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Hydroxocobalamin

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Methylcobalamin

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Cobalamin

Cyanocobalamin

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Vitamin B9

Patients receive oral Boswellia serrata extract 4 times a day and oral cyanocobalamin (vitamin B 12) once a day for 6 months in the absence of unacceptable toxicity.

Patients in the control arm receive oral cyanocobalamin (vitamin B 12) once a day for 6 months.

Boswellia serrata extract

cyanocobalamin

Glen Stevens, DO, PhD

RATIONALE: Giving the herb Boswellia serrata after surgery and radiation therapy may slow the growth of any remaining tumor cells. It is not yet known whether giving Boswellia serrata together with standard treatment is more effective than standard treatment alone in treating high-grade gliomas.

PURPOSE: This randomized phase II trial is the study of a combination of complementary and alternative medicine (CAM) herbal supplement intervention as an adjuvant to standard treatment of patients with newly diagnosed and recurrent high-grade gliomas (HGG). The central hypothesis of this application is that a herbal preparation that inhibits 5-LO activity, will produce measurable biologically meaningful decrease in 5-LO eicosanoid production and brain edema that will be associated with improved survival and quality of life in patients with HGG.

OBJECTIVES:

Primary

* To determine whether a herbal approach to decreasing 5-LO eicosanoid production reduces peritumoral brain edema in patients with HGG.

Secondary

* To determine if this adjuvant approach improves the quality of life and progression free and overall survival of patients with HGG.

OUTLINE: This a randomized, controlled study. Patients are randomized to 1 of 2 treatment arms.

* Arm I (intervention): Patients receive oral Boswellia serrata herbal extract 4 times a day and oral cyanocobalamin (vitamin B-12) once a day for 6 months in the absence of unacceptable toxicity.
* Arm II (control): Patients receive oral vitamin B-12 once a day for 6 months. All patients are encouraged to eat a regular balanced diet (as recommended by the American Cancer Society for cancer prevention) with limited consumption of red and processed meats.

Quality of life will be assessed at baseline and then at 2, 4, 6, 12, and 24 months.

After completion of study treatment, patients will be followed every 6 months.

PROJECTED ACCRUAL: A total of 70 patients (35 per treatment arm) will be accrued for this study.

Dietary, Herbal and Alternative Medicine in Glioblastoma Multiforme

Phase II Randomized Evaluation of 5-Lipoxygenase Inhibition by Herbal Complementary and Alternative Medicine Approach Compared to Control as an Adjuvant Therapy in Newly Diagnosed and Recurrent High-grade Gliomas

The 3-day food diary will be used to assess the dietary intake and to increase eating awareness of patients.

The relative change from baseline will be assessed longitudinally, however, the main comparison of interest is the relative change at the 4-month evaluation. For each patient change = edema at follow up - baseline edema

The relative change from baseline will be assessed longitudinally, however, the main comparison of interest is the relative change at the 4-month evaluation.For each patient change = edema at follow up - baseline edema.

The relative change from baseline will be assessed longitudinally, however, the main comparison of interest is the relative change at the 4-month evaluation. For each patient change = edema at follow up - baseline edema.

Quality of life as assessed by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 Items (EORTC QLQ-C30)

Percentage of participants with tumor progression (\>25% increase in tumor volume compared to time 0) will be measured from enrollment to documented progression or death whichever comes first. The method used to calculate the time to tumor progression was Kaplan Meier test method to define the 95% confidence levels.

Overall survival will be measured from the date of enrollment to date of death or last contact. Survival will be evaluated by the Kaplan Meier method to evaluate the median survival and 1 year survival rates.

National Cancer Institute (NCI)

Ali Altunkaya

Principal Investigator

Patients receive oral Boswellia serrata extract 4 times a day and oral cyanocobalamin (vitamin B 12) once a day for 6 months in the absence of unacceptable toxicity.

cyanocobalamin : 50 ug/day given orally

Boswellia serrata extract : 4x (3-12.5) ml/day given orally, that is 720-3000mg of total Boswellic acids (three isomers)/day

Arm I (Intervention)

Patients in the control arm receive oral cyanocobalamin (vitamin B 12) once a day for 6 months.

cyanocobalamin : 50 ug/daygiven orally

Arm II (Control)

Total

30-39 years

40-49 years

50-59 years

60-69 years

70-79 years

Age, Customized

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Baseline measure was acquired for 11 patients. Six on Arm I and five on Arm II.

Baseline edema measure

Certain outcome analysis not done due to low patient accrual.

Dr. Glen Stevens

Patients with baseline and follow up peritumoral edema measurement. Closest measurement to time point was used. When 4 month was not available last prior was used.

