Combining nivolumab with conventional multisite high dose radiotherapy seems to be an
interesting approach that could increase the antitumoral effect of nivolumab by increasing
the diversity and quantity of tumoral antigen presentation thanks to radiotherapy.
Multifractionated high dose radiotherapy (HR) targeting various tumor sites could also
increase occurrence of tumor mutations and the diversity of the T-cell receptor repertoire of
intratumoral T cells.
The purpose of this study is to combine nivolumab with 3 fractions of HR of one metastasis
for each tumor site (defined as skin/muscle, thoracic, abdomen, bone, other).
The investigators hypothesize that combining nivolumab with multisite, multifractionated HR
increases the overall survival rate at 1 year compared to published data with nivolumab
alone.
Recent progress has been made in advanced melanoma with drug targeting immune system such as
ipilimumab targeting CTLA-4 and nivolumab targeting PD-1. Some case reports and preclinical
data suggested that the antitumoral immune response of these immune check point inhibitors
(ipilimumab and nivolumab as well) could be enhanced if associated with massive tumoral
antigen release in the blood stream, due to local treatment such as high dose radiotherapy
(HR). The first rigorous scientific demonstration of this phenomenon was done by Demaria et
al. They showed that irradiation of xenograft tumor could induce decrease of tumoral growth
of a non-irradiated other xenograt tumor. This effect was due to immune response to
irradiation but it only occured when immune system was modulated by CTLA-4 inhibition. In
that experiences CTLA4 and radiation actions were synergistic.
Dovedi et al. also reported that targeting PD-1/PD-L1 pathway have greater anti-tumor
efficacy if concomitant radiotherapy was given and especially if radiotherapy was
multifractionated.
Very interestingly the fractionated radiotherapy also induced huge increase of tumoral PD-L1
expression by three times 5 days after beginning of radiotherapy. This could explain the
synergistic impact of this strategy.
At least eight clinical studies are ongoing, testing the combination of CTLA-4 blockade with
radiotherapy in metastatic melanoma or other tumors, with various treatment schedules either
for ipilimumab (3 or 10 mg/kg) or radiotherapy (before or after ipilimumab, fractions of 6 to
8 Gy; total body irradiation or treatment of only one metastasis).
One study (NCT01565837) is a phase II study that analyses the efficacy of 10mg/kg ipilimumab
(every 3 weeks) associated with HR for all metastatic sites but only for oligometastatic
patients (< 6 metastasis), which reflects only a minority of metastatic melanoma patients.
Such strategy is of high interest because it takes into account the putative tumoral
heterogeneity which could lead to failure of the association of nivolumab with the
irradiation of only one tumor site.
The investigators propose to combine nivolumab with 3 fractions of HR of one metastasis for
each tumor site (defined as skin/muscle, thoracic, abdomen, bone, other).They have chosen 3
fractions instead of only 1 for each tumor site because of preclinical data in mice showing
that one fraction is less efficient than several fractions to stimulate the immune system and
kill tumoral cells. The increase of the number of fractions could also lead to an increase of
the diversity of tumoral antigens released in the blood stream which could also favors
diversity of the T-cell receptor repertoire of intratumoral T cells.
In our protocol dose constraint for each tissue type can be easily achieved with the 3 X 6 Gy
schedule without excess of toxicity.
In conclusion the present protocol aims to increase the quantity and diversity of released
tumoral antigens by providing multisite, multifractionated HR during nivolumab treatment in
advanced untreated melanoma patients.
The investigators hypothesize that combining nivolumab with multisite, multifractionated HR
increases the overall survival rate at 1 year compared to published data with nivolumab
alone.
Inclusion Criteria:
1. Willing and able to give written informed consent
2. Men and women, ≥ 18 years of age
3. Histologically confirmed Stage III (unresectable) or Stage IV melanoma. Unknown
primary melanoma will be accepted.
4. Measurable disease by CT per RECIST 1.1 criteria
5. Indication of radiotherapy
6. Patient MUST be untreated for his/her Stage III (unresectable) or Stage IV melanoma
7. Prior treatment with INTERFERON in the adjuvant setting is authorized.
8. BRAF status must be determinate but patient will be eligible regardless the status
(BRAF wildtype and BRAF V600 mutation positive patients could be included)
9. A pre-treatment recent core, excision or punch biopsy must be provided for PD-L1
status determination prior to start the treatment and for exploratory biomarker
analyses. The biopsy must be from an unresectable or metastatic site, and the subject
must have had no intervening systemic therapy between the time of biopsy and the start
of inclusion
10. Patient must consent to allow the acquisition of existing formalin-fixed
paraffin-embedded (FFPE) material (" archival ") (block or a minimum of 10 unstained
slides) if available, for performance of correlatives studies
11. Subjects must consent to allow the acquisition of blood samples: one during the week
before the first nivolumab injection; the second 15 days +- 2 days after the first
injection of nivolumab; the third between 15 and 30 days after the first radiotherapy
session and the fourth at relapse, for performance of correlative studies,
12. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤1
13. Within the last 2 weeks prior to study day 1 the following laboratory parameters,
which should be within the ranges specified:
14. Subjects affiliated to an appropriate social security system NB: Patients will be
included regardless of the level of LDH.
Exclusion Criteria:
1. The patient requires concomitant chronic treatment with systemic corticosteroids or
any other immunosuppressive agents 7 days prior to inclusion,
2. Patient with brain(s) metastase(s), symptomatic(s) or not,
3. Ocular or mucosal melanoma (unknown primary melanoma will be accepted),
4. The patient has concurrent severe medical problems, unrelated to the malignancy, that
would significantly limit full compliance with the study or expose the patient to
unacceptable risk such as but not limited to: Cardiac insufficiency (III or IV as per
NYHA classification), Renal insufficiency, ongoing infection,
5. Subjects with previous malignancies (except non-melanoma skin cancers, in situ bladder
cancer, gastric or colon cancers, cervical cancers/dysplasia or breast carcinoma in
situ) are excluded unless a complete remission was achieved at least 2 years prior to
study entry and no additional therapy is required or anticipated to be required during
the study period,
6. Uncontrolled infectious diseases - requires negative tests for clinically suspected
HIV, hepatitis B virus (HBV) and hepatitis C virus (HCV). If positive results are not
indicative of true active or chronic infection, the subject may enter the study after
discussion and agreement between the Investigator and the Medical Monitor,
7. Active Autoimmune disease: subjects with a documented history of inflammatory bowel
disease, including ulcerative colitis and Crohn's disease are excluded from this study
as are subjects with a history of symptomatic disease (e.g., rheumatoid arthritis,
systemic progressive sclerosis [scleroderma], Systemic Lupus Erythematosus, autoimmune
vasculitis [e.g., Wegener's Granulomatosis]); 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,
8. Subjects with motor neuropathy considered of autoimmune origin (e.g., Guillain Barré
Syndrome) are excluded from this study,
9. Previous treatment with, chemotherapy, a CTLA-4 or PD-1/PD-L1 antagonist agent,
including treatment in adjuvant setting for immunotherapy,
10. The patient has psychiatric or addictive disorders that may compromise his/her ability
to give informed consent or to comply with the trial procedures,
11. Lack of availability for clinical follow-up assessments,
12. Pregnant or lactating women (a blood pregnancy test will be conducted) and effective
contraception will be used throughout the treatment for women of childbearing age,
13. Participation in another clinical trial protocol within 30 days prior to enrolment,
14. Persons protected by a legal regime (guardianship, trusteeship),
15. Vulnerable patients, patients kept in detention
