Neoplasms

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Glioblastoma

Astrocytoma

Glioma

Neoplasms, Neuroepithelial

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Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

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Micronutrients

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Pharmaceutical Solutions

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Ascorbic Acid

Temozolomide

Iron

Alkylating Agents

Ferrosoferric Oxide

Trace Elements

Antineoplastic Agents, Alkylating

Antioxidants

Protective Agents

Parenteral Nutrition Solutions

Vitamin C

Radiation Phase

* Ascorbate: 87.5 g administered intravenously (IV) three times each calendar week for approximately 8 weeks.
* Ferumoxytol: 512 g administered intravenously (IV) the day before radiation and then during weeks 5 to 6 of radiation therapy.
* Radiation: 61.2 Gray (given 1.8 Gray once daily, 5 days per week, for about 7 weeks) or 60 Gray (2.0 Gray once daily for 5 days per week for about 6 weeks)
* Temozolomide: 75 mg/m2, taken orally, once daily, every day, for up to 49 days or until radiation is completed (whichever comes first).

Adjuvant Phase

* Temozolomide: 150 to 200 mg/m2, taken orally, once daily, for five days out of 28 days (where 28 days is one cycle of chemotherapy) for up to six cycles
* Ascorbate: 87.5 g administered intravenously (IV) twice each calendar week of the cycle
* Ferumoxytol: 512 g administered intravenously (IV) the first day of the first cycle of chemotherapy.

Radiation Phase

* Ascorbate: 87.5 g administered intravenously (IV) three times each calendar week for approximately 8 weeks.
* Ferumoxytol: 512 g administered intravenously (IV) the day before radiation, about 1 week after dose 1, during weeks 5 to 6 of radiation therapy, and then a week after that (for a total of 4 ferumoxytol infusions).
* Radiation: 61.2 Gray (given 1.8 Gray once daily, 5 days per week, for about 7 weeks) or 60 Gray (2.0 Gray once daily for 5 days per week for about 6 weeks)
* Temozolomide: 75 mg/m2, taken orally, once daily, every day, for up to 49 days or until radiation is completed (whichever comes first).

Adjuvant Phase

* Temozolomide: 150 to 200 mg/m2, taken orally, once daily, for five days out of 28 days (where 28 days is one cycle of chemotherapy) for up to six cycles
* Ascorbate: 87.5 g administered intravenously (IV) twice each calendar week of the cycle
* Ferumoxytol: 512 g administered intravenously (IV) the first day of the first cycle of

Ferumoxytol is an iron replacement product FDA approved for treatment of iron deficiency anemia in adult patients with chronic kidney disease (CKD). This trial uses the FDA approved dosage (512 mg iron) for iron-deficiency anemia in CKD.

Ferumoxytol injection

Pharmacological ascorbate

Photon based, focal radiation therapy delivered consistent with national guidelines, standard for treatment of GBM.

External beam radiation therapy

Temozolomide is a cytotoxic alkylating agent administered orally that penetrates well into the central nervous system. It is a standard-of-care treatment for GBM.

John M. Buatti, MD

This clinical trial evaluates adding ferumoxytol and pharamcologic ascorbate (vitamin C) to standard of care treatment of glioblastoma multiforme (a type of brain tumor) in adults. All subjects will receive ferumoxytol and pharmacologic ascorbate in addition to the standard treatment.

The initial, standard treatment for glioblastoma multiforme (GBM) involves maximum safe surgical resection followed by radiation combined with temozolomide (a chemotherapy pill you take by mouth).

Participants in this trial will:

* receive intravenous (IV) ferumoxytol the day before starting radiation, then around radiation treatments 6, 25, and 31.
* receive high doses of intravenous (IV) ascorbate three times a week during the combined radiation and chemotherapy phase.
* provide feedback about how they feel and their quality of life. This is done through short surveys as well as discussing with the study team.

A Safety Study of Pharmacologic Ascorbate and Ferumoxytol in Addition to Standard of Care Chemoradiation in Glioblastoma

A First-in-Human Clinical Trial of Pharmacologic Ascorbate and Ferumoxytol Combined With Concomitant Temozolomide and External Beam Radiation Therapy for Newly Diagnosed Glioblastoma

Data will be released publicly as per participant consent and IRB approval. Individual researchers should contact the research team for data sharing.

