Clinical trial NCT06016452: A Study of Chlorophyllin for the Management of Brain Radio-necrosis in Patients With Diffuse Glioma
Official title: A Prospective Phase 2 Study of Chlorophyllin for the Management of Brain Radionecrosis in Patients With Diffuse Glioma
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Diffuse Glioma
Radionecrosis of Brain
High Grade Glioma
Glioblastoma Multiforme
Lead sponsor: Tata Memorial Centre
Sponsor class: OTHER
Collaborators: name: Bhabha Atomic Research Centre (BARC)
First posted: 2023-08-29
Enrollment: 118
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: The proposed phase II prospective study will be split into two strata: Stratum A (symptomatic RN) and Stratum B (asymptomatic RN).
Primary purpose: TREATMENT

Brief summary: Diffuse gliomas are common tumors involving the brain. They are usually treated by surgery followed by radiation and chemotherapy. Radiotherapy is used for the treatment of brain tumors which causes damage to the tumor cells. However, radiotherapy can also affect the surrounding healthy cells in the brain, causing inflammation and swelling in the region, which is known as radio necrosis (RN). This is considered a late side effect of radiation and is seen in 10-25% of patients treated with radiation for brain tumors. Sometimes, radionecrosis can be detected on routine imaging during follow-up without new symptoms (asymptomaticRN).

At the same time, in some patients, it can give rise to new symptoms like headaches, weakness, seizures,etc (symptomatic RN). The standard treatment of RN includes steroid medicines called dexamethasone, which is helpful in a proportion of patients.

This is a prospective phase 2 study. This study is being conducted to investigate the ability of the drug Chlorophyllin in the treatment of radionecrosis.

Chlorophyllin is a water-soluble compound obtained from the green plant pigment called chlorophyll. It has been shown to have anti-cancer, anti-bacterial, anti-viral, anti-inflammatory, and antioxidant properties. It is also used as an oral formulation and is an over-the-counter drug in various countries, and also as a food colouring agent.

This is the first time chlorophyllin will be used in the setting of brain radionecrosis. Our primary aim of the study is to assess whether CHL will improve the clinical-radiological response rates. This study will be conducted on a population of 118 patients for a duration of 3 months. The total study duration is 2 years.

The study is funded by Bhabha Atomic Research Centre (BARC).

Detailed description: Radiotherapy (RT) forms an integral role in the multi modality management of diffuse gliomas. Radiation is indicated in low-grade gliomas with high-risk features or high-grade gliomas following maximal safe resection. Higher doses of RT can lead to symptomatic radio-necrosis (RN) in approximately 5-15% of patients, typically within the first 2-3 years of RT completion. Development of RN can lead to significant morbidity with new-onset or worsening of pre-existing neurodeficit with substantial implications on quality of life, and in extreme situations, can lead to mortality as well. The pathogenesis of RN is multi factorial, with a complex interplay of vascular-mediated damage and injury to glial cells primarily postulated through the activation of several inflammatory markers like tumor necrosis factor, interleukins, and vascular endothelial growth factor. Corticosteroids, preferably dexamethasone, form the first line of management of RN, with variable response rates ranging from 25-60%, impacted by several factors like a dose of RT and response evaluation methods (neurological/ radiographic). The response rate in our practice concurs with the reported literature with combined clinical and radiological responses seen in approximately 50% of patients from institutional experience and audit. It is important to note the long-standing use of corticosteroids comes at the cost of complications like hyperglycemia, myopathy, and increased risk of infections precluding prolonged use. Also, a proportion of patients remain refractory to steroids or turn out to be dependent on steroids, where bevacizumab (anti-angiogenic agent) can be used as second-line therapy in appropriately selected patients. However, the major disadvantages of bevacizumab remain intravenous administration requiring regular hospital visits, treatment costs, and concerns for related toxicities like hypertension, and intracranial or extracranial haemorrhage. Other agents like hyperbaric oxygen therapy, pentoxifylline, and tocopherol have been suggested in refractory radionecrosis, with questionable benefits. Sodium-copper-Chlorophyllin is a phytopharmaceutical drug obtained from the green plant pigment chlorophyll. It is a semi-synthetic mixture of sodium copper salts derived from chlorophyll. Chlorophyllin scavenges RT-induced free radicals and reactive oxygen species. It is used as a food colorant and over-the-counter in the USA, Japan, Australia, and China for many years for a variety of health benefits, including prevention of body odor in geriatric patients, enhanced wound healing, antibacterial action, prevention of cancer in the high-risk population exposed to hepatocarcinogen aflatoxin B1, treatment of fecal incontinence, etc. Studies have shown that Chlorophyllin has immunostimulatory, anti-inflammatory, and antiviral effects in addition to antioxidant and radioprotective properties. It increases the expression of a transcription factor (protein) Nrf2, improving lymphocyte survival and enabling efficient detoxification after RT exposure. Chlorophyllin also delays microtubule polymerization and slows cell division in normal cells.

Eligibility criteria: Inclusion Criteria:

* Histological diagnosis of diffuse glioma.
* Radionecrosis on imaging with new neurological symptoms/ worsening of prior deficits (Stratum A) or
* without new symptoms (Stratum B).
* Karnofsky Performance Scale (KPS) ≥ 50.

Exclusion Criteria:

* No tissue diagnosis.
* KPS\< 50.
* Disease progression
* Contraindications to corticosteroids.
* Altered mental status with deficits in understanding or inability to consent to the study.
* Brainstem glioma
* Indeterminate for radionecrosis vs disease progression
* Prior treatment with bevacizumab (either for disease progression or radionecrosis)

Primary outcomes:
measure: Response rates
timeFrame: 1 month post treatment with chlorophyllin
Secondary outcomes:
measure: Survival Analysis
timeFrame: 3 months
measure: Health Questionnaire
timeFrame: 3 months
measure: Response rates
timeFrame: 3 months
Other outcomes:
measure: Biological response rate
timeFrame: 3 months
Locations:
city: Mumbai
country: India
facility: Tata Memorial Hospital
state: Maharashtra
Study officials:
affiliation: Tata Memorial Hospital
name: Archya Dasgupta, MD
role: PRINCIPAL_INVESTIGATOR
References: