Stage III/IV MelanomaPhase 1/2NIVIPITNCT02857569
A Trial Evaluating the Safety & Efficacy of Intra-Tumoral Ipilimumab in Combination With Intra-venous Nivolumab in Patients With Metastatic Melanoma
A Phase 1/2 study testing Ipilimumab IT, Ipilimumab IV and Nivolumab IV in people with Stage III/IV Melanoma, run by Gustave Roussy, Cancer Campus, Grand Paris at 1 site in France.
Trial summary
The study aims to evaluate the 6 month-treatment tolerance defined as the immune related grade 3-4 adverse event-free survival of the combination therapy IT ipilimumab + IV nivolumab. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Stage III/IV Melanoma
- What is being tested?
- Ipilimumab IT, Ipilimumab IV and Nivolumab IV
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 90 participants
- Where
- 1 siteFrance
- Study dates
- 5 Dec 2016to 20 May 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
- Men and women >/= 18 years of age
- Signed and dated written informed consent prior any study related procedure
- Histologically confirmed and clinically or radiologically progressing unresectable Stage III or Stage IV melanoma, as per AJCC staging system
- Patients with at least two lesions:
- At least one injectable tumor lesion (≥1cm3)
- At least one target lesion (measurable lesion as per RECIST 1.1)
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- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- Treatment naïve subjects or patients relapsing after prior local or systemic anticancer therapy. Note that systemic anticancer therapy is permitted if it was completed at least 28 days or 5 times its half life (whichever is shorter) prior to the first study dose, and all related adverse events have either returned to baseline or stabilized.
- Measurable disease by CT or MRI per RECIST 1.1 criteria.
- Recent (less than 3 month) tumor tissue must be provided for patient stratification and biomarker analyses. In order to be equally randomized, a subject must be classified as PDL1 positive, PD-L1 negative, or PD-L1 indeterminate. If an insufficient amount of tumor tissue is available prior to the start of the screening phase, subjects must consent to allow the acquisition of additional tumor tissue for performance of biomarker analyses.
- Subjects with wild-type BRAF. BRAF-mutant can be included only if they have been treated with, or developed toxicity with or refused to be treated with BRAF-and/or MEK-targeted therapy in front-line
- Prior radiotherapy must have been completed at least 2 weeks prior to study drug administration.
- Screening laboratory values must meet the following criteria and should be obtained within 14 days prior to randomization:
- WBC >/= 2000/μL
- Neutrophils >/= 1500/μL
- Platelets >/= 100 x103/μL
- Hemoglobin >/= 9.0 g/dL
- Serum creatinine </= 1.5 x ULN or creatinine clearance (CrCl) >/= 40 mL/min (using the Cockcroft-Gault formula):
- Female CrCl = [(140 - age in years) x weight in kg x 0.85] / (72 x serum creatinine in mg/dL) Male CrCl = [(140 - age in years) x weight in kg x 1.00] / (72 x serum creatinine in mg/dL)
- AST and ALT ≤3.0 x upper limit of normal (ULN); if liver metastases AST and ALT ≤5.0 x ULN
- Total Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL).
- Subject Re-enrollment: This study permits the re-enrollment of a subject that has discontinued the study as a pre-treatment failure (ie, subject has not been randomized / has not been treated) after obtaining agreement from the coordinator prior to re-enrolling a subject. If re-enrolled, the subject must be re-consented.
- Women of childbearing potential (WOCBP) must have a negative serum β-HCG pregnancy test within 7 days prior to initiation of treatment. Both sexually active females and males (and their female partners) patients must agree to use two methods of effective contraception, one of them being a barrier method, or to abstain from sexual activity during the study and for at least 5 months after last study drug administration
- Patients must be willing and able to comply with the visits, treatments, procedures, and laboratory tests, and other requirements that are scheduled in the protocol.
- Patient affiliated to a social security regimen or beneficiary of the same
Who cannot join
- Active brain metastases or leptomeningeal metastases. Subjects with brain metastases or leptomeningeal disease are eligible if these lesions have been treated or if they are asymptomatic and there is no clinical evidence of progression within 28 days prior to first dose of study drug administration. CNS lesions should be monitored bu contrast enhanced MRI at disease assessment timepoints. Justification for allowing patient with CNS disease: whereas tumor-targeting antibodies have limited access to the central nervous system because of the blood brain barrier, immune targeted antibodies can generate a T-cell mediated anti-tumor immune response which I able to cross the blood brain barrier. Indeed, anti-CTLA-4 and anti PD-1 imAbs have shown their ability to induce tumor responses from metastatic sites all over the body, including in the brain
- Ocular melanoma. Distant metastatic relapse of ocular melanoma outside the CNS can be discussed with the study coordinator on a case by case basis.
- Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration, impair the ability of the subject to receive protocol therapy, or interfere with the interpretation of study results.
- Prior malignancy active within the previous 3 years except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast.
