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The COC Protocol™ in Glioma

 

 

This document provides a brief summary of the current scientific evidence for the adjuvant use of the COC Protocol medications in glioma, including glioblastoma and other high-grade gliomas. A table of all currently ongoing or recently finished clinical trials related to the use of these medications in glioma and other brain tumours is provided in Table 1, which you can find at the end of this article.

For more information regarding your own personal situation, please contact the Care Oncology Clinic on 800-392-1353 or fill out the Patient Eligibility Form.

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Glioma

Glioma tumours grow from glial cells in the brain and are the most common type of brain tumour. Low-grade benign gliomas are slower growing and less dangerous than high-grade, aggressive (malignant) gliomas. Glioblastoma multiforme (GBM), a type of malignant astrocytoma, is the most common high-grade brain tumour in adults.

The standard treatment for high-grade glioma is usually surgery, followed by courses of chemotherapy (i.e. temozolomide) and radiation. Much current glioma research is focussed on adding extra (adjuvant) treatments alongside this standard regime in the hope of improving results for patients.

Scientific interest is growing in the use of treatments which target the metabolic pathways of cancer cells (i.e. the processes used by cells to generate energy) to slow or stop the growth of cancers. Care Oncology specialises in using already-licensed (off-label) medications with known anti-metabolic activity to help treat and control cancer. We have developed an adjuvant treatment called the COC Protocol, which combines what we believe to be the most effective metabolically-targeted offlabel medications available.

The COC Protocol as an adjuvant treatment for glioma

This section summarises briefly the existing evidence for effective use of COC Protocol medications in glioma, and of the current clinical trials in this area.

Statins

High-grade gliomas like GBM are thought to be very dependent on the cell processes primarily targeted by statins for survival, and fat-soluble ‘lipophilic’ statins like atorvastatin can cross the human BBB relatively easily (1). These qualities, along with the demonstrated ability of statins to slow and suppress glioma cancer cell growth in the lab and in preclinical mouse models makes atorvastatin a good candidate as a repurposed glioma treatment (2).
Several studies show that statins can target and damage glioma cells in a number of different ways, including by increasing programmed and unprogrammed cell death (eg apoptosis and necrosis) (3–5), and reducing cancer cell growth, division, and movement (proliferation and migration)(5–8).

Other lab studies have also shown that statins can help to reduce tumour resistance to other glioma treatments (9–11). One lab study using pitavastatin, a statin similar in profile to atorvastatin, showed that MDR-1, a molecule which is excessively produced in glioma cells in response to treatment and which helps these cells become resistant, is blocked by statins. In this study, statins helped to improve the effectiveness of chemotherapy (12). In a separate lab study, combining statins with an additional metabolically-targeted drug also appeared to increase potency on glioblastoma cells (13).

Most clinical studies for statin use in glioma patients are still ongoing or awaiting results (see Table 1). But completed clinical studies show promise. Early-phase studies from the 1990s, where adult and child patients with solid central nervous system (i.e. brain) tumours and high-grade gliomas took lovastatin or fluvastatin in 3 or 4 weekly cycles, showed that statins were well tolerated. Promising tumour responses were noted in patients with GBM and anaplastic astrocytoma, and study investigators suggested a less cyclical and more constant treatment regime could be more effective (14,15). Patient population studies monitoring survival in large numbers of people who took statins before and during glioblastoma diagnosis and treatment have had inconclusive results, possible due to different study designs (16–18).

Mebendazole

Scientific interest in mebendazole as a potential anticancer treatment is relatively new and is mostly based on promising mechanistic studies and compelling reports from case studies in cancer patients (19, 20).

Emerging evidence also suggests that mebendazole may have particularly high levels of activity against cancers of the brain. This is partly because mebendazole is a small, fat-soluble molecule which can easily cross the BBB. It is also thought to work in a similar way to vincristine, a chemotherapy drug currently used for treatment of some types of cancer, including some gliomas (18). Mebendazole is thought to kill cancer cells partly by disrupting special structures inside the cell, called microtubules (21). It can inhibit glioma tumour cell growth in the lab and has been shown to improve survival in preclinical mouse models of glioblastoma (22). In addition, some forms of mebendazole (including the form which is prescribed as part of the COC Protocol) are thought to cross the BBB more readily than vincristine (23), which has led to suggestions that mebendazole should replace vincristine in the treatment of brain tumours (24). In a computer modelling study which looked at 51 different drugs including all chemotherapies used or previously used for treatment of a childhood glioma called DIPG, mebendazole was one of just 8 drugs which was predicted to reach effective concentrations in the brain following systemic (i.e. by mouth or injection) administration (25). Evidence from lab studies also suggests that simultaneous use of microtubule disruptors like mebendazole can help to improve the effectiveness of radiotherapy and temozolomide, two standard glioma treatments (26,27). Numerous clinical trials are now underway to investigate this possibility (see Table 1).

Metformin

Metformin is not fat soluble but is predicted to cross the BBB using special transporter molecules (28–30). An impressive number of lab studies show metformin can block glioma and glioblastoma cell and tumour growth via a number of different mechanisms, including supressing growth, division and movement of glioma cells (31–33), increasing programmed glioma cell death (34, 35), and blocking growth of new blood vessels (angiogenesis) to glioma tumours (36).

Within the last 5 years scientists have also discovered that metformin can target and disrupt glioblastoma stem cells (37–39). This is important, because these cells are believed to be the initiating cells of a tumour. They can be less responsive to radio- and chemotherapies and are thought to be responsible for tumour regrowth following treatment. Scientists believe control of these cells is key for ensuring long-term survival for patients with glioblastoma (39,40).

Metformin’s real potential in glioma is revealed when metformin is tested in combination with standard therapies or newly-developed anticancer medications. These studies repeatedly show that metformin’s multi-targeted activity against cancer cells and cancer stem cells can potentially improve potency of a combinatorial anticancer treatment regimen. In lab studies, improved anticancer activity (33,41–43) and/or resistance of glioma cells and glioma stem cells to standard therapies such as temozolomide has been overcome using metformin in combination with other drugs (33, 44, 45).

Numerous clinical trials are now underway investigating metformin in combination with other therapies in the treatment of advanced glioblastoma in both adults and children.

Doxycycline

Doxycycline is an antibiotic with other extremely valuable properties, including anti-inflammatory and anticancer activity. This gives doxycycline real therapeutic potential in treating a range of other diseases, including cancer (46).

In glioma, a 2007 lab study has shown that doxycycline helps to block tumour cell growth and division and reduces glioma cells’ potential to move and invade other areas of the body (47). Importantly, doxycycline appears to be particularly good at targeting tumour stem cells. Doxycycline can block a process called ‘mitochondrial biogenesis’, which stem cells need to use to make energy for survival and growth. Lab studies show that doxycycline treatment could make glioma stem cells more susceptible to other treatments like radiotherapy (48), and less able to regrow after temozolomide treatment (49). The results of these lab studies are now starting to be replicated in patients- a very recent study has just reported that doxycycline was able to effectively reduce cancer stem cells in patients with early-stage breast cancer (50).

Doxycycline is also well absorbed by the body and is known to cross the BBB effectively (51). These qualities combine to make doxycycline a potentially very powerful anticancer treatment for brain tumours such as glioma (48).

Ongoing clinical research

Table 1 summarises current ongoing or recently completed clinical trials investigating individual metabolically targeted off-label COC Protocol medications in the treatment of brain tumours, including gliomas of all types, glioblastoma, and childhood brain tumours such as medulloblastoma.

It’s notable that whereas most studies are testing just 1 or 2 of these medications in combination with standard treatments, Care Oncology’s own METRICS study (NCT02201381) is currently the only study to investigate the tolerability and effectiveness of a combination of four off-label metabolic treatments (i.e. atorvastatin, mebendazole, metformin, and doxycycline) alongside standard treatments in glioma and other cancers. You can find out more about our study by contacting us.

