Chloroquine phase 1 trial

 Chloroquine combined with concurrent radiotherapy and temozolomide for newly diagnosed glioblastoma: a phase IB trial

Abstract

Treatment of glioblastoma xenografts with chloroquine results in macroautophagy/autophagy inhibition, resulting in a reduction of tumor hypoxia and sensitization to radiation. Preclinical data show that EGFRvIII-expressing glioblastoma may benefit most from chloroquine because of autophagy dependency. This study is the first to explore the safety, pharmacokinetics and maximum tolerated dose of chloroquine in combination with radiotherapy and concurrent daily temozolomide in patients with a newly diagnosed glioblastoma. This study is a single-center, open-label, dose-finding phase I trial. Patients received oral chloroquine daily starting one week before the course of chemoradiation (temozolomide 75 mg/m2/d) until the end of radiotherapy (59.4 Gy/33 fractions). Thirteen patients were included in the study (n = 6: 200 mg, n = 3: 300 mg, n = 4: 400 mg chloroquine). A total of 44 adverse events, possibly related to chloroquine, were registered including electrocardiogram QTc prolongation, irreversible blurred vision and nausea/vomiting resulting in cessation of temozolomide or delay of adjuvant cycles. The maximum tolerated dose was 200 mg chloroquine. Median overall survival was 16 months (range 2 - 32). Median survival was 11.5 months for EGFRvIII- patients and 20 months for EGFRvIII+ patients. A daily dose of 200 mg chloroquine was determined to be the maximum tolerated dose when combined with radiotherapy and concurrent temozolomide for newly diagnosed glioblastoma. Favorable toxicity and promising overall survival support further clinical studies.

https://pubmed.ncbi.nlm.nih.gov/32866424/

CBD + ALA combination (GBM)

Hi

Do you have any thoughts on combining CBD with alpha-lipoic acid (ALA)? I haven't found any specific research on a combination. I am particularly interested in IDH-wild



Also... I would like to link some interesting stuff :

Concomitant Treatment of Malignant Brain Tumours With CBD - A Case Series and Review of the Literature
https://pubmed.ncbi.nlm.nih.gov/31570484/
"a total of nine consecutive patients with brain tumours are described as case series; all patients received CBD in a daily dose of 400 mg concomitantly to the standard therapeutic procedure of maximal resection followed by radiochemotherapy. By the time of the submission of this article, all but one patient are still alive with a mean survival time of 22.3 months (range=7-47 months)".

Inhibition of autophagic flux differently modulates cannabidiol-induced death in 2D and 3D glioblastoma cell cultures
https://www.nature.com/articles/s41598-020-59468-4
(CBD + chloroquine + radiation)

RelA-activity is essential for Cannabidiol-mediated cytotoxicity
https://academic.oup.com/neuro-oncology/article-abstract/21/Supplement_6/vi70/5619524?redirectedFrom=fulltext (no full research report available)
"We observed therapeutic efficiency of CBD in a subset of GBM, obtained genetic markers indicating CBD-sensitive GBM and found that the p53 status segregated cell-death modes".

Additionally - if somebody is considering CBD, CBG, or FECO, there is a new report you might be interested in (sadly, no real specifics, that's commercial research):
https://thegreenfund.com/mcg-pharma-cannabinoid-formula-to-treat-glioblastoma

Sourcing chloroquine

I have been using chloroquine phosphate (250mg od) as part of a cocktail for anaplastic astrocytoma. It is becoming increasingly difficult to source in the UK and I think most places aren't stocking it anymore (presumably because of malaria resistance). Does anyone have any advice on how I may go about sourcing more?
Any advice welcomed!

Good news from MRI scan. GBM Tumor shrinkage from 4.5cm to 2cm

Happy New Year everyone. I wanted to give a positive news update as it is great motivation when there only seems to be negative news regarding glioblastoma. My dad had his 3 month MRI scan follow up (since the last scan in September) today and it shows tumor shrinkage from 4.5cm (in addition to swelling) down to 2cm and no swelling. 

What was added since the previous MRI scan (September) was starting these drugs in October:

• 16 mg dexamethasone and then slowly reducing to 2mg now; 
• Biweekly IV Bevacizumab - avastin ; 9 rounds completed; 
• 2g daily Valaciclovir - valtrex (1g in the morning, 1g in the night);
• 100mg daily Artemisinin;
• 500mg daily Astragalus. 

I think the Bevacizumab - avastin and Valaciclovir - valtrex really helped.

I want to share his treatment as I know there is no one cocktail list and it can be difficult to know what to take and also where to get the drugs or supplements. We began by taking the list of "A" drugs from the table which Stephen shared with us after I emailed him directly. Stephen also provided a link to the Ben William's and Richard Gerber's cocktail list. Since my dad is unmethylated we tried to follow Richard Gerber's cocktail list as closely as possible. We printed out the BT Cocktail list Stephen shared with us, modified it to the "A" drugs and printed this as my dads list to show his oncologists and GP with the dosage he was taking. We were lucky some friends were able to get chloroquine phosphate, Celebrex and melatonin over the counter in Spain. This meant we could start slowly adding drugs one by one before getting the GP to prescribe these drugs to my dad. His oncologist was happy for my dad to try whatever he wanted once he did the treatment they suggest - he was free to add any supplements or drugs once we provided the oncologist and GP with the cocktail list, dosage, purpose (this info from the cocktail list Stephen shared) and the date we added the drug and only one by one with two weeks apart. For the likes of Valaciclovir - valtrex we named the researchers who carried out the study and the publication and then our GP was happy to prescribe these drugs from our local pharmacy.

We check his drug interactions using drugs.com website. It allows you to enter the list of drugs and says potential side effects or which drug combinations throughout the day to avoid. We also get the pharmacist to make up weekly blister packs and they put his drugs into morning, lunch, evening and night - this service really helps us keep organise. We keep a day example of how the pharmacist previously made up the blister pack and hand that in to the pharmacist the following month so they remember - as even for the pharmacist its alot in the cocktail to remember.

