A Phase I Study of NBTXR3 Activated by Radiotherapy for Patients with Advanced Cancers Treated With An Anti-PD-1 Therapy

• Signed informed consent form
• Biopsy-confirmed cancer diagnosis indicated to receive anti-PD-1 therapy:

Dose Escalation:

1. Escalation Cohort 1: Is inoperable LRR with tumor in previously irradiated HN field that is amenable to re-irradiation or R/M HNSCC with tumor in previously irradiated HN field that is amenable to re-irradiation, or
2. Escalation Cohort 2: Has metastasized to the lung (including involved lymph nodes) with tumor in a previously non-irradiated lung field, or
3. Escalation Cohort 3: Has metastasized to the liver with tumor in a previously non-irradiated liver field

Expansion:

1. Expansion Cohorts 1 and 2: Is inoperable LRR or R/M HNSCC with at least one lesion that is amenable to irradiation within head and neck region, lung or liver
2. Expansion Cohort 3: Is inoperable NSCLC, malignant melanoma, HCC, RCC, urothelial cancer, cervical cancer, TNBC that has metastasized to soft tissues, lung (including mediastinal lymph nodes) or liver with at least one lesion that is amenable to irradiation
• Prior anti-PD-1 exposure as follows:

Dose Escalation (all cohorts):

1. Has not received prior anti-PD-1 therapy (i.e., anti-PD-1 naïve), or
2. Has received prior anti-PD-1 therapy and meets criteria consistent with anti-PD-1 primary resistance (i.e., primary anti-PD-1 non-responder), or
3. Has received prior anti-PD-1 therapy and meets criteria consistent with anti-PD-1 secondary resistance (i.e., secondary anti-PD-1 non-responder)

Expansion:

1. Expansion Cohorts 1 and 3: Has received prior anti-PD-1 therapy and meets criteria consistent with anti-PD-1 primary or secondary resistance as described above
2. Expansion Cohort 2: Has not received prior anti-PD-1 therapy (i.e., anti-PD-1 naïve)
• Has at least one tumor lesion that can be accurately measured according to RECIST 1.1. and is amenable for intratumoral injection
• ECOG performance status 0-2
• Life expectancy >12 weeks
• Adequate organ and bone marrow function
• Negative pregnancy test ≤ 7 days prior to NBTXR3 injection in all female participants of child-bearing potential

• History of immune-related adverse events related to administration of anti-PD-1/L1 that led to the termination of the previous anti-PD-1 therapy due to intolerance or toxicity and precludes further PD-1 exposure
• Symptomatic central nervous system metastases and/or carcinomatous meningitis
• Active autoimmune disease that has required systemic treatment in the past 1 year
• Known HIV or active hepatitis B/C infection
• Active infection requiring intravenous treatment with antibiotics
• Received a live virus vaccine within 30 days prior to study treatment
• History of pneumonitis that required steroids or with current pneumonitis
• Extensive metastatic disease burden defined as more than 5 lesions overall including the primary tumor
• Locoregional recurrent HNSCC with ulceration
• Has received prior therapy with a checkpoint inhibitor, within 2 weeks prior to NBTXR3 injection
• Has received prior systemic anti-neoplastic therapy, including investigational agents, within 4 weeks prior to NBTXR3 injection
• Has not recovered from AEs due to previous anti-neoplastic therapies and/or interventions (including radiation) to ≤ Grade 1 or baseline at screening
• Clinically significant cardiac arrhythmias
• Class III or IV Congestive Heart Failure as defined by the New York Heart Association functional classification system < 6 months prior to screening
• A pregnant or nursing female, or women of child-bearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception