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Gallium 68 PSMA-11

Radiopharmaceuticals

Functional imaging: 68Ga-PSMA and 18F-FDOPA PET-CT Immunohistochemistry of initial chirurgical sample with determination of PSMA expression

This study is a non-randomized, prospective, feasibility study assessing 68Ga-PSMA PET-CT and 18F-FDOPA PET-CT to differentiate early recurrence from post-radiation modifications in patients treated with radiotherapy for glioblastoma.

Patients with a MRI performed since the end of the radiotherapy until 12 months of follow up after the end of radiotherapy, will be referred for both 68Ga-PSMA and 18F-FDOPA PET-CT, whatever the conclusion of the MRI (post radiation modifications, relapse or doubtful MRI).

Feasibility study for the realization of 68Ga-PSMA PET-CT and 18F-FDOPA PET-CT for identification of early recurrence in patients treated with radiotherapy for glioblastoma.

Aurélie MOREAU, M.D

David KRYZA, Pharm.D

François DUCRAY, M.D

This study is a non-randomized, prospective, multicentric feasibility study assessing 68Ga-PSMA PET-CT and 18F-FDOPA PET-CT to differentiate early recurrence from post-radiation modifications in patients treated with radiotherapy for glioblastoma.

Patients with a MRI performed since the end of the radiotherapy until 12 months of follow up after the end of radiotherapy, will be referred for both 68Ga-PSMA and 18F-FDOPA PET-CT, whatever the conclusion of the MRI (post radiation modifications, relapse or doubtful MRI).

The rationale of doing 68Ga-PSMA and 18F-FDOPA brain PET-CT in each case will be discussed in detail with the referring physician and an informed consent will be taken from each patient for the study. The two imaging studies will be done at least with a gap of 6 hours, using the same PET-CT scanner.

Gliomas are the most common primary intra-axial brain tumors arising from the glial cells. The reference treatment consists in a surgical removal followed by radiotherapy and chemotherapy (Temozolomide).

Because of frequent recurrences after first-line therapy, an accurate neuroimaging is needed. The reference anatomical modality is represented by Magnetic Resonance Imaging (MRI), especially multimodal MRI (MRI with gadolinium injection associated with spectroscopy, perfusion and diffusion). One of the particular goals of this imaging is to discriminate recurrences after therapy from radiation-related complications, which can be challenging. These last ones are side effects which turn out after radiotherapy, particularly when high doses are delivered or if chemotherapy is associated. It can occur during the first 3 months after radiotherapy as a subacute radiation related side effects and is then denominated "pseudo-progression", or after the first 3 months of completing radiotherapy as a later and chronic inflammation radiation-related complication named radiation necrosis. It can display clinical symptoms and imaging features which can mimic a relapse. Biopsy is the gold standard but may be not feasible or inconclusive due to limited and non-representative sampling.

The functional nuclear imaging usually completes the anatomical imaging in the oncological response assessment, by providing further metabolic information. Many Positron Emission Tomography (PET) tracers have been studied such as 18F-FDG exploring glucose metabolism, 18F-FLT as a nucleoside analogue, and 18F-FDOPA, 18F-FET, 11C-MET which are radiolabeled amino acids.

A new promising PET radio-tracer is currently soaring. This is the Prostate Specific Membrane Antigen (PSMA) radiolabeled with Gallium 68, a positron emitter, readily available because of a "homemade synthesis". The PSMA is a transmembrane glycoprotein over-expressed in prostate adenocarcinomas

A few studies performed glioblastomas functional imaging based on this PSMA over expression. All achieved to display glioblastomas with 68Ga-PSMA PET-scanner. A recent publication performed on five patients compared 68Ga-PSMA and 18F-FDG in the diagnostic value of glioblastomas recurrence detection. 68Ga-PSMA showed better identification of recurrent lesions owing to a higher target to background ratio. However the place of this new promising tracer in the glioblastomas monitoring remains poorly documented.

Moreover, a study reported that 18F-FDOPA was more accurate than 18F-FDG in the diagnosis of brain tumor recurrence.

To the best of our knowledge, there are no findings concerning 68GA-PSMA and 18F-FDOPA comparison in distinguishing glioblastomas recurrence from radiation-related complications.

Because of the cost and availability of 68Ga-PSMA, if its performances were better than or similar to 18F-FDOPA ones, it could tend to replace this last one in the future. Whether it could be a surrogate to the 18F-FDOPA has not been elucidated yet, representing an interesting challenge.

In this study, the investigators will evaluate the feasibility of using 68Ga-PSMA PET-CT to distinguish recurrent glioblastomas from radiation-related complications, and its comparison with 18F-FDOPA. This study will not allow a proper evaluation of the sensitivity and specificity, which will be performed in a next larger research after completion of this preliminary phase.

Feasibility Study of 68Ga-PSMA PET-CT and 18F-FDOPA PET-CT in Glioblastoma's Patients

Feasibility Study for the Realization of 68Ga-PSMA PET-CT and 18F-FDOPA PET-CT for Identification of Early Recurrence in Patients Treated With Radiotherapy for Glioblastoma

Maximum Standardized Uptake Values (SUVmax) of both 68Ga-PSMA and 18F-FDOPA.

Target to Background Ratio (TBR) of both 68Ga-PSMA and 18F-DOPA.

Target to Background Ratio (TBR) of 68Ga-PSMA and Target to Striatum Ratio of 18F-DOPA.

Assessement of tumour recurrence or radiation-related complication.

Measure of agreement between the two techniques using Kappa coefficient based on tracer uptake (abnormal: yes/no).

PSMA expression by immunohistochemistry (IHC).

PSMA expression detectable on IHC: yes or not

The assessment of safety will be based mainly on the frequency of adverse events according to the common toxicity criteria (CTCAE v5.0) grade.

Centre Leon Berard

Sarcoma

Gliosarcoma

Soft Tissue Sarcoma

Antineoplastic Agents

Temozolomide

in addition to standard radiation and chemotherapy, you will also receive the experimental hyperbaric treatment prior to each radiation treatment (Monday-Friday) during the initial six weeks of treatment. Prior to the first hyperbaric treatment. The hyperbaric treatment lasts approximately thirty minutes. During the hyperbaric treatment, the participant will lie on a stretcher in the hyperbaric chamber and breathe oxygen at greater than normal atmospheric pressure. The investigator will monitor the increased oxygen levels in the tissue by placing a noninvasive electrode on your skin. After each hyperbaric treatment, we will measure your blood sugar by finger-stick to check for hypoglycemia (low blood sugar). If detected, hypoglycemia will be treated by standard medical measures.

Hyperbaric Oxygen Therapy

Kerry E McConie, RN

Julia Trojanowski, RN

J Paul Duic, MD

Jai Grewal, MD

Standard treatment for glioblastomas includes radiation and chemotherapy with a drug called temozolomide (Temodar); however, glioblastomas frequently develop resistance to standard treatment and recur or progress. Glioblastomas are known to have decreased levels of oxygen compared to normal tissues. There is evidence that these lower oxygen levels in glioblastomas may contribute to their ability to resist treatment effects of radiation and chemotherapy. In this study we will look to increase the oxygen concentration within the glioblastoma by adding hyperbaric treatments (the experimental part of this study) to standard treatment with radiation and temozolomide in order to see whether increasing the oxygen concentration within the tumor increases the tumor-killing ability of standard radiation and chemotherapy.

In addition, the investigators are interested to evaluate the effect of this treatment protocol on a person's quality of life and level of stress, and, therefore, the investigators will ask subjects to complete several brief questionnaires while they are on-study.

All enrolled study subjects will receive treatment. Nobody will receive placebo. Before starting on-study, the investigators require standard blood tests (blood counts, chemistries, liver function tests, etc), urinalysis, serum pregnancy test (females of childbearing potential only) and an MRI with contrast (or CAT scan if you are unable to obtain MRI) that the investigators routinely obtain before starting any new treatment or chemotherapy.

Standard treatment for newly diagnosed glioblastomas after surgery begins with six weeks of combined radiation (Monday-Friday) and chemotherapy with an oral drug called temozolomide (Temodar) that patients normally take at home daily (including weekends) during the six weeks. Patients then have four weeks off treatment. After four weeks off, patients resume taking temozolomide on a monthly basis. During this phase of treatment, patients take a higher dose of temozolomide for only five days out of every twenty eight days (they take the drug only during the first five days of every 28 day cycle with the remaining 23 days off drug). Patients continue taking temozolomide on a monthly basis until tumor progression, they complete six to twelve months of treatment or they are unable to tolerate the drug any longer due to side effects.