We are attending 2 hospitals because one is a general hospital to deal with his seizures and it is 10 mins drive away and his oncologist/neurologist hospital are 15 mins away from our house - we are very lucky with the excellent healthcare in Ireland and that it is all provided for (consultation, MRI scans, surgery, radiation, chemotherapy, Bevacizumab - Avastin, prescribed cocktail medication, social worker, counselling, hospital stays, blood tests, tumor analysis).

We were taking N-acetylcysteine early on (it is a Glutamate transporter 1 (GLT1)) but we stopped as we read it might enhance the tumor growth - we do not know if it is good or bad to take??? I think the seizure drugs blog glutamate transport?

We also obtained Disulfiram but never added this to our cocktail as we do not know if it interacts with the seizure drugs??

We also were taking Ranitidine (75mg daily) but stopped this after reading about side effects combined with Bevacizumab - avastin. Although my dad never had any issues. 

We are also interested in adding more to the cocktail perhaps similar to the CUSP9rv3 clinical trial cocktail such as ritonavir. We are also continuing to do research on HAART/HIV antriviral treatment as apparently HIV patients in Brazil/Mexico did not get GBM's over a 20 year period. 

My dad needed to take Duclox for constipation during chemo but is fine now.

My dad does not follow a ketogenic diet but we do encourage him to have a vegan diet as much as possible low in sugar. However if he wants to eat biscuits, bread, chocolate etc he does - he loves Latte's and dark mint chocolate. He does not have any alcohol due to the seizure medication.

BACKGROUND:

• My father was diagnosed with Grade 4 GBM after a grand mal seizure 24th Feb 2019. Located in the left temporal lobe, around 3cm.
• He had a successful craniotomy on the 7th of March 2019. About 95% removed, at least all visible tumor was removed.
• He completed the 30 sessions of radiation/310mg TMZ. 17th April 2019 to 30th May 2019
• He then did 3 months of 5/23 400mg TMZ chemo. July-September 
• TMZ was stopped and been doing Avastin every 2nd Monday since 23rd September 2019 - today 13th January 2020 still doing.
• Some notes to point out: he was swimming the evening before he had his 1st seizure. He couldn't finish a pint of guinness that night and had some pins and needles in his right arm before sleep - he had no other symptoms to indicate this tumor before 24th February 2019. He had the seizure in the middle of the night. 7th March Surgery went really well and was chatting away normally 1 hour afterwards. To this day he has never had any pain or headaches. He had no side effects during radiation and chemotherapy apart from the seizure 5 weeks after it finished. 

Side Effects:

• 30th June 2019: About 5 weeks after 30 sessions radiation/chemo and after having daily tingling, we spent the day walking around the countryside for many hours. We had a 2 hour car journey and he was 2 hours late taking his Keppra (at the time he was only on 1g total in the day, 500mg morning and 500mg evening). That night he had 4 multiple seizures. He came through after the 1st seizure but he seemed to have panicked when he saw the paramedics that he went into the 3 other multiple seizures. The hospital induced him into a coma for 24 hours which we were not expecting. His Keppra dosage was increased to 2.5g a day and they added phenytoin 300mg in the morning. They also restarted him in dexamethasone 2 weeks 4mg and then 2 weeks 2mg.
• 4th September 2019: He had been having foot twitching since 30th June every night when sleeping. From the end of August he was starting to mix up people's names and words due to aphasia resulting from the edema. Hospital increased the Keppra to 3g per day, added Clobazam 10mg x 2 and 16mg Dexamethasone daily - which we have been reducing since September until now (18th Jan) where he is on 2mg Dexamethasone. His speech has now returned to 100% and no seizures  after adding Phenytoin, Clobazam. There was alot of swelling/looked like the tumor was very active by MRI and due to MGMT unmethylation the hospital stopped the TMZ and have now been giving him Bevacizumab - Avastin on Mondays every 2 weeks, 9 rounds so far.  Bloods are all normal and within range.
• October 2019: My dad took Zovirax tablets and then switched to Valtrex as it apparently has better bioavailability. For 2 weeks when he started taking this we noticed he broke out in large cystic type spots around his face and neck - it almost looked like his body was trying to get rid of toxins??? These spots went away after about 2 weeks after starting the Acyclovir treatment.

Daily Routine: He carries around Midazolam injections in case he was ever to have a seizure

MORNING:

1. 8.30am: Ensomeprazole 40mg (One tablet a day). Stomach protector for steroid

After Porridge (with seeds):
9am: Following medication all prescribed by GP 

1. Dexamethasone 2mg (One tablet a day). Steroid to reduce swelling
2. Ramipril 5 mg (One tablet per day). ACE inhibitor, Lower Blood Pressure, Prevents accumulation of Tumor associated Macrophages) 
3. Phenytoin - Epanutin 300 mg - (3 x 100 mg tablets all taken at this time. Anti-seizure
4. Clobasam - Frisium 10 mg (twice a day, 10 mg in morning, 10 mg at night) Anti-seizure
5. Levetiracetam - Keppra 500mg x 3 (twice a day, 1.5g in morning, 1.5g at night) Anti-seizure
6. Metformin Hydrochloride 500 mg (twice a day, 500mg in morning, 500mg at night). Diabetes and Immune booster
7. Valaciclovir - Valtrex 500mg x 2 (twice a day, 1g in morning, 1g at night) Anti-viral, HSV, VZV, EBV, CMV. Guanosine binds to cancer cell DNA and converted by viral thymidine kinase and host cell kinases to aciclovir triphosphate (ACV-TP)
8. Chloroquine phosphate - Avloclor 250 mg. (One tablet per day, 155mg active chloroquine base). Malaria. Inhibition of late-stage autophagy
9. Minocyline 100 mg (twice a day, 100mg morning, 100mg evening - one month on and switch one month off to use Mebendazole instead). Targets macrophage/microglia. Anti-seizure
10. Mebendazole Vermox 100 mg (twice a day, 100mg morning, 100mg evening - one month on and switch one month off to use Minocycline instead). 

After omelette (with garlic):

10.00am: Supplements. Mainly obtained from iherb apart from Turkey tail which is difficult to get in Ireland and we get via evitamins.

1. Boswellia NOW 500mg tablet. (1 of 3 tablets per day) Reduces edema
2. ECG (green tea extract) . Now 400 mg. Sensitizer to TMZ by GRP78 inhibition
3. Maitake D Mushroom Wisdom (600 mg tablets – 1 tablet per day). Immune
4. Curcumin. Doctor's Best (1000mg tablets – 1 tablet once per day but give other brands of Curcumin later in the day as this is not Longvida and difficult to swallow) Immune; STAT3 inhibitor
5. Multivitamins. Optimum Nutrition, Opti-Men. (1 tablet once per day)
6. Vitamin D3.  NOW (10,000 IU tablets – 1 tablet once per day). Cell differentiation; Immune
7. Mushroom supplement mix from Fungi Perfecti Host Defense Stamets 7 (Royal Sun Blazei; Cordyceps; lions mane; Maitake; reishi; Chaga; Mesima); Immune
8. Artemisinin. Doctor's Best (100mg tablets – 1 tablet once per day) Malaria and Direct Cytotoxicity, apoptosis

LUNCH:

After snack:

1pm: Medication prescribed by GP 

1. Celecoxib - Celebrex (200mg tablet) Arthritis and COX-2 inhibitor, Immune (PGE2 inhibition),  reduces edema

1pm Supplements:

1. Astragalus NOW (500mg tablet) Immune

TEA: (meal followed by a glass of Kombucha or Kefir)
After snack:

5pm:

1. Omega 3-6-9  Now Foods, 1200 mg - 1 tablet per day) From Borage, Flax Seed & Fish Oils Increased oxidative stress in tumor cells
2. Milk Thistle, Silymarin Now Foods, (300 mg tablet) Immune and liver support
3. Berberine Natural Factors, WellBetX (500 mg tablet).Glucose metabolism and Induces senescence of  cells by down regulating the EGFR-MEK-ERK signalling pathway
4. Boswellia NOW 500mg tablet. (2 of 3 tablets per day) Reduces edema
5. Curcumin. Protocol for Life Balance, Curcumin SLCP Longvida 400 mg and  Advanced Orthomolecular Research (AOR) Curcuviva 400 mg (80 mg curcuminoids and Nordic Naturals Curcumin Gummies Mango 200mg Longvida. Prefers the Nordic Naturals gummies. Immune; STAT3 inhibitor

EVENING:

9pm: Medication prescribed by GP 

1. Clobasam - Frisium 10 mg (twice a day, 10 mg in morning, 10 mg at night) Anti-seizure
2. Levetiracetam - Keppra 500mg x 3 (twice a day, 1.5g in morning, 1.5g at night) Anti-seizure
3. Metformin Hydrochloride 500 mg (twice a day, 500mg in morning, 500mg at night). Diabetes and Immune booster
4. Valaciclovir - Valtrex 500mg x 2 (twice a day, 1g in morning, 1g at night) Anti-viral, HSV, VZV, EBV, CMV. Guanosine binds to cancer cell DNA and converted by viral thymidine kinase and host cell kinases to aciclovir triphosphate (ACV-TP)
5. Atorvastatin 20 mg (1 tablet a day) Manage Cholesterol
6. Minocyline 100 mg (twice a day, 100mg morning, 100mg evening - one month on and switch one month off to use Mebendazole instead). Targets macrophage/microglia. Anti-seizure
7. Mebendazole Vermox 100 mg (twice a day, 100mg morning, 100mg evening - one month on and switch one month off to use Minocycline instead). 

9pm Supplements:

1. Resveratrol Now Foods, 200 mg,
2. Soy Isoflavones with Vitamin B6. Holland and Barrett Contains active daidzin, genistin and other isoflavones, phyto-oestrogens
3. PSK or PSP (Turkey Tail Mushroom/Corilus versicolor/Trametes versicolor) NFH Hot-Water extract Immune 500mg (obtained from Walmart) have backup from evitamins from Mushroom Wisdom. 
4. Probiotics; Garden of Life, Dr. Formulated Probiotics, Mood+ ( 1 tablet once per day); 16 strains  50 Billion CFU¹ (203 mg)
5. Boswellia NOW 500mg tablet. (3 of 3 tablets per day) Reduces edema
6. Spirulina powder mixed in with green juice

NIGHT:

11pm: Medication prescribed by GP

1. Melatonin 20mg; 

Useful links we used:

Ben William's cocktail: https://btcocktails.blogspot.com/2015/08/ben-williams-cocktail-profile.html

Richard Gerber's MGMT unmethylated cocktail: https://btcocktails.blogspot.com/2015/10/rich-cocktail.html

CUSP9rv3 Cocktail list (Neurology consultant DR. Marc-Eric Halatsch) https://clinicaltrials.gov/ct2/show/NCT02770378

Positive correlation between HIV antiviral treatment and low occurrence of glioblastoma https://www.researchgate.net/publication/266011045_Gliomas_and_brain_lymphomas_in_HIV-1AIDS_patients_reflections_from_a_20-year_follow_up_in_Mexico_and_Brazil

https://virtualtrials.com/survive.cfm

https://virtualtrials.com/noteworth.cfm

http://www.anticanceralliance.com/cusp-nd/

https://www.survivingterminalcancer.com/

https://clinicaltrials.gov/ct2/show/NCT02770378

https://www.frontiersin.org/articles/10.3389/fphar.2018.00218/full

https://www.canceractive.com/article/repurposing-old-off-patent-drugs-as-new-and-effective-cancer-treatments

HAART Antivirals? Atorvastatin dosage?