- Subjects with active, known or suspected autoimmune disease. 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 a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids, and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
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- Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell costimulation or immune checkpoint pathways.
- Positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection.
- Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
- History of allergy to study drug components.
- History of severe hypersensitivity reaction to any monoclonal antibody.
- Pregnancy or breastfeeding
- Patients presenting coagulation abnormalities and/or patients requiring concomitant treatment with therapeutic doses of anticoagulants. Prophylactic low dose of anticoagulants for thrombo-embolic events is allowed. Prophylactic anticoagulants shall be stopped during 24h prior and after deep lesion biopsies/injections. No stopping rule for biopsies/injections of skin and sub-cutaneous lesions.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: A Randomized Phase I/II Trial Evaluating the Safety & Efficacy of Intra-Tumoral Ipilimumab in Combination With Intra-venous Nivolumab in Patients With Metastatic Melanoma
The study aims to evaluate the 6 month-treatment tolerance defined as the immune related grade 3-4 adverse event-free survival of the combination therapy IT ipilimumab + IV nivolumab.
The IV ipilimumab + IV nivolumab (same doses than in Phase I) arm will be used as an internal control to interpret the results obtained in the IT ipilimumab arm.
- Conditions
- Stage III/IV Melanoma
- Being tested
- Ipilimumab IT, Ipilimumab IV, Nivolumab IV
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Ipilimumab ITDrug
Ipilimumab IVDrug
Nivolumab IVDrug
| Study group | Role | What they receive |
|---|---|---|
| Experimental IT Arm | Experimental | * ipilimumab: 0.3mg/kg IT injection every 3 weeks until complete response, eradication of all injectable sites, disease progression or toxicity, for a maximum of 4 doses (to compare back to back to IV standard of care and marketing authorization).
* nivolumab: 1mg/kg, IV injection every 3 weeks during IT ipilimumab treatment period and 3mg/kg, IV injection every 2 weeks after IT ipilimumab treatment interruption. Treatment should be continued as long as clinical benefit is observed or until treatment is no longer tolerated by the patient for a maximum of 12 months. Receives: Drug: Ipilimumab IT; Drug: Nivolumab IV |
| Standard Arm | Active comparator | * ipilimumab: 3mg/kg, IV injection every 3 weeks for a maximum of 4 doses as per standard of care and marketing authorization.
* nivolumab: 1mg/kg, IV injection every 3 weeks during IV ipilimumab treatment period and 3mg/kg, IV injection every 2 weeks after IV ipilimumab treatment interruption. Treatment should be continued as long as clinical benefit is observed or until treatment is no longer tolerated by the patient for a maximum of 12 months. Receives: Drug: Ipilimumab IV; Drug: Nivolumab IV |
What is being measured
The primary outcome is the main question the study is designed to answer.
6-months treatment-related grade 3-4 toxicity event-free survival (EFS).
Measured: Assessed every 28 days after randomization up to 6 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted5 Aug 2016 (estimated)
- Study start5 Dec 2016
- Primary completionJan 2021
- Study completion20 May 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 Stage III/IV MelanomaStudies of the same condition, open and under way.
- More trials run by Gustave Roussy, Cancer Campus, Grand ParisThe 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
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 90 participants (actual)
Sponsor and investigators
- Lead sponsor
- Gustave Roussy, Cancer Campus, Grand Paris
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02857569
- Sponsor's protocol ID
- 2015-005429-37
- Other IDs
- 2015/2334, 2015
- Acronym
- NIVIPIT
- Status last verified
- Feb 2023
- First submitted
- 19 Jul 2016
- Last updated
- 15 Feb 2023
- Results posted
- No
- Data monitoring committee
- No
- Individual data sharing
- No
Publications
Tselikas L, Susini S, Texier M, Yurchenko A, Routier E, Amini-Adle M, Tihic E, Mouraud S, Danlos FX, Ammari S, Raoult T, Roy S, Bredel D, Farhane S, Cassard L, Molinaro I, Eggermont A, Soria JC, Zitvogel L, Massard C, Paci A, de Baere T, Scoazec JY, Chaput N, Nikolaev S, Meyer N, Lebbe C, Dalle S, Robert C, Marabelle A. Safety and efficacy of intratumoural anti-CTLA4 with intravenous anti-PD1. Nature. 2026 Jul;655(8121):219-229. doi: 10.1038/s41586-026-10341-w. Epub 2026 Apr 29.
PubMed 42056527
Study at a glance
From the registry record, last updated by the sponsor on 15 Feb 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Randomized Phase I/II Trial Evaluating the Safety & Efficacy of Intra-Tumoral Ipilimumab in Combination With Intra-venous Nivolumab in Patients With Metastatic Melanoma
- ClinicalTrials.gov ID
- NCT02857569
- Acronym / sponsor ID
- NIVIPIT / 2015-005429-37
- Conditions
- Stage III/IV Melanoma
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 90 participants (actual)
- Lead sponsor
- Gustave Roussy, Cancer Campus, Grand ParisUniversity, hospital or other
- Study start
- 5 Dec 2016 (actual)
- Primary completion
- Jan 2021 (actual)
- Study completion
- 20 May 2022 (actual)
- First posted
- 5 Aug 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.