Temozolomide is typically taken once daily on an empty stomach one-half hour after taking an anti-nausea medication that is also prescribed by your physician. Patients taking temozolomide are also instructed to take lactulose as needed for constipation.

During the initial six weeks of combined radiation and chemotherapy, patients also take an antibiotic to protect against a specific type of pneumonia that commonly occurs in people with weakened immune systems (pneumocystis carinii). Following completion of the combined phase of radiation and chemotherapy, continuation of the antibiotic depends upon the discretion of the treating physician.

In this study, in addition to standard radiation and chemotherapy described above, the patient will also receive the experimental hyperbaric treatment prior to each radiation treatment (Monday-Friday) during the initial six weeks of treatment. Prior to the first hyperbaric treatment, the patient will need to have a chest x-ray performed to make certain that you do not have any preexisting abnormal air spaces in the chest or lungs that could be worsened by hyperbaric treatment. The hyperbaric treatment lasts approximately thirty minutes. During the hyperbaric treatment, the patient will lie on a stretcher in the hyperbaric chamber and breathe oxygen at greater than normal atmospheric pressure. The investigators will monitor the increased oxygen levels in the tissue by placing a noninvasive electrode on your skin. After each hyperbaric treatment, the investigators will measure the participants blood sugar by finger-stick to check for hypoglycemia (low blood sugar). If detected, hypoglycemia will be treated by standard medical measures.

Blood tests will be obtained as per routine standard of care (weekly during the initial six weeks of combined radiation and chemotherapy) and on days # 21 and 28 (+/- 2 days) of each cycle of monthly temozolomide.After the initial MRI (or CAT scan), subsequent MRI's (or CAT scans) will be obtained per standard of care: four weeks after completion of radiation and then generally after every two cycles of chemotherapy unless medically indicated at other time points.

Other scans such as PET scans may be obtained if medically indicated as per standard of care.

This study also looks to evaluate the effect of this treatment regimen on the quality of life for the patient and level of stress. Therefore, the investigators will ask the patient to complete three brief questionnaires at several different time points: before starting the study, at the follow-up visit three to four weeks after completion of radiation, after completion of every two cycles of monthly temozolomide and after coming off study (if possible.) The patient will remain on study until completion of one year of treatment, the patient may voluntarily elect to withdraw from study, the patient cannot tolerate further treatment or side effects prevent continuing on study or there is evidence of tumor progression.

Hyperbaric Hyperoxygenation With Radiotherapy and Temozolomide in Adults With Newly Diagnosed Glioblastoma

Phase II Pilot Trial of Hyperbaric Hyperoxygenation in Conjunction With Radiotherapy and Temozolomide In Adults With Newly Diagnosed Glioblastomas

Neurological Surgery, P.C.

J. Paul Duic, MD

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Dihematoporphyrin Ether

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Photofrin photodynamic therapy. Drug - 2.5 mg/kg, light - 240 mJ/cm2.

The subjects will receive a dose of 2.5 mg/kg of Photofrin intravenously 24 hours before planned surgical resection. Tumor resection will be carried out in the standard fashion in order to achieve the maximum tumor resection compatible with preservation of neurological function. After resection, Intralipid will be infused into the craniotomy and kept for approximately 45 min, while PDT will be performed. The illumination time will be calculated from the power density (mW) emitted by the laser and the radius (r) of the cavity to deliver a total light dose of 240 J/cm2 at a using the following formula:

Treatment Time (sec) = Light dose (J/cm2) x Cavity surface (cm2) x 1000 Power density (mW) Cavity Surface (cm2) = 4 x 3.14 x r2 The optical fiber will be placed in the center of the surgical cavity and photoillumination will commence. After PDT, the Intralipid solution will be removed and the wound will be closed. The subject will be sent to the intensive care area for recovery.

Photofrin photodynamic therapy.

Harry T Whelan, MD

This study will be aimed at investigating the effectiveness of a treatment for brain tumors called Photodynamic Therapy, or PDT. Briefly, a subject will receive a light-sensitive drug, called Photofrin®, the day before a tumor removal surgery. The next day, after the tumor is removed, red light from a laser will be shone into the tumor cavity through a light-diffusing sphere. This light will activate the photosensitizer, and possibly kill any tumor cells that may be left.

We plan to measure how long the subject may go without a new tumor regrowth, and overall how long subjects survive. We will compare these results to typical results to see if we are seeing any improvements.

Objective: To define the antitumor activity of Photofrin® and laser light activation within the confines of a Phase II study.

Photodynamic therapy (PDT) is a well-known treatment for other type of tumors; however it is an experimental treatment for brain tumors. There is much we do not know about the effectiveness of PDT in patients with brain tumors. The purpose of this study is to define the antitumor activity of Photofrin® and laser light activation. Photofrin® is a photosensitizing drug (a dye that is activated by light) used in PDT. We want to test the activity of PDT and to see what are the effects (good and bad) on you and your brain tumor. We also want to learn if this treatment will cause brain tumors to shrink and whether it will help patients with brain tumors to live longer.

PDT is a cancer treatment that involves giving a photosensitive dye (Photofrin®), into your vein through a tube (called an IV). This dye will go inside of the cancer cells more than it will go inside the normal, healthy cells. PDT using Photofrin® is an approved treatment in patients with certain types of cancer such as lung, and esophageal (from the mouth to the stomach) cancers.

Everyone in this study will receive Photofrin® (porfimer sodium) for injection (Pinnacle Biologics, Inc., Bannockburn, IL, USA), and be treated with red light emitted by a red laser. The light will be sent from the laser to the surface of the brain where the tumor is located using a light transmitting fiber. The fiber will have a knob at the end that spreads the light out evenly in all directions.

Previous studies have shown that patients with malignant brain tumors called gliomas had a good response to PDT. The patients in these studies lived longer than they were expected to live. In one study of adults with brain tumors in Australia, patients given PDT had greatly improved survival rates. Fifty seven percent (57%) of the patients with gliomas called anaplastic astrocytoma survived for 36 months. Thirty seven percent (37%) of the patients with gliomas called glioblastoma multiforme survived for 36 months. Froedtert Hospital, in Milwaukee WI, has been involved in PDT studies in adults in the past. This current study is is being done in a very similar way to the study done in Australia, and will use increased Photofrin®) and light doses than our previous study.

Photodynamic Therapy (PDT) For Recurrent High Grade Gliomas

A Phase II Study of Photodynamic Therapy (PDT) With Photofrin® (IND 104,613) For Recurrent High Grade Gliomas in Adults

Relapse free survival is the proportion of subjects who have gone six months since PDT without the disease getting worse.

To obtain preliminary data toward determining whether this combination results in higher remission rate when compared to historical data.

To further explore and report progression-free survival and overall survival for three years post PDT treatment.

To measure complete response, partial response, stable disease or progressive disease using the response assessment for Neuro-Oncology (RANO) criteria with the follow-up medical imaging, which specifically incorporates volumetric measurements of brain tumor enhancement and clinical measures of neurological decline and to compare these outcomes to historical controls.

Pinnacle Biologics Inc.

Bleser Professor of Neurology

Photofrin photodynamic therapy. Drug - 2.5 mg/kg, light - 240 mJ/cm2.

Photofrin photodynamic therapy.: The subjects will receive a dose of 2.5 mg/kg of Photofrin intravenously 24 hours before planned surgical resection. Tumor resection will be carried out in the standard fashion in order to achieve the maximum tumor resection compatible with preservation of neurological function. After resection, Intralipid will be infused into the craniotomy and kept for approximately 45 min, while PDT will be performed. The illumination time will be calculated from the power density (mW) emitted by the laser and the radius (r) of the cavity to deliver a total light dose of 240 J/cm2 at a using the following formula:

Treatment Time (sec) = Light dose (J/cm2) x Cavity surface (cm2) x 1000 Power density (mW) Cavity Surface (cm2) = 4 x 3.14 x r2 The optical fiber will be placed in the center of the surgical cavity and photoillumination will commence.

Photofrin Photodynamic Therapy.

Age, Categorical

Sex: Female, Male

Race and Ethnicity were not collected from any participant.

Race and Ethnicity Not Collected

Early termination with only one participant enrolled.