The recommended dose will be determined by incidence of dose limiting toxicities.

Time (measured in days) to documented disease progression in MRI imaging as described by the RANO criteria.

Objective response rate, measured using standardized RANO criteria, is a reflection of complete tumor response and partial tumor response. The radiation planning MRI will be used as baseline.

Tumor measurements completed as per RANO criteria and compared to the radiation-planning MRI (baseline)

Neurologic assessment in Neuro-Oncology (NANO) composite score evaluating gait, strength, ataxia, sensation, visual fields, facial strength, language, level of consciousness, and behavior and comparing to baseline.

Categorize and quantify adverse events using the Common Terminology Criteria for Adverse Events (v5)

Holden Comprehensive Cancer Center

National Cancer Institute (NCI)

Bryan Allen

Associate Professor

Symptoms and General Pathology

Digestive System Diseases

Carcinoma

Neoplasm Metastasis

Liver Cirrhosis

Carcinoma, Hepatocellular

Atrophy

Liver Neoplasms

Neoplastic Processes

Adenocarcinoma

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Liver Diseases

Fibrosis

Liver Extracts

This study is a single arm prospective study that will enroll 25 patients with primary and metastatic liver tumors and hepatic cirrhosis eligible for liver SBRT who will be receiving treatment at a single center - Allegheny General Hospital.

This is a prospective observation study of 1.5T MR-Linac-SPION imaging with Ferumoxytol for radiotherapy planning in patients with pre-existing liver condition in order to increase safety of liver SBRT with assessment of tumor and hepatic parenchyma response.

Alexander Kirichenko, MD, PhD

There is a high prevalence of hepatic cirrhosis in patients with hepatocellular carcinomas (HCC), or chemotherapy-induced hepatic atrophy or hepatosteatosis in patients with liver metastases associated with high risk of radiation-induced liver disease (RILD) after stereotactic body radiotherapy (SBRT). MRI-SPION radiotherapy planning will facilitate detection and maximize avoidance of residual functionally active hepatic parenchyma from over-the-threshold irradiation thus increasing safety of liver SBRT in patients with pre-existing liver conditions. The investigators have previously demonstrated that liver SBRT with SPECT/CT functional treatment planning utilizing 99mTc sulfur colloid in transplant eligible patients associated with minimal hepatotoxicity and without hastening of advanced hepatic cirrhosis progression while patients await liver transplant. Switching from nuclear medicine to an MR-Linac-SPION based quantitative treatment-planning platform will substantially improve diagnostic accuracy in defining safe volumes of residual functional hepatic parenchyma for liver SBRT planning on MR-Linac.

Setting/Participants:

The study will be performed at a single center - Allegheny General Hospital (AGH) in a setting of referral-based outpatients within the Allegheny Health (AHN) network.

25 patients with primary and metastatic liver tumors and hepatic cirrhosis eligible for liver SBRT will be enrolled in this study.

Study Interventions and Measures:

MRI cellular imaging of hepatic parenchyma with SPION will be performed on a 1.5T MRI (Elekta MR-Linac) on the day of radiotherapy planning. Hepatic SPION accumulation will be quantified and delineated to designate volumes for conformal avoidance on the MR-Linac during liver SBRT. This quantitative assessment will be compared to the already established methodology using CT/SPECT images developed at AGH. Treatment outcomes and toxicity due to improved conformal avoidance of functional normal liver volumes will be assessed for these patients. Dose-response of tumor and hepatic parenchyma to SBRT will be examined using MR-Linac imaging, pathologic criteria and molecular profiling of explanted livers in a subset of patients who received liver SBRT as a bridge to transplant.

Main outcome of the study:

Development and evaluation of a novel MRI-Linac based functional treatment planning platform with DICOM-compatible applications for visualization and subsequent conformal avoidance of residual, functionally active hepatic parenchyma in patients undergoing liver SBRT to primary and metastatic malignancies with the assessment of tumor and hepatic parenchyma response using MR imaging correlated with both pathologic and genomic criteria in a subset of patients receiving SBRT as a bridge to liver transplant.