Change From Pooled Baseline in Peritumoral Brain Edema

Change From Baseline in Peritumoral Brain Edema

At baseline and the most recent post treatment point in time, the QOL data for group 1 consist of n=3 patients and for group 2, n=2. Because of low patient numbers, no analysis was done.

Quality of Life at 6 Months

All 12 patients followed to progression or death, or censored at last visit when known alive

Time-to-tumor-progression: Percentage of Patients With Tumor Progression at 6 Months

Time-to-tumor-progression: Percentage of Patients With Tumor Progression at 1 Year

All 12 patients followed to death or censored at last visit when known alive

Overall Survival: Percentage of Patients That Were Alive at 1 Year

Patients in the control arm receive oral cyanocobalamin (vitamin B 12) once a day for 6 months.

cyanocobalamin : 50 ug/day given orally

Food Intake as Assessed by the Block 98 Food Frequency Questionnaire and a 3-day Food Record

Overall Study

Neoplasm Metastasis

Brain Neoplasms

Neoplastic Processes

Hypoglycemic Agents

Glyburide

Step 1: Patients with brain metastases requiring SRS and not taking corticosteroids 5 days prior to SRS. Treatment planning MRI may be done within 21 days prior to SRS treatment.

Step 2: Take Glyburide 1.25mg (twice a day by mouth) beginning 5 days prior to SRS. Receive glucose monitoring materials and blood glucose education- begin glucose monitoring (4 times a day).

Step 3: 1 week after SRS, return to clinic to review glucose logs- continue glyburide and blood glucose monitoring.

Step 4: 1 month after SRS, discontinue both glyburide and blood glucose monitoring, undergo MRI.

Step 5: 3 months after SRS, undergo MRI.

Step 1: Patients with brain metastases requiring SRS and not taking corticosteroids 5 days prior to SRS.Treatment planning MRI may be done within 21 days prior to SRS treatment.

Step 2: Randomization (1:1)

* Group 1: take Glyburide (1.25mg, twice a day by mouth) beginning 5 days prior to SRS. Receive glucose monitoring materials and blood glucose education. Begin glucose monitoring (once a day) {This portion will be double blinded}.
* Group 2: Take Placebo (1 pill, twice a day by mouth) beginning 5 days prior to SRS. Receive glucose monitoring materials and blood glucose education. Begin glucose monitoring (once a day) {This portion will be double blinded}.

Step 3: 1 week after SRS, return to clinic to review glucose logs, continue investigation medication, but discontinue glucose monitoring.

Step 4: 1 month after SRS, discontinue investigation medication, undergo MRI.

Step 5: 3 months after SRS, undergo MRI.

Placebo

Primary Objectives:

Pilot Portion: To determine the feasibility and safety of administering oral glyburide to non-diabetic patients receiving stereotactic radiosurgery (SRS) for newly diagnosed brain metastases.

Randomized Portion: To determine the number of patients with newly diagnosed brain metastases who have an increase in edema as measured on volumetric FLAIR imaging and the number of patients that require dexamethasone administration (or any corticosteroid administration with the purpose of treating cerebral edema) from the day of SRS to one month follow-up MRI in the group receiving glyburide versus placebo.

Many patients with cancer that has spread to the brain have side effects caused by swelling around the tumors. A common treatment for this swelling is a medicine called dexamethasone. Dexamethasone is a steroid. Long-term use of steroids has several known side effects.

Recent studies have shown that a drug commonly used in to control high blood sugar in diabetes, called glyburide, can decrease brain swelling in patients with brain damage or stroke. Animal studies have shown that this drug may also reduce swelling from tumors in the brain. Researchers are interested in whether glyburide could treat brain swelling as well as dexamethasone with fewer side effects.

This study is being done to see whether glyburide is safe to be used in patients without diabetes in combination with receiving SRS for brain metastases. This study will also find out if glyburide will decrease brain swelling in patients that get radiosurgery (SRS) for brain metastases. This study will also find out if taking glyburide will decrease the chance of needing steroids due to brain swelling that is causing symptoms. It is not yet known, but it is the investigators' hope that glyburide will both decrease brain swelling and lessen the chance of needing steroids.

Glyburide vs Placebo as Prophylaxis Against Cerebral Edema in Patients Receiving Radiosurgery for Brain Metastases (RAD 1502/UAB 1593)

A Pilot Study and Phase II Double Blind Placebo Controlled Randomized Trial Examining the Safety and Efficacy of Glyburide as Prophylaxis Against Cerebral Edema in Patients Receiving Radiosurgery for Brain Metastases

Assessed between the time of glyburide initiation and the time of the one month follow-up MRI.

Assessed between the time of SRS and the time of the one month follow-up MRI.

