NBTXR3 Crystalline Nanoparticles and Stereotactic Body Radiation Therapy in the Treatment of Liver Cancers

• ClinicalTrials.gov Identifier: NCT02721056
• Recruitment Status: Unknown
• First Posted: March 28, 2016
• Last Update Posted: February 3, 2017
• Sponsor: Nanobiotix
• Collaborator: Quintiles, Inc.
• Information provided by (Responsible Party): Nanobiotix

Study Description

Brief Summary:

The purpose of this Phase I / II study is to evaluate the safety and preliminary efficacy of NBTXR3 nanoparticles given by intralesional (IL) or intraarterial (IA) injection and activated by Stereotactic Body Radiation Therapy in the treatment of liver cancers.

Condition or disease	Intervention/treatment	Phase
Hepatocellular Carcinoma; Liver Cancer	Radiation: NBTXR3, IL or IA injection + SBRT	Phase 1; Phase 2

Detailed Description:

This is a prospective, open-label, non-comparative and non-randomized study, to be conducted in 2 phases:

• a dose-escalation phase, to determine the recommended dose of NBTXR3 and to evaluate its safety/tolerability and preliminary clinical activity; and
• a dose-expansion phase, which will be a cohort expansion at the recommended dose of NBTXR3.

Patients will receive a single administration of NBTXR3 on day of injection, as a super selective transcatheter arterial or intrahepatic lesion injection activated by Stereotactic Body Radiation Therapy starting 24 hours post injection. The total radiotherapy dose will be maximum 45 Gy, delivered as three fractions of 15 Gy each max, over 5 to 7 days (45 Gy, 3x15 Gy, over 5 to 7 days).

the visit of End of Treatment (EOT) will take place 12 to 13 weeks after the administration of the last radiotherapy fraction and includes the evaluation of global clinical, radiological and laboratory parameters.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 200 participants
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I-II Study of NBTXR3 Activated by Stereotactic Body Radiation Therapy (SBRT) in the Treatment of Liver Cancers
• Study Start Date: November 2015
• Estimated Primary Completion Date: June 2017
• Estimated Study Completion Date: December 2018

Arms and Interventions

Arm

Intervention/treatment

Experimental: NBTXR3, IL or IA injection +SBRT; Patients will receive a single intralesional (IL) injection of NBTXR3 at four increasing dose levels (Volume levels) equivalent to: 10%, 15%, 22%, and 33% of the baseline tumor volume, activated by SBRT.; Patients with primary and secondary nodular intra hepatic cancers only will receive a single superselective transcatheter arterial (IA) injection of NBTXR3 at five increasing dose levels (Volume levels) equivalent to: 10%, 15%, 22%, 33% and 45% of the baseline tumor volume, activated by SBRT.

Radiation: NBTXR3, IL or IA injection + SBRT; Patients will receive a single administration of NBTXR3 on day of injection, as intralesional or super selective transcatheter arterial injection activated by Stereotactic Body Radiation Therapy starting 24 hours post injection. The total radiotherapy dose will be maximum 45 Gy, delivered as three fractions of 15 Gy each max, over 5 to 7 days (45 Gy, 3x15 Gy, over 5 to 7 days).

Outcome Measures

Primary Outcome Measures :

1. Determination of the Recommended Doses Toxicities (DLT) [ Time Frame: 20 Months ]
   To determine the Recommended Doses (DLT) of NBTXR3 administered as two different schedules (intra-lesional or intra-arterial injection), activated by Stereotactic Body Radiation Therapy (SBRT)
2. Determination of the early Dose Limiting [ Time Frame: 20 Months ]
   To determine the early Dose Limiting Toxicities

Secondary Outcome Measures :

1. Number of patients with treatment-related adverse events as assessed by CTCAE v4.0 [ Time Frame: 20 Months ]
2. Response Rate [ Time Frame: 20 Months ]
3. Local Progression Free Survival [ Time Frame: 20 Months ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Age ≥ 18
• Written Informed Consent obtained, signed and dated
• Eastern Cooperative Oncology Group performance status 0 or 1
• Life expectancy > 6 months
• Liver metastases from other primary cancers 1) with histologic confirmation of metastases, or 2) histologic confirmation of primary cancer and multiple new enhancing lesions in the liver consistent with metastases, or 3) histologic confirmation of primary cancer and a growing enhancing lesion in the liver consistent with a metastasis
• Unresectable tumor/s, based on the opinion of an experienced surgeon specializing in hepatic resection, or the patient must be medically inoperable
• Patients with extra-hepatic metastases controlled by supportive care or concomitant hormonotherapy are eligible.
• Previous liver resection or local treatment (radiofrequency ablative therapy, chemoembolization, microwave treatment…) is permitted
• Patients must have recovered from the effects of previous therapy (residual AE grade 0 or 1)
• At least one tumor lesion that can be accurately measured in at least one dimension according to RECIST 1.1
• Normal permeability of hepatic artery evaluated by injected CT-scan (arterial phase)
• 700 cc of liver volume without tumor involvement and a radiation therapy dose < 15 Gy
• Female patients must have a negative serum/urinary pregnancy test

