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

• ClinicalTrials.gov Identifier: NCT03589339
• Recruitment Status: Recruiting
• First Posted: July 17, 2018
• Last Update Posted: June 24, 2022
• Sponsor: Nanobiotix
• Information provided by (Responsible Party): Nanobiotix

Tracking Information

• First Submitted Date: April 10, 2018
• First Posted Date: July 17, 2018
• Last Update Posted Date: June 24, 2022
• Actual Study Start Date: January 16, 2019
• Estimated Primary Completion Date: March 30, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 16, 2020)

Determination of the Recommended Dose [ Time Frame: 24 Months ]

Determination of DLTs, the MTD (if possible), and RP2Ds for each cohort

Original Primary Outcome Measures (submitted: July 4, 2018)

• Phase1: Determination of the Maximum Tolerated Doses and the early Dose Limitting Toxicities (DLT) [ Time Frame: 24 months ]
  To determine the Maximum Tolerated Dose/s and the early Dose Limiting Toxicities (DLT) of intratumoral/intralesional injection of NBTXR3 activated by SABR in combination with an anti-PD1 antibody,
• Phase1: Determination of the Recommended Doses [ Time Frame: 24 months ]
  To determine the Recommended Dose/s of NBTXR3 given as intratumoral/Intralesional injection and activated by SABR in combination with an anti-PD1 antibody, in patients with: Locoregionally recurrent or metastatic HNSCC amenable to re-irradiation (RD1), Lung metastasis from HNSCC (not amenable to reirradiation if synchronous locoregional recurrence and metastasis) or NSCLC (not previously irradiated) (RD2), Liver metastasis from HNSCC (not amenable to reirradiation if synchronous locoregional recurrence and metastasis) or NSCLC (not previously irradiated) (RD3)
• Phase2: Complete Response rate by RECIST version 1.1 [ Time Frame: 24 months ]
  To measure by RECIST v1.1 the Complete Response rate.
• Phase2: Incidence of clinical and laboratory adverse events and serious adverse events [ Time Frame: 24 months ]
  To assess the incidence of clinical and laboratory adverse events and serious adverse events.

Current Secondary Outcome Measures (submitted: January 19, 2020)

• Evaluation of the anti-tumor response of R3/RT/PD-1 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 24 months ]
  Evaluation of the time-course dependent accumulation of hafnium in blood and urine following NBTXR3 intratumoral injection

Original Secondary Outcome Measures (submitted: July 4, 2018)

• Phase1: Incidence of clinical and laboratory adverse events and serious adverse events [ Time Frame: 24 months ]
  To assess the incidence of clinical and laboratory adverse events and serious adverse events.
• Phase1: Late onset grade ≥ 3 NCI CTCAE adverse events [ Time Frame: 24 months ]
  To determine the late onset toxicity of NBTXR3 given as intratumoral/intralesional injection activated by SABR in combination with an anti-PD1 antibody. To assess the "late onset" grade ≥ 3 NCI CTCAE adverse events.
• Phase2: Body Kinetic characterization by quantification of Hafnium in whole blood and urine. [ Time Frame: 24 months ]
  To characterize the body kinetic profile by quantification of Hafnium at day 1 of NBTXR3 intratumoral/intralesional injection, activated by SABR in combination with an anti-PD1 antibody.Whole blood will be collected at the end of injection up to 4 hours post end injection. Urine sample will be collected twice after injection.
• Phase2: Tumor response assessment by RECIST version 1.1 and iRECIST criteria [ Time Frame: 24 months ]
  To assess tumor response by RECIST version 1.1 and iRECIST criteria

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: NBTXR3 Activated by Radiotherapy for Patients With Advanced Cancers Treated With An Anti-PD-1 Therapy
• 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
• 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.

• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: N/A; Intervention Model: Sequential Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• 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

• 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 Name: Opdivo
• Drug: Pembrolizumab
  Anti-PD-1 monotherapy
  Other Name: Keytruda

Study Arms

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

Interventions:

• Drug: NBTXR3
• Radiation: SABR
• Drug: Nivolumab
• Drug: Pembrolizumab

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: June 21, 2022): 145
• Original Estimated Enrollment (submitted: July 4, 2018): 125
• Estimated Study Completion Date: May 30, 2028
• Estimated Primary Completion Date: March 30, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• 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

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Pavel Tyan, MD; +49 176 81319375; pavel.tyan@nanobiotix.com

Contact: Rodney Carter; +1 (617) 460-6609; rodney.carter@nanobiotix.com

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03589339
• Other Study ID Numbers: 1100
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Nanobiotix
• Original Responsible Party: Same as current
• Current Study Sponsor: Nanobiotix
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Pavel Tyan, MD; Nanobiotix

• PRS Account: Nanobiotix
• Verification Date: June 2022