The study aims to evaluate the 6 month-treatment tolerance defined as the immune related grade 3-4 adverse event-free survival of the combination therapy IT ipilimumab + IV nivolumab.
The IV ipilimumab + IV nivolumab (same doses than in Phase I) arm will be used as an internal control to interpret the results obtained in the IT ipilimumab arm.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Experimental IT Arm | Experimental | Drug: Ipilimumab IT, Drug: Nivolumab IV* ipilimumab: 0.3mg/kg IT injection every 3 weeks until complete response, eradication of all injectable sites, disease progression or toxicity, for a maximum of 4 doses (to compare back to back to IV standard of care and marketing authorization). * nivolumab: 1mg/kg, IV injection every 3 weeks during IT ipilimumab treatment period and 3mg/kg, IV injection every 2 weeks after IT ipilimumab treatment interruption. Treatment should be continued as long as clinical benefit is observed or until treatment is no longer tolerated by the patient for a maximum of 12 months. |
| Standard Arm | Active comparator | Drug: Ipilimumab IV, Drug: Nivolumab IV* ipilimumab: 3mg/kg, IV injection every 3 weeks for a maximum of 4 doses as per standard of care and marketing authorization. * nivolumab: 1mg/kg, IV injection every 3 weeks during IV ipilimumab treatment period and 3mg/kg, IV injection every 2 weeks after IV ipilimumab treatment interruption. Treatment should be continued as long as clinical benefit is observed or until treatment is no longer tolerated by the patient for a maximum of 12 months. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (25 listed)
- Men and women >/= 18 years of age
- Signed and dated written informed consent prior any study related procedure
- Histologically confirmed and clinically or radiologically progressing unresectable Stage III or Stage IV melanoma, as per AJCC staging system
- Patients with at least two lesions:
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
Key exclusion criteria (13 listed)
- Active brain metastases or leptomeningeal metastases. Subjects with brain metastases or leptomeningeal disease are eligible if these lesions have been treated or if they are asymptomatic and there is no clinical evidence of progression within 28 days prior to first dose of study drug administration. CNS lesions should be monitored bu contrast enhanced MRI at disease assessment timepoints. Justification for allowing patient with CNS disease: whereas tumor-targeting antibodies have limited access to the central nervous system because of the blood brain barrier, immune targeted antibodies can generate a T-cell mediated anti-tumor immune response which I able to cross the blood brain barrier. Indeed, anti-CTLA-4 and anti PD-1 imAbs have shown their ability to induce tumor responses from metastatic sites all over the body, including in the brain
- Ocular melanoma. Distant metastatic relapse of ocular melanoma outside the CNS can be discussed with the study coordinator on a case by case basis.
- Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration, impair the ability of the subject to receive protocol therapy, or interfere with the interpretation of study results.
- Prior malignancy active within the previous 3 years except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast.
- Subjects with active, known or suspected autoimmune disease. 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.
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 |
|---|---|---|
| Ipilimumab IT | Drug | Experimental IT Arm |
| Ipilimumab IV | Drug | Standard Arm |
| Nivolumab IV | Drug | Experimental IT Arm, Standard Arm |
Primary outcome
6-months treatment-related grade 3-4 toxicity event-free survival (EFS).
Time frame: Assessed every 28 days after randomization up to 6 months
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 Feb 2023.
- Derived from this study: PubMed 42056527Tselikas L, Susini S, Texier M, Yurchenko A, Routier E, Amini-Adle M, Tihic E, Mouraud S, Danlos FX, Ammari S, Raoult T, Roy S, Bredel D, Farhane S, Cassard L, Molinaro I, Eggermont A, Soria JC, Zitvogel L, Massard C, Paci A, de Baere T, Scoazec JY, Chaput N, Nikolaev S, Meyer N, Lebbe C, Dalle S, Robert C, Marabelle A. Safety and efficacy of intratumoural anti-CTLA4 with intravenous anti-PD1. Nature. 2026 Jul;655(8121):219-229. doi: 10.1038/s41586-026-10341-w. Epub 2026 Apr 29.
- 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.
The record lists no contact. Use the official record to reach the sponsor.
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 Ipilimumab IT, Ipilimumab IV and Nivolumab IV in people with Stage III/IV Melanoma, run by Gustave Roussy, Cancer Campus, Grand Paris 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 25 inclusion and 13 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 Feb 2023. 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?
6-months treatment-related grade 3-4 toxicity event-free survival (EFS). (time frame: Assessed every 28 days after randomization up to 6 months). 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 NCT02857569, 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 Feb 2023.