Measured between the time of SRS and the time of the one and three month post SRS MRI scans.

Incidence of CTCAE version 4.0 reportable toxicities of grades 2-5.

Incidence of CTCAE version 4.0 reportable toxicities of grades 1-2 Cardiac Disorders or Hepatobiliary Disorders.

Defined from MRI taken at the time of SRS and the time of the one and three month post SRS MRI scans.

Absolute volume change of index tumor(s) that received radiosurgery as manually contoured by the radiation oncologist defined from T1 post gadolinium sequences at the time of SRS and the time of the one and three month post SRS MRI scans.

University of Alabama at Birmingham

While one patient was enrolled, this patient did not experience any AEs.

Step 1: Patients with brain metastases requiring SRS and not taking corticosteroids 5 days prior to SRS. Treatment planning MRI may be done within 21 days prior to SRS treatment.

Step 2: Take Glyburide 1.25mg (twice a day by mouth) beginning 5 days prior to SRS. Receive glucose monitoring materials and blood glucose education- begin glucose monitoring (4 times a day).

Step 3: 1 week after SRS, return to clinic to review glucose logs- continue glyburide and blood glucose monitoring.

Step 4: 1 month after SRS, discontinue both glyburide and blood glucose monitoring, undergo MRI.

Step 5: 3 months after SRS, undergo MRI.

Glyburide: 1.25mg, twice a day

Pilot Portion

Step 1: Patients with brain metastases requiring SRS and not taking corticosteroids 5 days prior to SRS.Treatment planning MRI may be done within 21 days prior to SRS treatment.

Step 2: Randomization (1:1)

* Group 1: take Glyburide (1.25mg, twice a day by mouth) beginning 5 days prior to SRS. Receive glucose monitoring materials and blood glucose education. Begin glucose monitoring (once a day) {This portion will be double blinded}.
* Group 2: Take Placebo (1 pill, twice a day by mouth) beginning 5 days prior to SRS. Receive glucose monitoring materials and blood glucose education. Begin glucose monitoring (once a day) {This portion will be double blinded}.

Step 3: 1 week after SRS, return to clinic to review glucose logs, continue investigation medication, but discontinue glucose monitoring.

Step 4: 1 month after SRS, discontinue investigation medication, undergo MRI.

Step 5: 3 months after SRS, undergo MRI.

Glyburide: 1.25mg, twice a day

Placebo: 1.25mg, twice a day

Randomized Portion

Age, Categorical

Age, Continuous

Dr. Hunter Boggs

Number of Participants With Dose Limiting Toxicities (DLTs)

Randomized Portion: Occurrence of Edema Increase and Initiation of Dexamethasone (or Any Corticosteroid Administration With the Purpose of Treating Cerebral Edema)

Number of Participants Administered Dexamethasone (or Any Corticosteroid Administration With the Purpose of Treating Cerebral Edema)

Number of Participants With CTCAE Version 4.0 Reportable Toxicities of Grades 2-5.

no patients were accrued to the randomized portion

Number of Participants With CTCAE Version 4.0 Reportable Toxicities of Grades 1-2 Cardiac Disorders or Hepatobiliary Disorders.

no patients accrued to the randomized portion

Number of Participants With Cerebral Edema Increase as Measured on FLAIR Volumetric Imaging

Number of Participants With Absolute Volume Change of Index Tumor(s)

Gastrointestinal Agents

Antisecretory factor

Loperamide

Antidiarrheals

Salovum®, an egg powder enriched for anti secretory factor.

Egg yolk powder enriched for anti secretory factor

Salovum

Peter Siesjö, MD, PhD

This is a non-randomised, open-label, single center-centre, Phase I-II study in patients with newly diagnosed glioblastoma. 5 patients with newly diagnosed glioblastoma are enrolled in the study and will receive an egg powder enriched for antisecretory factor (AF), Salovum, daily from 2 days before concomitant radio-chemo therapy until 14 days after finalisation.The primary aim of the study is to asses safety and feasibility of this regimen.

Glioblastoma (GBM) is the most common primary brain tumor and also has the worst prognosis with a mean survival time below 1 year and a 5-year survival rate of less than 2%.

AF is a 41kilodalton endogenous and essential protein encompassing antisecretory and anti-inflammatory effect. Endogenous AF activity increases after exposure to bacterial toxins and endogenous triggers of inflammation. The active amino-terminal portion of AF has been synthesized as a 16 amino acid peptide (AF-16) and has been used in animal experimental studies. Salovum® is a product based on egg yolk powder B221® and contains high levels of AF. Salovum® is classified as food for special medicinal purposes (FSMP) by the European Union.