My dad is on valtrex (valaciclovir/valacyclovir) daily and I noticed it is a guanosine analogue. I was wondering if anyone is taking HIV HAART treatment, such as tenofovir as well? It is a adenosine analogue and therefore I would imagine would work well to bind to Cytosine and Valtrex to Thymine in the cancer DNA? I would imagine antiviral drugs are limited if only 1 of 4 potential DNA base analogues is used? I know the CUSP9 protocol is using ritonavir but it is just used by itself - perhaps a cocktail of antivirals need to be used to combine with the cancer DNA?

Also we were wondering about Atorvastatin dosage as he is on 20mg a day but Care Oncology seem to recommend people are on 80mg a day? Do people get side effects on this dosage? Should we increase the dosage?

Background on my dad:

My father was diagnosed with Grade 4 GBM after a grand mal seizure 24th Feb 2019. Located in the left temporal lobe. 

He had a successful craniotomy on the 7th of March 2019

He completed the 30 sessions and then 3 months of 5/23 TMZ chemo. In September 2019, there was alot of swelling/looked like the tumor was very active by MRI and due to MGMT unmethylation the hospital stopped the TMZ and have now been giving him Avastin on Mondays every 2 weeks.  Bloods are all normal and within range.


He was having trouble with speach and twitching in September time but this is now gone and he is back to 100% after adding Phenytoin, Clobazam and Dexamethasone

Daily:

Seizure drugs: 1.5g x 2 Keppra ; Phenytoin; clobazam daily. 
He carries around Midazolam injections in case he was ever to have a seizure but has only had 2 occassions this year.

2 x 2 mg Dexamethasone daily

Experimental Drug Cocktail (Ben Williams):

1g x 2 Valtrex (valaciclovir/valacyclovir); Chloroquine (155mg active ingredient); Celebrex 200mg; metformin 500mg x 2; 20mg Atorvastatin; ramipril; ranitidine 75 mg;  melatonin 20mg; 100mg mebendazole (1 month on/1 month off); 100 mg x 2 minocycline (1 month on/1 month off);

Daily supplements of multivitamin; 16 strain Probiotics; PSK; Maitake D; ; Mushroom supplement mix for brain (lions mane 300mg; bacopa 250 mg; reishi 150 mg; gotu kola 130 mg; ginko 120 mg); curcumin (longvida); vitamin D; ECG; Milk Thistle; Berberine; Boswellia; Resveratrol; Omega 3-6-9; Soy Falvonoids (geinistein); Astragalus; Artemisinin

Avastin alone?

Further to a recent previous post.

3 months of TMZ 5/23 showed that chemo is not working for unmethylated GBM. The tumor is very active according to MRI comparison between July and September 2019. There was alot of swelling which is currently being reduced with 16 mg steroids per day in the past week. Speech has improved alot with this. Was told it is too close to previous radiation or surgery to have either done again.

2 weeks ago clonazepam was prescribed 10mg x 2 and Keppra increased to 1500mg x 2 and Phenytoin 300mg in the morning -  all of this is keeping seizures, twitches and focal seizures away.

Oncologist is going to start IV Avastin today and stop all treatment - asked if it was pallatiative but answer no it is not pallatiative treatment yet. Thought it was unusual to go ahead with Avastin by itself and not combine it with another chemo treatment such as lomustine?

Have been following cocktail since during radiation treatment back in April 2019 which I posted about in previous post. This includes daily chloroquine (155mg active ingredient); celebrex 200mg; metformin 500mg x 2; Atorvastatin; ramipril; ranitidine 75 mg; mebendazole; melatonin 20mg.

Also the usual daily supplements of mulitvitamin; 16 strain Probiotics; PSK; Maitake D; ; Mushroom supplement mix for brain (lions mane 300mg; bacopa 250 mg; reishi 150 mg; gotu kola 130 mg; ginko 120 mg); curcumin (longvida); vitamin D; ECG; Milk Thistle; Berberine; Boswellia; Resveratrol; Omega 3-6-9; Soy Falvonoids (geinistein)

Wondering if anyone has any experience of just Avastin being prescribed? I am wondering what is even the point in doing avastin alone? Appears to have more side effects and very little extra benefits, or OS? I was optimistic that Richard Geiber had Avastin and low dose TMZ but that doesnt seem to be on offer to us? Or any chemo alternative?

Very disappointing TMZ stupps protocol + cocktail did not seem to work. 

Question about TP53 Mutated Tumors and Use of Chloroquine

In reviewing the section on TP53 from Astrocytoma Options, I noted "autophagy inhibition with chloroquine prevented restoration to normal P53 function" and therefore best to avoid autophagy inhibitors. Would someone kindly clarify whether this suggests chloroquine should be avoided for my husband who was found to have TP53 Variants including insertions/deletions? 
We have been using it for its purported benefit for EGFR amplification.
If so, are there other autophagy inhibitors to avoid?
Would Zinc be worth adding? (Tried it briefly in the past and experienced GI upset).

Many thanks and healing wishes to all--

Questions on Chloroquine for my mom

Hi folks/Stephen,

My mom is a GBM patient who is EGFRvIII amplified, and basis my research and Stephen's inputs, I realised that Chloroquine is a great adjuvant for my mom. I have been reading up on Chloroquine and had the following questions on the same:

1. I am not able to find Chloroquine in my country, but Chloroquine phosphate instead. Can they both be used interchangeably? Is the efficacy of both just as good?

Basis my research, the dosage of Chloroquine should be 150 mg. What should be the dosage of Chloroquine Phosphate, if it can be used interchangeably?

2. I also read that Chloroquine is a chemo sensitiser, but couldn't find any information on what the timing of this drug should be for maximum efficacy.

My mom takes lomustine+temozolomide in the morning. Can you please help me on when the Chloroquine/Chloroquine Phosphate should be timed for maximum efficacy?

3. How long should chloroquine be taken for? Should it just be done till the chemotherapy or should it be done post the chemotherapy too? I see different researches doing this protocol differently.