Radiotherapy With Iron Oxide Nanoparticles (SPION) on MR-Linac for Primary & Metastatic Hepatic Cancers

Adaptive Stereotactic Radiotherapy With Superparamagnetic Iron Oxide Nanoparticles (SPION) Cellular Magnetic Resonance Imaging on MR-Linac (MR-L-SPION) for Primary and Metastatic Hepatic Malignancies With Assessment of Treatment Response.

Only de-identified data will be shared with collaborators of the trial.

The primary goal of the study is to develop MRI-linac SPION based radiotherapy planning platform for detection and conformal avoidance of residual, functionally active hepatic parenchyma during liver SBRT for primary and metastatic hepatic malignancies in patients with hepatic cirrhosis. Treatment outcomes and toxicity due to improved conformal avoidance of functional normal liver volumes will be assessed for these patients.

Progression in Child-Pugh and MELD scores, disease free survival, and overall survival (with and without liver transplant) will be evaluated via Kaplan Meier analysis. Freedom from MELD score progression will be measured against residual volumes of functionally active hepatic parenchyma defined on MRI-linac SPION via Cox proportional hazard regression models. Statistical analysis will be conducted with MedCalc version 11.3.

MRI and planning CT images will be co-registered using deformable image registration, and volumes with SPIO accumulation will be delineated as avoidance structures by the physician and clinical physicist. DICOM-compatible applications will be developed for contouring and quantitative assessment of functionally active volumes of hepatic parenchyma obtained from MR-Linac-SPIO images with subsequent conformal avoidance in the beam placement process during 3-D Conformal radiotherapy planning.

A non-contrast enhanced liver MR images will be acquired per fraction with propagation of the previously identified avoidance volumes in the adapted plans.

Follow-up MR-imaging of the patients will be obtained to assess tumor and hepatic parenchyma response treatment.

The dose-response of tumor and hepatic parenchyma to SBRT will be examined using MR imaging (on MR-Linac), pathologic criteria and molecular profiling of explanted livers in a subset of patients who received liver SBRT as a bridge to transplant.

In patients undergoing liver transplant MRI data sets will be merged with 3D dosimetry data and evaluated by a clinical physicist. Radiographic liver responses will be compared with explant liver pathology. The pathologic and genomic analysis will document both tumor and hepatic parenchymal response to SBRT. The chronology of tumor and hepatic parenchymal response and regeneration to radiotherapy will be evaluated. Initial 3D dosimetry will be combined with the pathologic assessment to determine any dose threshold for healthy liver regeneration following SBRT with MR-Linac SPION functional imaging.

Allegheny Singer Research Institute (also known as Allegheny Health Network Research Institute)

Associate Professor Temple University School of Medicine System Director Stereotactic Body Radiotherapy and GI Cancer Programs Division of Radiation Oncology Allegheny Health Network Cancer Institute

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Safety Study of Pharmacologic Ascorbate and Ferumoxytol in Addition to Standard of Care Chemoradiation in Glioblastoma	NCT04900792	Glioblastoma Glioblastoma Mu...	Ferumoxytol inj... Pharmacological... External beam r... Temozolomide	18 Years -	University of Iowa
A Safety Study of Pharmacologic Ascorbate and Ferumoxytol in Addition to Standard of Care Chemoradiation in Glioblastoma	NCT04900792	Glioblastoma Glioblastoma Mu...	Ferumoxytol inj... Pharmacological... External beam r... Temozolomide	18 Years -	University of Iowa
Radiotherapy With Iron Oxide Nanoparticles (SPION) on MR-Linac for Primary & Metastatic Hepatic Cancers	NCT04682847	Liver Neoplasms Hepatic Cirrhos... Hepatic Carcino... Liver Cancer Liver Metastase... Liver Carcinoma Hepatocellular ... Hepatocellular ... Hepatic Atrophy	Ferumoxytol inj...	18 Years - 89 Years	Allegheny Singer Research Institute (also known as Allegheny Health Network Research Institute)

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