NBTXR3 Activated by Radiotherapy for Patients With Advanced Cancers Treated With An Anti-PD-1 Therapy

Study Overview
=================
Brief Summary
-----------------
The 1100 study is an open-label, Phase I, dose escalation and expansion prospective clinical study to assess the safety of intratumoral injection of NBTXR3 activated by radiotherapy in combination with anti-PD-1 therapy.

Detailed Description
-----------------
The 1100 study aims to evaluate the safety, efficacy, and tolerability of NBTXR3 activated by radiotherapy in combination with an anti-PD-1 therapy in three cohorts of patients in dose escalation and expansion parts. The Escalation Cohort 1 includes patients with LRR or R/M HNSCC with the injectable lesion in a previously irradiated field. In Escalation Cohorts 2 and 3, patients present with lung or liver metastases from any primary cancer eligible for anti-PD-1 therapy. The Expansion cohort 1 includes patients with LRR or R/M HNSCC with the injectable lesion located either in head and neck area or in lung or liver, who are resistant to anti-PD-1 therapy. The Expansion cohort 2 includes patients with LRR or R/M HNSCC with the injectable lesion located either in head and neck area or in lung or liver, who are naive to anti-PD-1 therapy. The Expansion Cohort 3 includes patients with inoperable NSCLC, malignant melanoma, HCC, RCC, urothelial cancer, cervical cancer or TNBC with metastases to lungs, liver or soft tissue and who are resistant to anti-PD-1 therapy. These patients have a high unmet need and the Sponsor hypothesizes that NBTXR3 activated by radiotherapy will act synergistically with anti-PD-1 to enhance the therapeutic index of radiotherapy maximizing local effect, to overcome radio-resistance, to increase the local efficacy of immunotherapy, and to improve distant tumor control via an abscopal effect. Eligible patients will receive a single intratumoral injection of NBTXR3 subsequently activated by radiotherapy and then an approved anti-PD-1. The end of treatment visit will take place 4 weeks after the last radiotherapy fraction. Patients will be followed for long-term safety and efficacy for 2 years after the EOT visit.

Official Title
-----------------
A Phase I Dose Escalation / Dose Expansion Study of NBTXR3 Activated by Radiotherapy for Patients With Advanced Cancers Treated With An Anti-PD-1 Therapy

Conditions
-----------------
Radiotherapy, Immunotherapy, Microsatellite Instability-High Solid Malignant Tumour, Metastasis From Malignant Tumor of Liver, Squamous Cell Carcinoma of Head and Neck, Metastasis From Malignant Tumor of Cervix, Metastatic Renal Cell Carcinoma, Metastasis From Malignant Melanoma of Skin (Disorder), Metastatic Triple-Negative Breast Carcinoma, Metastatic NSCLC, Metastasis From Malignant Tumor of Bladder (Disorder)

Intervention / Treatment
-----------------
* Drug: NBTXR3
* Radiation: SABR
* Drug: Nivolumab
* Drug: Pembrolizumab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Signed informed consent form Biopsy-confirmed cancer diagnosis indicated to receive anti-PD-1 therapy: Dose Escalation: 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 Escalation Cohort 2: Has metastasized to the lung (including involved lymph nodes) with tumor in a previously non-irradiated lung field, or Escalation Cohort 3: Has metastasized to the liver with tumor in a previously non-irradiated liver field Expansion: 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 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): Has not received prior anti-PD-1 therapy (i.e., anti-PD-1 naïve), or 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 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: 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 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 Exclusion Criteria: 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 Any condition for which participation would not be in the best interest of the participant

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NBTXR3 activated by SABR followed by anti-PD-1 monotherapy<br>Intratumoral injection of NBTXR3 followed by SABR followed by monotherapy with nivolumab or pembrolizumab | Drug: NBTXR3<br>* Single intra Tumoral injection<br>Radiation: SABR<br>* Radiotherapy given as a definite number of fractions at the dose defined for each radiation field<br>* Other names: Stereotaxic Body Radiation Therapy;Drug: Nivolumab<br>* Anti-PD-1 monotherapy<br>* Other names: Opdivo;Drug: Pembrolizumab<br>* Anti-PD-1 monotherapy<br>* Other names: Keytruda;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| [Dose Escalation Part]: Determination of the Recommended Dose | Determination of DLTs, the MTD (if possible), and RP2Ds for each cohort | 24 Months | 
| [Dose Expansion Part]: Safety Evaluation at RP2D | Incidence of Grade 3 and higher treatment-related AEs | 24 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluation of the anti-tumor response of R3/RT/PD-1 | Evaluation of the Objective Response Rate: complete or partial response, as defined by RECIST 1.1 and iRECIST | 24 months | 
| Assessment of the safety and feasibility of R3/RT/PD-1 | Assessment of the number of participants with related late onset toxicities defined as any Grade ≥3 AE occurring after the EOT visit and determination of the number of participants with feasible NBTXR3 intratumoral injection | 24 months | 
| Evaluation of the body kinetic profile of intratumorally injected NBTXR3 | Evaluation of the time-course dependent accumulation of hafnium in blood and urine following NBTXR3 intratumoral injection | 24 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Oral Cavity Cancer, Oropharynx Cancer, Lung Metastasis, Liver Metastasis