Hello Stephen and all,

We have finally received the MGMT status of my aunt's tumour, it is methylated. Now waiting on EGFR amplification, which Princess Margaret in Toronto said they would test for as part of her participation in the marizomib clinical trial.

Grade IV Glioblastoma

• idh(-) wildtype, ATRX(+), GFAP(+), p53(+)
• The ki67 proliferation status is estimated at 10%
• MGMT status: Methylated

I tried to come up with what I think is a list of the drugs with the most potential to put in a cocktail for my aunt. I do not want to overwhelm her with tons of prescription pills…so trying to keep it on the smaller side right now. I also do not know how much difficulty we will have in obtaining the prescriptions (mainly chloroquine given its use primarily with Malaria).

She is already taking:

Imipramine 25mg – should we consider switching this to Chlorimipramine?

Atenol 50mg

Hydrochlorothiazide 25mg

Apo-Phenytoin 300mg – this is her anti-seizure med

Co-Ranitidine 150mg

PMS-Dexamethasone 4mg

Not sure if any of these have any benefits in cancer treatment, perhaps Imipramine?

Wondering if we should ask to switch to Keppra or Depatoke for anti-seizure?

She will be starting a Ketogenic diet today, and her treatment of concurrent TMZ and Radiation will begin in about a week once we find out if she will receive Marizomib as part of the trial.

Is there anything you would suggest I add or remove?

I am still looking into the dosage of cannabis oils.

Drug	Dosage
Valproic Acid (Depatoke)?? OR Levetiracetam (Keppra)	1000mg
Chloroquine	250mg daily
Cimetidine (Tagamet)	800mg daily
Celebrex	200-400mg daily
Fluoxetine (Prozac) Not sure if this would be helpful since she is methylated?	40mg daily
Metformin	500mg
Chlorimipramine	25mg daily escalated to 150mg daily

Supplement	Dosage
Boswellia (Wokvel Brand)	500-1000mg
Green Tea or Extract	700 mg 40% EGCG
Curcumin (Longvida) (AOR Brand)	2000mg +
Berberine	500-100mg daily (divided doses)
Melatonin	10-20mg
Omega 3 Fish Oil	TBD
Probiotic	TBD
Vitamin D3	5000-10,000 UI
Maitake D-Fraction (mushroom)	100mg
Reishi mushroom extract	1g  per day
Turkey Tail - ie PSK (mushroom)	3000mg
milk thistle	1000-2000mg
CBD / THC	200 mg THC 200 mg CBD 50 mg THCa

Thanks for your help,

Palma

Acetazolamide - a new drug for a cocktail approach?

Acetazolamide came into medical use in 1952. Acetazolamide, sold under the trade name Diamox among others, is a medication used to treat glaucoma, epilepsy, altitude sickness, periodic paralysis... There has been a lot of research on Acetazolamide on invitro glioblastoma cells.

In July 2018, an interesting study was published about the use of Acetazolamide in mice. Unfortunately, I missed it and now I decided to write about it.

https://www.ncbi.nlm.nih.gov/pubmed/29973405

http://sci-hub.tw/https://doi.org/10.1126/scitranslmed.aar2238

The study showed that repurposing ACZ might be particularly effective in a subgroup of MGMT promoter methylated tumors that have high BCL-3 expression.

ACZ greatly increased the effectiveness of temozolomide in some types of glioblastoma cells. The effectiveness of ACZ depended on its administration schedule. In experiments with mice, a dose of 5 mg / kg ACZ was used, which seems to be achievable in humans.

The most impressive results were in mice with glioblastoma GBM43S (BCL-3 high):

Kaplan-Meier curves of mice bearing intracranial GBM43S PDX (n = 7 per group) treated with TMZ on days 5, 7, and 9 (5 mg/kg
per dose) and/or ACZ on days 5 to 26 (15 mg/kg per day).

posted by  oldcookie48

My husband is 77 yr old. He was diagnosed 2013 w/GBM 4. Full Resection & Radiation. Took TMZ for 12 mos, then CCNU for 6 mos. Optune for 15 mos/stopped due to skin issues-skin cancer. Recurrence in 2018. Full resection/radiation. Now on 10th round of TMZ. Taking Ben Wms' Supplement cocktail since 2013. Only RX: Valproic Acid (never had seizures), Celebrex, Bactrim. Only issues are cognitive, motivation, fatigue. He is MGMT meth. Seattle NO says go to 12 mos (that 2 left). UCSF NO suggesting he stop TMZ due to fatigue since no validation it helps past 6 mos. Blood runs are good. 

Stephen, do you think we should finish the last two rds to make 12 or stop at 10?? NO's leaving it up to us. Any other recommendations based on his gene testing below? I have been ill so difficult for me to focus very well. My husband can't focus at all so leaving it up to me. 
Appreciate your thoughts. Thank you kindly. 

