NU-0129 in Treating Patients With Recurrent Glioblastoma or Gliosarcoma Undergoing Surgery

Study Overview
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Brief Summary
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The purpose of this research study is to evaluate the safety of the study drug, NU-0129, based on Spherical Nucleic Acid (SNA) platform when infused in patients with recurrent glioblastoma multiforme or gliosarcoma. The SNA consists of nucleic acids arranged on the surface of a small spherical gold nanoparticle. This is a first-in-human trial to determine the safety of NU-0129. NU-0129 can cross the blood brain barrier (a filtering mechanism that carry blood to the brain). Once within the tumor, the nucleic acid component is able to target a gene called Bcl2L12 that is present in glioblastoma multiforme, and is associated with tumor growth. This gene prevents tumor cells from apoptosis, which is the process of programmed cell death, thus promoting tumor growth. Researchers think that targeting the Bcl2L12 gene with NU-0129 will help stop cancer cells from growing.

Detailed Description
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PRIMARY OBJECTIVES: I. To assess the safety of intravenous NU-0129 in patients with recurrent glioblastoma multiforme (GBM) or gliosarcoma (GS). SECONDARY OBJECTIVES: I. To analyze drug concentration in serum at specific time points after drug administration. II. To demonstrate intratumoral penetration of NU-0129. III. To assess the feasibility of giving NU-0129 as a standard treatment for recurrent GBM or GS. TERTIARY OBJECTIVES: I. To analyze tumor tissue for Bcl2L12 expression levels after NU-0129 administration. II. Preliminary response (progression free survival [PFS] and overall survival [OS] at 6 months; overall response rate [ORR]). OUTLINE: Patients receive NU-0129 intravenously (IV) over 20-50 minutes and undergo standard of care tumor resection within 8-48 hours. After completion of study treatment, patients are followed up at 7, 14, 21, and 28 days and then every 84 days for up to 2 years.

Official Title
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A Phase 0 First-In-Human Study Using NU-0129: A Spherical Nucleic Acid (SNA) Gold Nanoparticle Targeting BCL2L12 in Recurrent Glioblastoma Multiforme or Gliosarcoma Patients

Conditions
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Gliosarcoma, Recurrent Glioblastoma

Intervention / Treatment
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* Other: Laboratory Biomarker Analysis
* Other: Pharmacological Study
* Drug: Targeted Molecular Therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have histologically proven glioblastoma multiforme (GBM) or gliosarcoma (GS) Patients must have measurable disease by Response Assessment in Neuro-Oncology (RANO) 2010 criteria at the time of registration (pre-operative) Patients must have failed at least one regimen of chemo or radiation therapy; NOTE: There is no limit to the number or types of prior therapy The patient must be a candidate for surgical debulking (either subtotal or gross total resection); biopsy-only candidates will not be eligible All patients must be capable to voluntarily sign an informed consent indicating that they are aware of the investigational nature of this study prior to registration Patients must have a Karnofsky performance status of >= 70 Patients must have adequate bone marrow, liver, coagulation and renal function within 7days prior to study registration, as defined below: White blood cell count (WBC) >= 3,000/uL Absolute neutrophil count (ANC) >= 1,500/mm^3 Platelet count of >= 100,000/mm^3 (Note: Transfusion or growth factor may be used for eligibility outside of 7 days) Hemoglobin >= 8 mg/dL (Note: Transfusion may be used for eligibility outside of 7 days) Bilirubin =< 2 x upper limit of normal (ULN) Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2 x ULN Creatinine =< 1.5 x ULN Urine protein =< 3 x ULN Cholesterol =< 300 mg/dL International normalized ration (INR) =< 1.5 x ULN Prothrombin time (PT)/partial thromboplastin time (PTT) =< 1.5 x ULN Any patient who has had a recent surgery should have recovered from all effects of the surgery and be cleared by their surgeon Patients must have confirmed availability of archival or freshly biopsied tumor tissue meeting protocol-defined specifications (10 unstained slides) prior to study enrollment Females of child-bearing potential (FOCBP) and males must agree to use adequate contraception (e.g. hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 28 days following completion of therapy; should a female patient, or a male patient's partner, become pregnant or suspect she is pregnant while participating in this study, the patient should inform her or his treating physician immediately NOTE: A FOCBP is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria: Has not undergone a hysterectomy or bilateral oophorectomy Has had menses at any time in the preceding 12 consecutive months (and therefore has not been naturally postmenopausal for > 12 months) FOCBP must have a negative pregnancy test (either urine or serum) within 14 days prior to registration Exclusion Criteria: Patients must not have any significant infections or medical illnesses that in the investigator's opinion cannot be adequately controlled with appropriate therapy or would compromise the patient's ability to tolerate NU-0129 Patients must not have a history of any other cancer unless they are in complete remission and off of all therapy for that disease for a minimum of 3 years Note: Non-melanoma skin cancer or carcinoma in-situ of the cervix are exceptions and may be permitted after discussion with study quality assurance manager (QAM) Patients must not have had radiation therapy within 12 weeks prior to registration Patients must not have had prior cancer therapy (including biologic, cytotoxic, and experimental therapies, nitrosoureas, and Gliadel wafers or other surgically implantable antitumor treatment) within 21 days of registration; if questions arise, please ask the principal investigator (PI) NOTE: Patients must not have Novocure within 24 hours Hormonal tumor therapies should not be administered within 14 days of registration; exceptions may be discussed with the PI Patients must not have symptomatic hypertension Patients with known human immunodeficiency virus (HIV) infection or chronic or acute hepatitis B or C are not eligible; Note: Patients do not need to have HIV, hepatitis B, or hepatitis C testing at screening Female patients who are pregnant or breast feeding are not eligible Patients are not eligible if they are unwilling or unable to comply with the protocol

