NBTXR3 Activated by SABR for Patients With Advanced HNSCC or NSCLC Treated With an Anti-PD1 Antibody

Escalation dose part:

Elegible patients will receive a single intratumoral injection of NBTXR3 concurrently with an
approved anti-PD1 and will receive external beam radiotherapy starting 24 hours after the
injection up to completion of 15 days of treatment.

Expansion dose part:

Elegible patients will receive a single intratumoral injection of NBTXR3 concurrently with an
approved anti-PD1 and will receive external beam radiotherapy starting 24 hours after the
injection up to completion of 15 days of treatment at recommended NBTXR3 dose and recommended
radiotherapy dose.

A visit of end of treatment will take place approximately 3-4 weeks after last radiotherapy
fraction. Patients will be followed for evaluation of their disease status and adverse event
until the end of the study.

Inclusion Criteria:

- Age ≥ 18

- Histologically-proven inoperable loco- regional recurrent HNSCC with tumor in
previously irradiated Head Neck field which is amenable to re-irradiation with SABR

- Histologically-proven recurrent AND metastatic HNSCC with tumor in previously
irradiated Head Neck field which is amenable to re-irradiation with SABR

- Histologically-proven lung metastasis, accessible to intratumoral injection, not
previously irradiated, from HNSCC not amenable to re-irradiation if synchronous
locoregional recurrence and metastasis, or from NSCLC (squamous and non squamous
types),

- Histologically-proven liver metastasis, accessible to intratumoral injection, not
previously irradiated, from HNSCC not amenable to re-irradiation if synchronous
locoregional recurrence and metastasis, or from NSCLC (squamous and non squamous
types),

- Known status of human papillomavirus infection, in patients with oropharyngeal SCC

- HNSCC with prior irradiation, concurrent or not with platin-based chemotherapy or
cetuximab

- Non symptomatic CNS metastasis is elegible

- NSCLC previously treated or not with a platinum based-regimen

- Patients with NSCLC tumors with EGFR or ALK genomic aberrations must have had disease
progression under approved molecular targeted therapy

- Metastatic patients must have received an approved anti-PD1 with SD for at least for
12 weeks or with confirmed PD at 12 weeks

- Karnofsky performance status ≥60

- Life expectancy >12 weeks

- Adequate function of bone marrow

- Adequate liver function

- Adequate kidney function:

- Non-childbearing potential:

- All female patients of childbearing potential must have a negative serum
pregnancy test within the 7 days prior to NBTXR3 administration.

- Female patients of childbearing potential must agree and use at least 2 forms of
highly effective methods of contraception, including at least 1 barrier method
starting with the first dose of study therapy through 150 days after the last
dose of study therapy.

- Male patients and their sexual partner(s) of childbearing potential must agree
and use at least 2 forms of highly effective methods of contraception, including
at least 1barrier method starting with the first dose of study therapy through
150 days after the last dose of study therapy.

Exclusion Criteria:

- Written Informed Consent not obtained, signed and dated

- Hypersensitivity to anti-PD1 monoclonal antibody

- History of severe immune-related adverse event requiring treatment discontinuation

- Diagnosis of immunodeficiency or receiving systemic steroid therapy in excess of
physiologic dose within 7 days prior to treatment start

- Active autoimmune disease requiring systemic treatment in the past year

- History of non-infectious pneumonitis or HIV

- Active hepatitis B or hepatitis C

- Peripheral neuropathy >grade 2

- Loco-regional recurrent HNSCC with ulceration

- Target lung metastatic lesion <2 cm

- Metastatic lesion not easily accessible for intratumoral/intralesional injection.

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
severe infection, symptomatic congestive heartfailure, acute coronary syndrome, etc.

- Medical history of life-threatening ventricular arrhythmia

- Concurrent treatment with any other anticancer therapy not determined by the study
treatment or planning to receive these treatments during the study

- Patients unable to comply with scheduled visits, treatment plans, laboratory tests,
and other study procedures or those with severe psychiatric illness/social situations
that would limit compliance with study requirements

- Patients participating in another clinical investigation at the time of signature of
the informed consent