Dr. Harry T. Whelan

Six Month Relapse-free Survival (RFS).

Study closed before three year period was completed. Only one participant was enrolled.

Remission Rate.

Progression-free Survival and Overall Survival.

Participant lost to followup before secondary outcome was assessed.

Tumor Response.

Overall Study

Nutritional and Metabolic Diseases

Ketosis

Hypoglycemic Agents

Metformin

Insulin

Insulin, Globin Zinc

Biguanides

Partial brain re-irradiation combined with metabolic intervention (low carbohydrate diet and/or metformin treatment)

Partial brain re-irradiation to a dose of 30-35Gy delivered over 2 weeks (10 fractions).

Partial brain re-irradiation.

Different cohorts will receive no, low dose or higher dose metformin.

Under close supervision of a dietician, patients will receive a low carbohydrate diet, enriched as necessary with medium chain triglyceride (MCT) supplements.

low carbohydrate diet

Yaacov R Lawrence, MBBS MA MRCP

Hila Gnessin, Bsc

Yaacov R Lawrence, MA MBBS MRCP

Recurrent brain tumours are extremely aggressive and despite optimal treatment, median survival is less than two years. One of the standard treatment options in this situation is radiation therapy. Currently there is intense scientific interest concerning the abnormal energy metabolism in cancer cells. All cells require energy in order to function, obtaining 'fuel' molecules such as glucose and fatty acids from the blood stream. Brain tumours exhibit "metabolic reprogramming", meaning that their energy requirements and utilization of fuel molecules are quite different from normal cells. Brain tumour cells are exquisitely dependant on glucose as a source of energy. Animal studies have shown that when these tumours are deprived of glucose they are very sensitive to radiation therapy.

In this clinical trial the investigators combine radiation therapy with a low-carbohydrate diet, in patients with recurrent brain tumours. In addition, subjects will receive medication with metformin, a drug usually used to treat diabetes. Metformin inhibits glucose metabolism within cancer cells, and additionally has reported intrinsic anti-cancer activity. Subjects will undergo advanced imaging and hormonal studies before, during and after the trial in order to obtain maximal translational-scientific impact.

The hypothesis:

The metabolic changes induced by the combination of a moderately-low carbohydrate diet combined with supplementary MCT and metformin therapy will selectively starve tumor cells. While normal brain cells are capable of deriving energy from ketone bodies during glucose restriction, tumor cells remain largely glucose-dependent for energy due to oncogene induced down-regulation of oxidative phosphorylation. While the tumor cells are in this 'vulnerable' state they will be less able to repair the damage induced by ionizing radiation.

Short-term implementation of the metabolic intervention (i.e. combined diet and metformin therapy) prior to, during, and after hypofractionated (2 week) radiation therapy is expected to increase tolerability, increase compliance and avoid the chronic metabolic complications associated with extreme carbohydrate restriction diets.

Treatment of Recurrent Brain Tumors: Metabolic Manipulation Combined With Radiotherapy

Improving the Response of Recurrent Glioma to Radiation Therapy Through Metabolic Intervention

The investigators will track adverse events in order to determine the safety of the intervention.

We will track patient compliance in order to determine the tolerability of the intervention.

We will assess plasma levels of glucose, insulin and other relevant hormones before, during and after the intervention.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Feasibility Study of 68Ga-PSMA PET-CT and 18F-FDOPA PET-CT in Glioblastoma's Patients	NCT03903419	Glioblastomas	Feasibility stu...	18 Years -	Centre Leon Berard
Hyperbaric Hyperoxygenation With Radiotherapy and Temozolomide in Adults With Newly Diagnosed Glioblastoma	NCT00936052	Glioblastomas Gliosarcoma	Hyperbaric Oxyg...	18 Years -	Neurological Surgery, P.C.
Photodynamic Therapy (PDT) For Recurrent High Grade Gliomas	NCT01966809	Brain Tumor, Re...	Photofrin photo...	18 Years -	Medical College of Wisconsin
Treatment of Recurrent Brain Tumors: Metabolic Manipulation Combined With Radiotherapy	NCT02149459	Brain Neoplasms	Partial brain r... Metformin low carbohydrat...	18 Years -	Sheba Medical Center

Spots Global Cancer Trial Database for glioblastomas