Table 1: Clinical trials for COC Protocol medications in brain tumours

NCT number

Cancer type

Summary

Completion date

Metformin

NCT02496741

Glioma

Cholangiocarcinoma

Chondrosarcoma

Phase 1/2 trial in approx. 20 adults investigating tolerability and effectiveness of metformin and chloroquine in IDH1/2 positive solid tumours

Dec 2016; Results NA

NCT02149459

Brain neoplasms

Phase 1 trial in approx. 18 adults investigating safety and effectiveness of treatment of recurrent brain tumours using metabolic manipulation (metformin and low carb diet) combined with radiotherapy

Jul 2018; Results NA

NCT02040376

Brain tumour treated with cranial or cranial-spinal radiation

A Phase 3 trial in approx. 24 children with medulloblastoma treated with cranial-spinal radiation investigating effectiveness of added metformin for brain repair

Mar 2018

Results NA

NCT02780024

Glioblastoma multiforme

A Phase 2 trial in approx. 50 adults investigating the effectiveness and tolerability of metformin, neo-adjuvant temozolomide and hypo-accelerated radiotherapy followed by adjuvant temozolomide

Dec 2021

NCT03243851

Recurrent or refractory glioblastoma

A Phase 2 trial in approx. 108 adults investigating safety and effectiveness of low dose temozolomide plus metformin or placebo

Dec 2018

NCT03151772

Glioblastoma

An early Phase 1 trial in approx. 40 patients investigating the bioavailability (activity in the body) of disulfiram and metformin in glioblastoma

Jun 2019

NCT01430351

Glioblastoma multiforme

A Phase I trial in approx. 144 adults investigating the safety and effectiveness of temozolomide plus various combinations of memantine, mefloquine, or metformin for post-radiation therapy of glioblastoma multiforme

Sep 2019

NCT01528046

Relapsed or refractory solid tumours and primary brain tumours

A Phase 1 trial in approx. 25 children investigating safety and effectiveness of metformin in combination with vincristine, irinotecan and temozolomide

Dec 2020

Statins

NCT02115074

Glioma

A Phase 1 trial in approx. 21 children investigating the safety and effectiveness of fluvastatin and celebrex in low-grade and high grade optico-chiasmatic gliomas

Oct 22

NCT02029573

Glioblastoma multiforme

A Phase 2 trial in approx. 36 adults investigating the efficacy and safety of atorvastatin in combination with radiotherapy and temozolomide in glioblastoma

Dec 2016

Results NA

NCT02104193

Brain metastases

A Phase 2 trial in approx. 50 adults investigating the efficacy and safety of simvastatin with radiation therapy of brain metastases

Dec 2015;

Trial terminated, results NA

Mebendazole

NCT01729260

Newly diagnosed high-grade glioma

A Phase 1 trial in approx. 24 adults investigating the tolerability of mebendazole in glioma patients receiving temozolomide

Sep 2020

NCT01837862

Childhood glioma

A Phase I/2 trial in approx. 36 children investigating the safety and effectiveness of mebendazole in combination with vincristine, carboplatin and temozolomide or bevacizumab and irinotecan for the treatment of childhood gliomas

Apr 2020

NCT02644291

Recurrent/progressive childhood brain tumours

Phase I study in approx. 21 children investigating the safety and effectiveness of mebendazole therapy

Jun 2021

NB: Table accurate according to www.Clinicaltrials.gov website as of October 2018.

Important Notice

Purpose of this article

This article is an overview of some of the scientific and medical published literature concerning the medications which comprise the patented Care Oncology protocol. Care has been taken to select relevant articles supporting the off-label use of these medicines in a clinical setting for the adjunct treatment of cancer. This article does not purport to be a comprehensive review of all the evidence, nor does it capture all of the potential side-effects of such treatment.

This article is for information purposes only and it does NOT constitute medical advice. The medicines discussed herein are available on prescription-only and should not be taken without consultation with your doctor or other professional healthcare provider. Care Oncology doctors will discuss the suitability of these medicines with you and will liaise with your doctor or oncologist to discuss their suitability for you.

You must NOT rely on the information in this article as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter you should consult your doctor or other professional healthcare provider. If you think you may be suffering from any medical condition you should seek immediate medical attention. You should never delay seeking medical advice, disregard medical advice, or discontinue medical treatment because of information contained in this article.

Copyright

The copyright in this article is owned by Health Clinics LLC and its licensors.

Patent

The Care Oncology (“COC”) Protocol is protected by United States patent US9622982B2 and by various additional international patents.

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