The following laboratory parameters:

• Platelet count ≥ 50 x 10^9/L
• Hemoglobin ≥ 8.5 g/dL
• Absolute neutrophil count ≥ 1.5 x 10^9/L,
• Prothrombin Ratio > 50%
• Prothrombin time - International Normalized Ratio (INR) < 1.5 or correctable with vitamin K
• Patients receiving anti-coagulation or anti-aggregant therapy must stop temporarily during treatment.
• Total bilirubin <30 μmol/l
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 5 x upper limit of normal
• Albumin >2.5 g/dL
• Very low or undetectable Hepatitis B Virus DNA and Hepatitis C Virus RNA
• Serum Creatinine ≤ 1.5 time the upper limit of normal value
• Glomerular Filtration Rate > 44 mL/min/1.73m2
• Pa O2 > 85 mm Hg

Exclusion Criteria:

• Patients with ongoing chronic active viral B or C hepatitis must have received an antiviral treatment with negativation of the viremia or very low viremia before the onset of the radiation therapy
• Biliary tract dilatation, biliodigestive anastomosis, bile duct drainage
• Uncontrolled extra-hepatic metastatic disease with a symptomatic treatment or well tolerated hormonotherapy (AE 0/1)
• Previous cancer cured for less than 2 years
• Previous anticancer treatment (chemotherapy or/and biologicals) with a wash out < 4 weeks
• Previous treatment with intra-arterial injection of Y90 loaded microspheres
• Previous intra-arterial chemotherapy
• Prior radiation therapy to the right upper abdomen, precluding reirradiation of the liver. That is, any previous radiation therapy in which a mean dose to the liver of 15 Gy in conventional fractionation was delivered, or previous doses to critical normal structures that would make re-irradiation unsafe
• Impossibility to follow the dosimetry constraints (mean total liver dose > 15Gy)
• Presence of arterio-veinous intra tumoral shunting
• Encephalopathy related to liver failure
• Clinical ascitis
• Previous or concurrent cancer that is distinct in primary site or histology from Hepatocellular Carcinoma, except cervical carcinoma in situ, treated basal cell carcinoma, or superficial bladder tumors (Ta, Tis &T1)
• Presence of hepato pulmonary syndrome
• Auto immune hemolytic anemia
• Auto immune disorder, excepted auto immune thyroiditis
• Uncontrolled hypertension or congestive heart failure
• Active coronary artery disease (myocardial infarction more than 6 months prior to study entry is permitted)
• Previous gastrointestinal bleed within the past 2 months
• Known syndrome AIDS-related illness or serious non controlled acute or chronic illness
• Active, clinically severe bacterial or fungal infections (> grade 2 CTCAE, version 4.0)
• Complete initial work up earlier than 4 weeks prior to patient registration
• Patient whose general health condition does not allow treatment feasibility
• Patients unable and/or unwilling to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures
• Patients participating in another clinical investigation at the time of signature of the informed consent.

Contacts and Locations

Contacts

Contact: Eveline BOUCHER, MD; eveline.boucher@nanobiotix.com

Contact: Anouar SARI, PhD; anouar.sari@nanobiotix.com

Locations

France

CHU La Croix Rousse; Recruiting

Lyon, France, 69004

Contact: Philippe Merle, MD-PhD

Institut de Cancérologie de Loraine; Recruiting

Nancy, France, 54500

Contact: BAUMANN Anne Sophie, MD

CHU de NANCY; Recruiting

Nancy, France, 54511

Contact: BRONOWICKI Jean-Pierre, MD

Centre René Gauducheau; Recruiting

Nantes, France, 44805

Contact: RIO Emmanuel, MD

Hôpital Haut-Lévêque; Recruiting

Pessac, France, 33604

Contact: VENDRELY Veronique, MD

Centre Eugène Marquis; Recruiting

Rennes, France, 35000

Contact: Elisabeth FLEURY LE PRISE, MD

Institut Gustave Roussy; Recruiting

Villejuif, France, 94800

Contact: France NGUYEN, MD

Sponsors and Collaborators

Nanobiotix

Quintiles, Inc.

Investigators

• Study Director: Mikaela DIMITRIU, PhD; Nanobiotix

More Information

• Responsible Party: Nanobiotix
• ClinicalTrials.gov Identifier: NCT02721056 History of Changes
• Other Study ID Numbers: NBTXR3-103
• First Posted: March 28, 2016
• Last Update Posted: February 3, 2017
• Last Verified: October 2016

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

Additional relevant MeSH terms:

Carcinoma, Hepatocellular; Liver Neoplasms; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Liver Diseases