Tumor Hypoxia and Proliferation in Patients With High-Grade Glioma

A Phase-I Trial for Simultaneous Imaging of Tumor Hypoxia and Proliferation in Patients With Treatment- Naïve High-Grade Glioma

This is a pilot study to assess a new methodology developed for High Grade Glioma (HGG). FMISO PET (Fluoromisonidazole-PET) allows researchers to study whether tumor cells lack oxygen (hypoxia). FLT PET (Fluorodeoxythymidine-PET) allows researchers to study the increase in the number of cells as a result of cell growth and cell division (proliferation). Tumors that have low oxygen levels and/or are dividing fast shall resist to standard cancer treatment. The study will compare FMISO PET and FLT PET imaging techniques with molecular biomarkers of hypoxia, angiogenesis, and cellular proliferation in tissue. proliferation).This information could help researchers develop new treatment techniques to better treat cancer.

Study Overview

• Status: Recruiting
• Conditions: Glioma
• Intervention / Treatment: Drug: 18F-FMISO PET; Drug: 18F-FLT PET

Detailed Description

This is a pilot study to assess a novel methodology recently developed to simultaneously image tumor hypoxia and proliferation by means of simultaneous FMISO and FLT PET acquisition. FMISO (18F-Fluoromisonidazole) PET is a non-invasive method for detecting tumor hypoxia in solid tumors. FLT (3'-deoxy-3'[(18)F]-fluorothymidine) PET is a non-invasive method to image Cell proliferation rate. Imaging of tumor hypoxia and proliferation with FMISO and FLT PET respectively are two very well established techniques in in high-grade glioma. The long-term goal of this proposal is to establish clinically robust methodology to simultaneously image multiple tumor hallmarks. The central hypothesis is that combined information from multiple tumor hallmarks will offer complementary information about the underlying physiological processes, and will yield synergistic prognostic and predictive values. The rationale is that these findings will enhance the understanding of the underlying biology and pathophysiology, and will open new therapeutic strategies to target radioresistant and highly aggressive regions within the tumor, as well as aiding in the development of imaging theragnostics. The method used in this proposal is based on our previous work on simultaneous imaging of FMISO/FLT PET, and is facilitated by prior knowledge of the tissue pharmacokinetics, and an ability to distinguish the two radiotracers fractions in blood by thin-layer chromatography (TLC). The study will compare FMISO and FLT imaging findings with those from molecular biomarkers of hypoxia, angiogenesis, and cellular proliferation in tissue.

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Sadek Nehmeh, PhD; Phone Number: 212-746-4645; Email: san2028@med.cornell.edu
• Study Contact Backup: Name: Eileen Chang; Phone Number: 646-962-6282; Email: eic2002@med.cornell.edu

Study Locations

• United States
  • New York
    • New York, New York, United States, 10021
      • Recruiting
      • Weill Cornell Medical College
      • Contact: Sadek Nehmeh, Ph.D; Phone Number: 212-746-4645; Email: san2028@med.cornell.edu
      • Principal Investigator: Sadek Nehmeh, Ph.D
      • Contact: Eileen Chang; Phone Number: 646-962-6282; Email: eic2002@med.cornell.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 100 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Male or female ≥ 18 years of age
• Documentation of a suspected HGG diagnosis based on clinical and MRI findings

Exclusion Criteria:

• Pregnant or breastfeeding
• Contraindications to receiving Positron Emission Tomography (PET) imaging (e.g. claustrophobia)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: High Grade Glioma (HGG); Thirty newly diagnosed treatment-naïve subjects with suspected HGG based on clinical presentation and MRI findings and undergoing surgical planning will be accrued in this study.

Drug: 18F-FMISO PET; Suspected HGG subjects will undergo combined FMISO/FLT dyn-PET at baseline as part of surgical planning. Dyn-PET images will be acquired with staggered FMISO/FLT injections using a lag time of 50 minutes. Preoperatively FMISO/FLT dyn-PET data will be used for intraoperative neuro-navigation and targeted sampling of PET avid tumor subregions prior to tumor excision. Paraffin blocks will be analyzed with immuno-histochemistry and in situ hybridization for HIF-1α, Ki-67, VEGF, EGFR, IDH, and pimonidazole, as well as TERT. FMISO-PET uptake rate, k3, (surrogate for hypoxia) and FLT-PET influx rate, Ki (surrogate for proliferation) will be correlated with time to progression, progression-free survival at 9 months, and overall survival (OS) at 1 year.; Other Names: 18F-Fluoromisonidazole; Drug: 18F-FLT PET; Suspected HGG subjects will undergo combined FMISO/FLT dyn-PET at baseline as part of surgical planning. Dyn-PET images will be acquired with staggered FMISO/FLT injections using a lag time of 50 minutes. Preoperatively FMISO/FLT dyn-PET data will be used for intraoperative neuro-navigation and targeted sampling of PET avid tumor subregions prior to tumor excision. Paraffin blocks will be analyzed with immuno-histochemistry and in situ hybridization for HIF-1α, Ki-67, VEGF, EGFR, IDH, and pimonidazole, as well as TERT. FMISO-PET uptake rate, k3, (surrogate for hypoxia) and FLT-PET influx rate, Ki (surrogate for proliferation) will be correlated with time to progression, progression-free survival at 9 months, and overall survival (OS) at 1 year.; Other Names: 3'-deoxy- 3'[(18)F]-fluorothymidine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Quantitation of tumor hypoxia (FMISO) by measuring Dyn PET	Simultaneous quantitation of tumor hypoxia (FMISO): Dyn-PET data will be acquired with staggered FMISO/FLT injections and then the two radiotracer signals will be deconvolved using our novel pharmacokinetics modeling approach (Sections D2, D3, and D4 of Preliminary Data)	1 year
Quantitation of proliferation (FLT) by measuring Dyn PET	Simultaneous quantitation of proliferation (FLT): Dyn-PET data will be acquired with staggered FMISO/FLT injections and then the two radiotracer signals will be deconvolved using our novel pharmacokinetics modeling approach (Sections D2, D3, and D4 of Preliminary Data)	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
FMISO/FLT PET Metrics and Molecular Biomarkers of Tissue Hypoxia, Tissue Angiogenesis, and Tissue Proliferation	FMISO/FLT images will be used for intraoperative neuro-navigation and targeted sampling of FMISO and FLT avid tumor subregions prior to tumor excision. PET metrics will be correlated with immuno-histochemistry (IHC) analyses for HIF-1α, Ki-67, VEGF, EGFR, IDH1, and pimonidazole, as well as molecular analyses of TERT promoter mutation status. Results will be based on a composite score from all measurements. These markers contribute to disease progression in HGG.	1 year

Collaborators and Investigators

• Sponsor: Weill Medical College of Cornell University
• Collaborators: William Rhodes Center for Glioblastoma
• Investigators: Principal Investigator: Sadek Nehmeh, PhD, Weill Medical College of Cornell University

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2021
• Primary Completion (Estimated): December 1, 2024
• Study Completion (Estimated): December 1, 2024

Study Registration Dates

• First Submitted: March 12, 2020
• First Submitted That Met QC Criteria: March 12, 2020
• First Posted (Actual): March 16, 2020

Study Record Updates

• Last Update Posted (Actual): March 25, 2024
• Last Update Submitted That Met QC Criteria: March 22, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Signs and Symptoms, Respiratory; Glioma; Hypoxia; Anti-Infective Agents; Antiviral Agents; Alovudine
• Other Study ID Numbers: 20-02021553

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No