My mom has completed 3 cycles of temozolomide and 4 cycles of temozolomide+lomustine. We plan to do two more cycles of temozolomide+lomustine and stop the chemo post that.

4. My mom is also doing the supplements in the table below.

a. My major concern is Artemisia since it is an anti malarial drug too. Is it safe to do both? If yes, how I should I time them so that I get the efficacy of both for my mom?

b. Is there any drug reaction that I should be concerned of? I researched on drugs.com for the interaction list, but all that I could find were two reactions since most of the naturopathic supplements were not there in their database(Interaction list for my mom is here). The two reactions that they talk of is reaction between Chloroquine and Keppra, Chloroquine and Celebrex, how big a concern are they?

Supplement	Cap count
Boswellia Serratta 500 mg	8
Keppra 500 mg	2
Curcumin + Piperine 1 g	4
Longvida 400 mg	2
Metformin 500 mg	3
Quercetin 865 mg	4
Resveratrol 200 mg	2
Bromelain 500 mg	6
TMG 1 g	3
Reishi 1g	2
Mebendezole 100 mg for 3 months + Doxycycline 100 mg for 1 month (We have skipped the statins from the care oncology protocol fearing it might be too heavy on her liver)	1
Artimisia 1 g	2
Ashwagandha 500 mg	1
Selinium 200 mcg	1
Vitamin A + D + K2 - 5000 IU	1
Molybdenum Glycenate 1g	1
Celebrex 200 mg	2
Green tea extract 500 mg 40% EGCG	2
Marrow Plus	6
Echinisea 500 mg	3
Astragalus tea 3g	1
Juice from 5g of Ginger	1
Garlic 2 cloves	3

I look forward to your response!

Tagrisso ?

Hello, first post here, from the husband of a dear wife recently diagnosed with a Grade IV glioblastoma.  Red flags at a UCLA Urgent Care led to a ct scan followed by an MRI and admission.  Complete resection was performed 30 hours later. She followed up with radiochem, and is now in her second course of adjuvant Temodar. We were approved for Optune and are now two weeks in with that, holding firm at about 95% compliance and are also madly ingesting basically everything in the "A" list from the list in the library, thanks to a lot of wonderful help from Mike B here.

Anyway, our doctor suggested we might benefit from a drug called Tagrisso, from AstraZeneca Medicines.  Don't see anything about that in the stacks so far, so was wondering if anyone has any thoughts regarding it. It's proven to be an efficacious treatment for lung cancer but could have crossover value since apparantly it crosses the BBB. 

Sensitization of cancer (stem) cells by Doxycycline to Vitamin C, Berberine, Chloroquine and others

Dear all,


I recently came across the below study, which I thought was rather interesting:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5620172/

The authors used incrementally higher dosages of Doxycycline (12.5 uM, 25 u.M, 50 uM) in vitro on cancer cells in an effort to create metabolically inflexible cells and to test whether these would be then be more sensitive to metabolic inhibitors, including natural agents (Vitamin C and Berberine) and various meds (Atovaquone, Irinotecan, Sorafenib, Niclosamide, Chloroquine, and Stiripentol).

The cancer cells in the study ended up being highly sensitized to some of these agents, for example Vitamin C (4-10 x more sensitive), Berberine and Chloroquine. It's noteworthy that, following Docycycline treatment, cells became sensitive to Vitamin C at a dosage level which is reachable orally (IC-50 = within the range of 100uM - 250 uM). My understanding is that newer Vitamin C formulations using oral Liposomal delivery (e.g.: https://www.livonlabs.com/cgi-bin/start.cgi/liposome-encapsulated/lypo-spheric-vitamin-c.html) can reach concentrations of up to 400 uM in the blood, a level at which cell elimination in vitro was in excess of 90%).

I'm curious if these results could be replicated at least directionally in a human setting, as it would be a rather cost effective and non-toxic approach. Any thoughts?

A few questions I'd have for example are:

1. Is this Doxycycline cell sensitization replicable in a human setting? If so, at what dosage?
2. Is there any chance an oral Vitamin C formulation (e.g. Liposomal) could replicate the effect seen in vitro? Alternatively, I presume IV infusions would do the job?
3. Which of the other agents would be the most feasible otherwise?

Best regards,
John

Inhibitors of autophagy

Given the increasing role of inhibitors of autophagy, I would like to discuss the choice of an inhibitor of autophagy, as well as the possibility of enhancing their effect.
___________________________________

This study focuses on the comparison of some of these inhibitors:
2015 http://thejns.org/doi/10.3171/2014.12.FOCUS14748
"...the authors of this study set out to investigate whether chloroquine (CQ) analogs, in particular clinically established antimalaria drugs, would also be able to exert antitumor properties, with a specific focus on glioma cells.
...the authors treated different glioma cell lines with quinine (QN), quinacrine (QNX), mefloquine (MFQ), and hydroxychloroquine (HCQ) and investigated endoplasmic reticulum (ER) stress–induced cell death, autophagy, and cell death.
All agents blocked cellular autophagy and exerted cytotoxic effects on drug-sensitive and drug-resistant glioma cells with varying degrees of potency (QNX > MFQ > HCQ > CQ > QN)."

Thus, it follows from the study that cloroquine (CQ) shows a weak effect, even lower, that hydroxychloroquine (HCQ) (?!) Maybe this explains the choice of hydroxychloroquine instead of chloroquine in some tests?

And another quotes from the study:

"Cytotoxicity of QBAs for Glioma Cells:
To determine whether other quinoline-based antimalarial (QBA) compounds could mimic the cytotoxic effects of CQ in glioma cells, we used MFQ and QNX. Results showed that these drugs effectively killed U251 cells at much lower concentrations than CQ."

Blocking Autophagy and Inducing Apoptosis in Glioma Cells:
Based on information that CQ induces apoptosis by blocking autophagy, we analyzed whether the other QBA compounds can function in a similar manner.
Quinacrine, the most potent QBA, not only blocked autophagy, but at 20 μM it completely disrupted U251 cellular functioning, which was evidenced by a high level of PARP cleavage, as well as the absence of CHOP/GADD-153 and LC3B expression.

In Vivo Antitumor Activity:
The TUNEL assay for apoptosis demonstrated a significant increase in the number of TUNEL-positive cells in QNX- and QN-> MFQ-> CQ-treated tumors, as compared with untreated controls."

There are also many reports of another inhibitor of autophagy - 3-methyladenine (3-MA).

___________________________________

Since many people here take chloroquine, I would like to discuss the possibility of enhancing its effect. While I see there are the following options:

chloroquine + cimetidine
"Cimetidine pre-treatment caused a 53% decrease in the clearance rate of chloroquine, and a 49% increase in the elimination half-life. Cimetidine inhibited the conversion of chloroquine to monodesethylchloroquine in terms of reductions in the AUC, Cmax, and urinary excretion of monodesethylchloroquine. The serum Cmax of chloroquine was increased by approximately 30% in the cimetidine pre-treated group."
The downside is that since there are many medicines in the cocktail, numerous unpredictable interactions with cimetidine are possible.

increase in the dose of Chloroquine
Instead of using cimetidine, can it be easier to increase the dose of Chloroquine? The standard is 250 mg / day.

chloroquine + hypoxia-inducing agents
2017 https://www.ncbi.nlm.nih.gov/pubmed/28797031
"This work shows that inhibition of autophagy is a promising strategy against GBM and identifies ATG9 as a novel target in hypoxia-induced autophagy. Combination with hypoxia-inducing agents may provide benefit by allowing to decrease the effective dose of autophagy inhibitors."
What hypoxia-inducing agents are they talking about?
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I also found several preliminary studies on the synergy of chloroquine and other drugs. It is interesting to study more ..

Dihydroartemisinin + Сhloroquine
2017 https://www.ncbi.nlm.nih.gov/pubmed/29033794
Dihydroartemisinin Exerts Anti-Tumor Activity by Inducing Mitochondrion and Endoplasmic Reticulum Apoptosis and Autophagic Cell Death in Human Glioblastoma Cells.
"Co-treatment with chloroquine (CQ) significantly induced the above effects. Furthermore, ER stress and mitochondrial dysfunction were involved in the dihydroartemisinin-induced autophagy."

Asparaginase + Сhloroquine
2017 https://www.ncbi.nlm.nih.gov/pubmed/29207624
"combination treatment with autophagy inhibitor CQ significantly enhanced anti-glioblastoma efficacy of asparaginase in U87MG cell xenograft model."

Sorafenib + Сhloroquine 
2016 https://www.ncbi.nlm.nih.gov/pubmed/26971793
"we combined sorafenib treatment in GBM cells (U373 and LN229) and tumors with the autophagy inhibitor chloroquine. We found that blockage of autophagy further inhibited cell proliferation and migration and induced cell apoptosis in vitro and in vivo. These findings suggest the possibility of combination treatment with sorafenib and autophagy inhibitors for GBM."

Chloroquine for GBM with EGFRvIII mutation

EGFRvIII expression triggers a metabolic dependency and therapeutic vulnerability sensitive to autophagy inhibition
http://www.tandfonline.com/doi/pdf/10.1080/15548627.2017.1409926?needAccess=true

Some of the data contained in this study was used as justification for the CHLOROBRAIN trial
https://clinicaltrials.gov/ct2/show/NCT02378532

Chloroquine has therapeutic effect in IDH-mutant U87 mouse model

This was an orthotopic mouse model: U87 GBM cells with either wild-type IDH or genetically engineered to contain the IDH1 R132H mutation were injected into brains of nude (immunodeficient) mice. Chloroquine was injected intraperitoneally.

According to this study, 2-hydroxyglutarate produced by the mutant IDH1 enzyme leads to endoplasmic reticulum (ER) stress, autophagy of the endoplasmic reticulum, and reduced biosynthesis of membrane phospholipids (as the ER is the site of phospholipid synthesis). Inhibiting autophagy with chloroquine triggered apoptosis (programmed cell death).

Chloroquine-treated IDH1-mutant U87 tumors had increased caspase activity (a marker of apoptosis), while the IDH1 wild-type U87 tumors had no increase in caspase activity with chloroquine treatment.

Study title:
2-hydroxyglutarate-mediated autophagy of the endoplasmic reticulum leads to an unusual downregulation of phospholipid biosynthesis in mutant IDH1 gliomas
Pubmed link

I've uploaded the full study to the Library (Folder 2 Therapies - preclinical -> Chloroquine)

Treatment options post-RT/TMZ phase for IDH1 mutated, MGMT unmethylated GBM

Hi all,

I was diagnosed in late September with a GBM (frontal, left, with large cyst, IDH1 mutated, MGMT unmethylated), which was subsequently successfully operated (gross total resection) at the end of September. I guess as many/most here, I eventually stumbled across Ben William's book, the Glioblastoma Treatment options guide and ultimately this invaluable blog and community, which I have been studying and following closely since. I recently concluded the first phase of my treatment, following standard Stupp Protocol (6 weeks concomitant RT/TMZ) and am currently planning next steps (plus waiting for first post-RT MRI next week...).

While I did not get 'smart' in time to save my tumor material from being paraffined post-OP (unbelievably, this is still standard practice here in Germany in most hospitals), I did actively supplement my first phase of treatment with what I think is a reasonably aggressive 'cocktail' approach, including the following components:

--------------------------------------------------------------------------------------

Meds:
- Chloroquine, 1x 250mg
- Celebrex, 2x 200mg
- Disulfiram, 1x 250mg - 500mg (+4mg copper)
- Sativex (THC/CBD spray), ca. 3-4 sprays (approx. 15-20mg)

In general, I tolerated these medications without any major problems or side effects, with a few exceptions. Notably, towards the end of the treatment I developed some peripheral neuropathy in my left foot, which has now almost recovered, however (took around 3-4 weeks to recover). Nevertheless, it cause me to cease the Chloroquine and Disulfiram shortly before the end of my RT treatment phase. In addition, I found it a little hard to tolerate Sativex as I wasn't too keen on the psychoactive effect, which gave me some anxiety / mild panic attacks from time to time at night. As a result, I took it only for around 3 weeks or so.

Supplements:
- Berberine: 1000mg
- Boswellia Serrata: up to 4400mg (gradually increased dosage over course of RT to protect from Edema)
- CBD oil (8%), 5 drops (started after ceasing to take Sativex)
- PSP, 2100mg
- Curcumin (Longvida), 2000mg, increased to 3000mg towards end of treatment
- Green Tea Extract, 3625mg
- Lycopene, 20mg
- Matiake D-Fraction Pro, 65mg (3x 23 drops)
- Melatonin, 20mg
- Omega 3 DHA/EPA, 3528mg
- Probiotics, ca. 40bn units
- Pterstilbene, 250mg
- Resveratrol, 500mg
- Selenium, 200ug
- Silymarin, 1500mg
- Soy extract, 3750mg
- Vitamin D, 9000IU

In general, all of the above were well tolerated without side effects. I'd also like to mention I was able to avoid any kind of Edema / Cortisone use during my RT therapy, which I believe may have been at least in part facilitated by Boswellia in combination with Celebrex.


Other:
- Ketogenic diet, max 40 g Carbs per day; generally constant medium to high Ketone bodies when measuring. Started 1 week before RT, and continued to last day
- Caloric restriction, lost ca. 8 kilos in 6.5 weeks of RT, which I think equates approx. 600kcal or so in daily caloric restriction
- Daily morning smoothie, with variety of hopefully beneficial things like berries, broccoli sprouts, spirulina, tumeric powder, Matcha green tea, cocoa powder,  etc.
- Daily walks of ca. 1 hour to combat radiotherapy fatigue and keep fit

Ketogenic diet was somewhat difficult to maintain psychologically, but possible due to my partner's kind help in continuously seeking out new and often tasty dishes to keep things interesting. Caloric restriction much easier, since Temodal anyway caused me lack of appetite. I believe daily walks were very helpful to avoid RT fatigue, which affected me only in very minor way and much less than I expected.

--------------------------------------------------------------

NEXT STEPS & QUESTIONS

I am currently considering next steps, and having talked to various NOs and other Brain Tumor specialists, I am still not entirely convinced what the right way forward is. As expected, most doctors do not want to deviate from the Stupp Protocol (i.e. follow up the RT/TMZ phase with 6 months of 5/23 TMZ cycles). However, I am not convinced such a treatment would necessarily add much benefit in my case, since my tumor is MGMT unmethylated.

One of the leading specialists in Germany told me that the unmethylated MGMT status is irrelevant in the case of IDH1 mutated tumors like mine, since a study (NOA-4) showed that there was no significant difference in responsiveness  between MGMT methylated or unmethylated IDH1 tumors.

https://www.ncbi.nlm.nih.gov/pubmed/19901110

However, upon further research I stumbled across the following interesting study from China, which seems to suggest that IDH1 mutated tumors might in fact be particularly resistant to TMZ (3-10x more resistant in cell culture test). The study also notes that in China they observed relatively little additional benefit of TMZ cycles for the IDH1 mutated group of patients compared to RT alone, and the authors argue that survival benefits for IDH1 mutated tumors may simply be the result of a less invasive / more benign type of tumor relative to wildtype. It makes me wonder if the fact that MGMT doesn't seemingly play as big a role for IDH1 mutated tumors is simply the result of the fact that neither responds well to TMZ...:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4747376/

I'm therefore a bit hesitant to simply go ahead with TMZ therapy hoping for the best, and would like to consider other options.
One approach I am considering is Immunotherapy at the IOZK clinic in Cologne, which is not far from my house. However, because I don't have frozen tumor material, they would have to make a personalized vaccine using a liquid biopsy approach. This, in turn, could make the treatment even more unproven than vaccines anyway are even when made from tumor lysate. An additional option which could possible materialize down the road (but not yet, as no trials are running here presently to my knowledge) is to try to get hold of an IDH1 vaccine on a compassionate use basis.


My immediate next step is to see the MRI results next week, but I'd be very grateful for any advice on how to proceed from here. Especially, I'd like to try and resolve the following questions:

1. Would it be unwise to not do any additional TMZ cycles? Are there any obvious chemotherapy alternatives perhaps?

2. Would the immunotherapy using liquid biopsy at IOZK clinic be a good alternative for ongoing chemotherapy cycles? Would it be advisable to start this right away (i.e. without any additional TMZ cycles), or should I do some TMZ cycles first just to hedge my bets?

3. Any other recommendations in terms of maintenance strategies. E.g. what medication(s) could make a good maintenance therapy, without concurrent chemotherapy?


Thanks in advance for any comments, and wish you all a very happy and most importantly healthy 2018!

Best,
John

How to take chloroquine phosphate

Stephen:


Sorry, I need your help again.


Should the patient take the chloroquine phosphate with TMZ just at the beginning 5 days of TMZ cycle? or take it at 28 days - the whole TMZ cycle?


Do you have ACT 001 clinical trial I report?


Best Regards
James Zhou

Question for Hydroxychloroquine sulfate

Stephen:


It is hard for us to buy chloroquine phosphate to treat my mother's GBM. Can we use hydroxychloroquine sulfate to replace it?


Some forums say both these two medicines can be used to treat GBM, but Ben William's book says hydroxychloroquine sulfate can't be used to treat GBM. We are not sure who is right.




Best Regards
James Zhou

Chloroquine and non-P53, non-EGFR mutant tumors

I know that chloroquine has been discussed to death in this site and the original message board but I couldn't find an answer to my question there and am hoping someone can provide some insight.