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (NU-0129)<br>Patients receive NU-0129 IV over 20-50 minutes and undergo standard of care tumor resection within 8-48 hours. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Pharmacological Study<br>* Correlative studies<br>Drug: Targeted Molecular Therapy<br>* Given NU-0129 IV<br>* Other names: molecularly targeted therapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Adverse Events | To evaluate the safety of intravenous NU-0129 in patients with recurrent GBM or GS, the number of adverse events will be assessed and will be graded according to the NCI's Common Terminology Criteria in Adverse Events (CTCAE) version 4.03 where the grading is as follows: Grade 1: Mild Grade 2: Moderate Grade 3: Severe Grade 4: Life-threatening Grade 5: Fatal | Up to 21 days after study drug administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| NU-0129 Concentration in Blood After Drug Administration Using Maximum Concentration | Blood samples will be collected post-infusion to analyze drug concentration at specific time points after drug administration. Median plasma concentrations of NU-0129 were derived from time profiles for both Seven different small interfering RNA (siRNA) and gold (Au) concentrations, with Au plasma concentration determined by inductively coupled plasma mass spectrometry (ICP-MS) and siRNA concentration assessed by liquid chromatography-high performance liquid chromatography (LC-HPLC) using an atto dye-labeled PNA probe. | At 1, 3, 5, 10, 30, and 60 minutes, and 4, 8, and 24 hours post infusion | 
| Biodistribution of NU-0129 in Tumor Tissue | Tissue will be collected during the scheduled surgery and assayed with Inductively Coupled Plasma Mass Spectrometry (ICP-MS) to analyze the concentration of particles in various parts of tumor tissue. To analyze spatial distribution of Au within tumor tissue, synchrotron XFM elemental maps of GBM tissue slices were acquired at micron and submicron resolution and matched to adjacent hematoxylin and eosin (H&E)- and Ki67-stained tumor sections. Approximate percentage of gold (Au) found in cancer cells is reported below. | At time of surgery | 
| Feasibility of Giving NU-0129 as a Standard Treatment | Feasibility will be calculated as the rate of successful production, delivery, and administration of the investigational product and subsequent resection. | At time of infusion (8-48 hours prior to resection) and during surgery | 
| NU-0129 Concentration in Blood After Drug Administration Using Half-life | Blood samples will be collected post-infusion to analyze drug concentration at specific time points after drug administration. Median plasma concentrations of NU-0129 were derived from time profiles for both Seven different small interfering RNA (siRNA) and gold (Au) concentrations, with Au plasma concentration determined by inductively coupled plasma mass spectrometry (ICP-MS) and siRNA concentration assessed by liquid chromatography-high performance liquid chromatography (LC-HPLC) using an atto dye-labeled PNA probe. | At 1, 3, 5, 10, 30, and 60 minutes, and 4, 8, and 24 hours post infusion |