This study is a phase I/II, multicenter, open-label study starting with a phase I part
followed by a Phase II part.
The phase I part of the study aims at evaluating the safety and efficacy (in terms of
abscopal effect at week 6) of the treatment combination schema of Stereotactic Body Radiation
Therapy (SBRT) and PD-1 plus CTLA-4 inhibitors in patients with metastatic melanoma. Patients
will be assigned in one of 3 cohorts depending the metastatic site. 18 patients will be
enrolled in each cohort.
Once the recommended optimal radiotherapy dose has been declared for the 3 cohorts, patients
will be enrolled in the phase II part of the study in order to evaluate the activity
(progression-free survival at 6 months) of SBRT given in combination with immune checkpoints
inhibitors in patients with metastatic melanoma.
66 patients will be included in the phase II.
1. Patients with histologically-proven metastatic and/or unresectable melanoma (stage
IIIc-IV, M1a-c as per AJCC 8th Edition), including mucosal melanoma, without evidence
of active intra-cranial disease.
2. Patients with tumor PD-L1 expression <1%.
3. Patients are included regardless of BRAFV600 mutation status. BRAFV600 mutation status
must be documented.
4. Patients with a metastatic lesion located on liver, lung, or bone and eligible for a
5. Patients should present at least two lesions: one lesion to be irradiated and one
distant lesion that will serve as control. Lesion to be irradiated will be selected on
the basis of symptomatology, safety and/or location. Preferentially, both lesions
should be measurable per RECIST 1.1. If only the control lesion is measurable but not
the irradiated lesion, eligibility will be discussed with the sponsor.
6. Age ≥18 years at the time of study entry.
7. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1.
8. Life expectancy of at least 3 months.
9. Patients able to participate and willing to give informed consent prior to performance
of any study-related procedures and to comply with the study protocol.
10. Screening laboratory values must meet the following criteria and should be obtained
prior to commencement of treatment:
- White blood count (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 (if using
the Cockcroft-Gault formula)
- AST/ALT ≤ 3 x ULN (except subjects with hepatic metastasis, who can have AST/ALT
≤ 5 x ULN)
- Total Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome, who can have
total bilirubin < 3.0 mg/dL)
11. Adequate cardiac and respiratory functions defined as New York Heart Association
(NYHA) class 1 and SaO2 > 90%.
12. Patient must be naïve to systemic treatment for locally advanced and/or metastatic
disease (i.e., no prior systemic anticancer therapy for advanced disease; stage IIIc
and IV). Prior adjuvant therapies (including Interferon α and Ipilimumab) is permitted
if it was completed at least 12 weeks before start of treatment and all related AEs
have either returned to baseline or stabilized.
13. Prior radiotherapy or radiosurgery must have been completed at least 4 weeks prior to
the first dose of the study treatment.
14. Women of childbearing potential (WOCBP) must use two appropriate methods of
contraception to avoid pregnancy for 23 weeks (30 days plus the time required for
Nivolumab/Ipilimumab to undergo five half-lives) after the last dose of
15. Women of childbearing potential must have a negative serum or urine pregnancy test
(minimum sensitivity 25IU/L or equivalent units of HCG) within 24 hours prior to the
start of study treatment.
16. Men who are sexually active with WOCBP must use two contraceptive methods including at
least one method with a failure rate of less than 1% per year for a period of 31 weeks
after the last dose of investigational product. Women who are not of childbearing
potential (i.e., who are postmenopausal or surgically sterile) as well as azoospermic
men do not require contraception
17. Absence of any psychological, familial, sociological or geographical condition that
potentially hampers compliance with the study protocol and follow-up after treatment
18. Patient affiliated to a Social Health Insurance in France.
1. Patient pregnant, or breast-feeding.
2. Uveal melanoma.
3. Active and/or symptomatic intra cranial metastasis (including melanomatous
4. Previous treatment with B-RAF or MEK inhibitors within 12 weeks prior start of
5. Hypersensitivity to the drugs of the study.
6. Any 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
7. Clinically significant cardiac dysfunction including congenital, familial, and genetic
cardiac disorders, current instable angina, current symptomatic congestive heart
failure of NYHA class 2 and higher, current uncontrolled hypertension ≥ grade 3; Left
Ventricular Ejection Fraction (LVEF) below institutional lower limit of normal (LLN)
or below 50%, whichever is lower.
8. Patient with active malignancy other than melanoma or a history of previous within the
past 3 years; except for patients with resected Basal cell carcinoma or resected
Spindle cell carcinoma, resected carcinoma in situ of the cervix and resected
carcinoma in situ of the breast.
9. Active, known or suspected autoimmune disease including but not restricted to multiple
sclerosis, optical nephritis and demyelinating neuropathy. Subjects are permitted to
enroll if they have 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
10. Positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus
(ribonucleic acid or HCV antibody) indicating acute or chronic infection.
11. Known history of testing positive for human immunodeficiency virus (HIV) or known
acquired immunodeficiency syndrome (AIDS).
12. Vaccination with any live attenuated conventional vaccine within the 3 months
preceding the start of study treatment.
13. Any current severe or uncontrolled disease, including, but not limited to ongoing or
14. Patient included in another study with an experimental molecule and/or procedure.
15. Unwillingness or inability to provide written informed consent.
16. Any psychological, familial, geographic or social situation, according to the judgment
of investigator, potentially preventing the compliance of treatment and the study
17. Patient who has forfeited his/her freedom by administrative or legal award or who is