Many tumors show elevated interstitial fluid pressure (IFP) compared to the surrounding tissue due to vascular leakage, providing a barrier for drug uptake in solid tumors, as well as poor perfusion, resulting in hypoxia and relative resistance to radiochemotherapy.

In a mouse model of malignant brain tumor, preliminary findings show that intratumoral infusion of AF-16 greatly enhances the effect of simultaneous intratumoral temozolomide treatment (90% and 40% survival, respectively). AF-16 also has preliminarily significant immune modulatory effects on myeloid cells in vitro, but also effects on the secretion of immune modulatory agents from tumor cells. AF-16 was reported to significantly reduce the IFP in xenotransplanted human glioblastoma by inhibiting an ionic pump, NKCC1, in the tumor tissue. Both Salovum® and AF-inducing specific processed cereals (SPC) prolonged survival in the same models. Systemic temozolomide treatment combined with AF inducing SPC completely blocked tumor growth in GBM xenografts. Likewise, SPC treatment abrogated 90% of pre-established syngeneic tumors in immune competent animals.

Mechanistically, it remains unclear whether AF's effect in tumor models is mediated through decrease of IFP and/or immunomodulation. Also, an effect on the complement system through modulation of circulating complement complexes with proteasome units has been proposed.

Salovum® has been administered to patients with various diseases as, inflammatory bowel disease, Mb Ménière and mastitis and traumatic brain injury without signs of any adverse effects.

The described study is a safety and feasibility study and if these criteria are fulfilled, will be followed by a randomised controlled trial.

Phase 1-2, open label, single arm, single center.

Antisecretory Factor in Primary Glioblastoma 1

Antisecretory Factor, Administered as an Enriched Egg Powder, Salovum®, as Supplementary Therapy for Primary Glioblastoma During Concomitant Radio-chemotherapy.

As there are only 5 patients in this study individual patient data without age and gender will be shared after publication

Number of participants with decreased cognitive function assessed by Mini Mental State Examination (MMSE)

Neurologic function assessed by Neurologic Assessment in Neuro-Oncology (NANO) scale. Minimum 0 (no deficits) and maximum 25 (maximum deficits)

Number of participants with decreased performance assessed by Eastern Oncology Cooperative Group (ECOG) scale. Minum 0 (normal function) and maximum 4 (maximum disability)

Number of participants with decreased quality of life assessed by European Organization of Research and Treatment of Cancer (EORTC) quality of life questionnaire (QLQ) C30 and brain cancer module (BN20) questionnaire

Treatment related adverse events as assessed by CTCAE v 5.0

Defined as completing prescribed full Salovum treatment

Blood levels of triglyceride and cholesterol above normal range or increased from baseline

Intake of oral corticosteroids assessed weekly during and after intervention.

Analysis of anti secretory factor-16 (AF-16) blood levels by enzyme linked immunoassay

Analysis of interleukin-6 (IL-6), interleukin- (IL-8), monocyte chemotactic protein-1 (MCP-1), macrophage inflammatory protein-1a (MIP-1a), macrophage inflammatory protein-1b (MIP-1b) by multiplex analysis

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Dietary, Herbal and Alternative Medicine in Glioblastoma Multiforme	NCT00243022	Brain and Centr... Cerebral Edema	Boswellia serra... cyanocobalamin	18 Years -	Case Comprehensive Cancer Center
Dietary, Herbal and Alternative Medicine in Glioblastoma Multiforme	NCT00243022	Brain and Centr... Cerebral Edema	Boswellia serra... cyanocobalamin	18 Years -	Case Comprehensive Cancer Center
Dietary, Herbal and Alternative Medicine in Glioblastoma Multiforme	NCT00243022	Brain and Centr... Cerebral Edema	Boswellia serra... cyanocobalamin	18 Years -	Case Comprehensive Cancer Center
Glyburide vs Placebo as Prophylaxis Against Cerebral Edema in Patients Receiving Radiosurgery for Brain Metastases (RAD 1502/UAB 1593)	NCT02460874	Cerebral Edema Brain Metastase...	Glyburide Placebo	18 Years -	University of Alabama at Birmingham
Antisecretory Factor in Primary Glioblastoma 1	NCT04116138	Glioblastoma Cerebral Edema Chemotherapy Ef...	Salovum	18 Years - 69 Years	Skane University Hospital
Antisecretory Factor in Primary Glioblastoma 1	NCT04116138	Glioblastoma Cerebral Edema Chemotherapy Ef...	Salovum	18 Years - 69 Years	Skane University Hospital
Antisecretory Factor in Primary Glioblastoma 1	NCT04116138	Glioblastoma Cerebral Edema Chemotherapy Ef...	Salovum	18 Years - 69 Years	Skane University Hospital

Spots Global Cancer Trial Database for cerebral edema