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
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.
1. Men and women >/= 18 years of age
2. Signed and dated written informed consent prior any study related procedure
3. Histologically confirmed and clinically or radiologically progressing unresectable
Stage III or Stage IV melanoma, as per AJCC staging system
4. 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)
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
6. 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
7. Measurable disease by CT or MRI per RECIST 1.1 criteria.
8. 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.
9. 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
10. Prior radiotherapy must have been completed at least 2 weeks prior to study drug
11. 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).
12. 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.
13. 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
14. 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.
15. Patient affiliated to a social security regimen or beneficiary of the same
1. Active brain metastases or leptomeningeal metastases. Subjects with brain metastases
or leptomingeal 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
2. Ocular melanoma. Distant metastatic relapse of ocular melanoma outside the CNS can be
discussed with the study coordinator on a case by case basis.
3. 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.
4. 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.
5. 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
6. 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.
7. 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
8. Positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus
ribonucleic acid (HCV antibody) indicating acute or chronic infection.
9. Known history of testing positive for human immunodeficiency virus (HIV) or known
acquired immunodeficiency syndrome (AIDS).
10. History of allergy to study drug components.
11. History of severe hypersensitivity reaction to any monoclonal antibody.
12. Pregnancy or breastfeeding
13. 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.