My understanding is that chloroquine generally works best for those with EGRF mutations. My wife does not have this.

It's a bit unclear as I came across another post in another site (that I cannot find again) that seemed to say that chloroquine works better for those with a P53 mutation while other posts, particularly Stephen's comment in this post, noted that it works better for those without a P53 mutation. I note that we also have a PTEN loss as well.

Finally, this post noted that Chloroquine provides a "strong antimutagenic effect" but it's unclear if it's universally so or if it's only for those that with the aforementioned mutations.

Question: If someone has both a non-P53 and a non-EGFR mutant tumor, is it worth adding Chloroquine if we're past radiation and chemotherapy? We are currently on Optune and Nivo along with our cocktail.

Followup Questions: For those on chloroquine, has anyone noticed any side-effects beyond the retinopathy issue?

My wife's pill burden is heavy enough so I have to be judicious in what we add. I am most drawn to Chloquine because it's one pill, seems to have few side effects, and is a small pill at that.

Tom Wangerin - Cocktail Profile and Questions

Hi all,

Although this is my first post, I have been reading every minute of every day. Such an amazing wealth of information on here. I would appreciate any advice on our current course of action and opinions on our cocktail.

My dad was diagnosed with a grade IV GBM. He had surgery on 11/23/16 with 95% resected.

Lab Results:
MGMT Gene Promoter Methylation – Detected.
Percent of MGMT Methylation is 36.19%
IDH1/2 Mutation – Not detected
Positive for 1p Deletion

• Completed his first round of daily chemo/radiation on 1/19/17.
• Our first image was taken on 2/3/17. We had our first consultation with the UCSF Tumor Board (Dr. Butowski) on 2/7/17.
• Tumor had not seemed to grow in size any, but did morph into a new shape/area which is scary to see. Next image in 2 months.

Currently taking:
·       Dexamethasone (Decadron) – He is currently taking 4mg/day but we are doing what we can to wean him off. We have been told this will dictate whether we go on Avastin.
·       Eliquis – blood thinner - 5mg twice a day
·       Keppra – 500mg twice a day.
·       Bactrim (Antibiotic) – Original oncologist prescribed during chemo.

Supplements:
1:1 CBD/THC – Tincture drops in day, Oil at night.
Probiotics – Sibiotica (K-97)
Curcumin - Nutrivene Longvida 1000mg - 1x Morning 1x Night (1000-2000mg daily)
Fish Oil - Vital Nutrients - EPA-720mg, DHA-480mg per cap - 1x Morning
Boswellia Serrata Extract - Progena Meditrend – Currently taking (3) 333mg daily.
Melatonin - Vital Nutrients - 10mg/cap - 1x at Night (eventually will do 20mg)
Mushroom Extracts - Turkey Tail (Coriolus), Maitake D-faction, and Reishi each once a day.
Berberine - Vital Nutrients - 200mg/cap – starting with 1x day, soon 3/day.
Debating whether to add - Resveratrol and Green Tea Extract

Our NO was okay with all and suggested adding Cronaxal. I’ve struggled to find much convincing information out there, but I do trust our NO. Now the question is to use Cronaxal (expensive and high dosage) or get Sulfasalim (which Stephen ranked pretty high on his spreadsheet).
I read that this can benefit those that are NOT IDH mutated (which is us).

Genetic Testing
We are getting the tumor tested from Foundation One for more details – once we make sure there is enough tumor for them to test, and have some left for potential clinical trials. I’m keeping an eye out for EGFR, p53, VDR, HIF-1.
Any thoughts here?

Hoping for some advice in a selection of the following:

**Vitamin D3 – In some cases Vitamin D3 caused proliferation in some patients (Stephen W speaks of this: http://astrocytomaoptions.com/supplements/). Our NO was okay w/ Vitamin D3. Would checking his VDR receptor be of value for determining this, or is it safe (and potentially beneficial) to take 5,000-10,000iu daily regardless of tumor type?

I was very excited about a few of the prescription drugs below, but our NO was certain that none of them get past the blood brain barrier while taking doses safe for humans. We are still willing to give a few of them a shot, but I’m struggling to decide which combinations.

·       **Chloroquine Phosphate – (if overexpressing the EGFR protein or p53 status is unmutated) & **DCA - Sodium Dichloroacetate –(if HIF-1 is expressing) http://astrocytomaoptions.com/targeting-tumour-metabolism/
·      **Disulfiram – This drug looks like it has amazing potential.
http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=707

·       **Sildenafil & Celebrex: can work synergistically for both getting past blood brain barrier, anti-tumor qualities, and Celebrex potentially helping with a bit of edema.
http://onlinelibrary.wiley.com/doi/10.1002/jcp.24843/abstract

·      VT-122 (Etodolac & Propranolol) – with low dose daily TMZ schedule. This had great results. Any reason why more people aren’t doing this themselves?
(http://meetinglibrary.asco.org/content/151704-156)

·       CUSP9 – Looks like an amazing plan. I am yet to read of any results but I know many are starting to replicate this cocktail on their own.
http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path[]=2408

Current Plan:

I.         TMZ Schedule – Because he is MGMT methylated it was an easy decision to go forward with the monthly TMZ cycles. All of our docs have insisted on the high dose 5days/month schedule rather than a metronomic schedule, regardless of whether EGFR is over expressed. Thoughts?
https://academic.oup.com/jnci/article/107/5/djv041/891259/EGFR-Amplified-and-Overexpressing-Glioblastomas

II.         Optune Machine – The UCSF board feels it’s not as beneficial as some of the studies make it out to be, and with it being such a pain to wear for the rest of your life… it’s not that easy of decision even with insurance coverage. I’m undecided here.

III.         Prescriptions with TMZ/Avastin - If you had to pick one prescription duo to take with TMZ and one prescription duo to take with Avastin to make them more effective which would you pick?

Thank you all for pitching in. This journey has been life changing, but manageable with the help you all bring.