRELIER|
|Sub-Investigator: Roberto Luigi CAZATTO|
|Sub-Investigator: Pierre AULOGE|
|Sub-Investigator: Guillaume KOCH|
|Sub-Investigator: Alice KIENY|
|Sub-Investigator: Hervé LANG|
|Sub-Investigator: Mousselim GHARBI|
|Principal Investigator: Dan LIPSKER|
|Sub-Investigator: Lise LECOINTRE|
|Principal Investigator:||Dan LIPSKER, MD PhD||Hôpitaux Universitaires de Strasbourg|