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

Sponsor

Nanobiotix (Industry)

Overall Status

Recruiting

CT.gov ID

NCT03589339

Collaborator

(none)

145

Enrollment

Locations

Arm

112.4

Anticipated Duration (Months)

20.7

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
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)	Drug: NBTXR3 Radiation: SABR Drug: Nivolumab Drug: Pembrolizumab	Phase 1

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

145 participants

Allocation:

N/A

Intervention Model:

Sequential Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Jan 16, 2019

Anticipated Primary Completion Date :

Mar 30, 2023

Anticipated Study Completion Date :

May 30, 2028

Arms and Interventions

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

Arm

Intervention/Treatment

Experimental: NBTXR3 activated by SABR followed by anti-PD-1 monotherapy

Intratumoral injection of NBTXR3 followed by SABR followed by monotherapy with nivolumab or pembrolizumab

Drug: NBTXR3

Single intra Tumoral injection

Radiation: SABR

Radiotherapy given as a definite number of fractions at the dose defined for each radiation field

Other Names:

Stereotaxic Ablative Radiotherapy

Stereotaxic Body Radiation Therapy

Drug: Nivolumab

Anti-PD-1 monotherapy

Other Names:

Opdivo

Drug: Pembrolizumab

Anti-PD-1 monotherapy

Other Names:

Keytruda

Outcome Measures

Primary Outcome Measures

Determination of the Recommended Dose [24 Months]
Determination of DLTs, the MTD (if possible), and RP2Ds for each cohort

Secondary Outcome Measures

Evaluation of the anti-tumor response of R3/RT/PD-1 [24 months]
Evaluation of the Objective Response Rate: complete or partial response, as defined by RECIST 1.1 and iRECIST
Assessment of the safety and feasibility of R3/RT/PD-1 [24 months]
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
Evaluation of the body kinetic profile of intratumorally injected NBTXR3 [24 months]
Evaluation of the time-course dependent accumulation of hafnium in blood and urine following NBTXR3 intratumoral injection

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Christiana Care Health Services	Newark	Delaware	United States	19713
2	Moffitt Cancer Center	Tampa	Florida	United States	33612
3	University of Chicago Medical Center	Chicago	Illinois	United States	60637
4	Johns Hopkins University, Sidney Kimmel Comprehensive Cancer Center	Baltimore	Maryland	United States	21287
5	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
6	Quantum Santa Fe	Santa Fe	New Mexico	United States	87505
7	University of North Carolina, School of Medicine	Chapel Hill	North Carolina	United States	27516