INTERPRETATION: 
Tumor-only sequencing of this recurrent glioblastoma demonstrates a hotspot mutation in the promoter region of the TERT gene, focal deep deletion of the CDKN2A and CDKN2B tumor suppressor genes on chromosome 9p21, focal amplification of the MDM4 oncogene on chromosome 1q32, focal amplification of the PDGFRA oncogene on chromosome 4q12, a nonsense mutation in the PTEN tumor suppressor gene with loss of the remaining wildtype allele, a frameshift mutation in the BCOR tumor suppressor gene, and focal amplification of the EGFR oncogene on chromosome 7p11. This EGFR amplification is accompanied by a missense mutation that localizes within the extracellular ligand-binding domain and has been recurrently found in glioblastomas, often in conjunction with gene amplification as seen in this tumor [refs. 1-2]. This EGFR mutation is present on a majority of the amplified EGFR alleles given its allele frequency of 74%. Extracellular domain mutations in EGFR have been shown to correlate with resistance to type I EGFR inhibitors such as erlotinib but sensitivity to type II EGFR inhibitors [ref. 3]. 

The quantity of somatic mutations and mutational signature of this recurrent tumor is not suggestive of the hypermutation that is known to occur in a subset of gliomas following treatment with alkylating agents such as temozolomide [ref. 4]. 

Chromosomal copy number changes in the tumor include gain of 7 and losses of distal 2p, interstitial 3q, 8p, 9p, 10, portions of 11q, 13q, distal 14q, and distal 
Only 11 of the 1,068 microsatellites assessed in the tumor (<2%) demonstrate instability, consistent with a microsatellite stable tumor. 

Together, the genetic profile is consistent with the diagnosis of recurrent glioblastoma, IDH-wildtype, WHO grade IV. The cytogenetic alterations (trisomy 7, monosomy 10) and genetic alterations (CDKN2A deletion, TERT promoter and PTEN mutations, amplifications of EGFR, PDGFRA, and MDM4) are some of the most common seen in IDH-wildtype glioblastomas arising within the cerebral hemispheres in adults [ref. 1]. Additionally, this glioblastoma demonstrates a truncating mutation in BCOR, which encodes a transcriptional co-repressor protein that is commonly inactivated in pediatric high-grade gliomas but is not known to be a recurrently mutated or deleted gene in adult IDH-wildtype glioblastoma [refs. 5-6]. 
Genetic features of a diffuse lower-grade glioma (e.g. chromosomes 1p/19q co-deletion or mutations involving IDH1, IDH2, TP53, ATRX, CIC, and FUBP1) are not identified.

Hello,

I’m hoping that someone can help me understand the situation that my husband is currently in. He has right temporal AA3 that was 80% respected in July 2016.  He did Proton radiation. With 6 months of Temozolomide. He also did immunotherapy vaccination at IOZK. He has not been doing any treatment since February of this year when he decided that he didn’t want to use Optune for a little while. His scans have been looking good and his NO said that she felt what remained was “treatment effect.” In June he suffered from a grand mal seizure that we attributed to cutting back on seizure meds. August’s MRI showed what his NO called leaky blood vessels but nothing too serious. November’s MRI was moved up to the end of October because he fell down. It showed a soap bubble  lesion in his cerebellum and brain stem area. A PET scan made her feel confident that it wasn’t tumor recurrence but treatment effect. She didn’t say radiation necrosis even though he is at the two year mark of finishing radiation. She prescribed 4mg of Dex and then had him taper to 2mg. After a week or so of 2mg, his right chin has started to be tingling. She upped his Dex to 8mg but it hasn’t touched his tingling symptom. What I don’t understand is how it took away the balance issues but won’t take away the new symptom of tingling. Are there other potential causes for this symptom that I’m not understanding? How could he have so much inflammation from late effects of radiation when he takes Longvida curcumin, WokVel Boswellia, Celebrex and Dex?? What questions should I be asking her? So far I’m being shut down until they do another MRI, either this Friday or next Wednesday. Any insight would be most appreciated!! Until then I’ll just go scare myself with google.

PS: I’m interested in hyperbaric oxygen therapy if it could help, but am scared it would wake up any more cancer cells.

Hello Stephen, and all

My aunt's tumour was discovered about a week ago, and she underwent surgery shortly after. The doctor said he was able to remove about 60% of the tumour, which is in her right frontal lobe. She is 65 yrs of age.

Pathology Report:

·         Grade IV Glioblastoma

• Tumour shows marked cellular pleomorphism, scattered mitosis, and microvascular proliferation.
• There is no definite tumour necrosis
• idh(-) wildtype, ATRX(+), GFAP(+), p53(+)
• The ki67 proliferation status is estimated at 10%
• Result of MGMT Gene methylation status to follow as an addendum….. still do not have it, but hoping to get this information at the first appt with the oncologist tomorrow morning*

I am trying to get as familiar as I can with GBM and I am doing some research on currently recruiting clinical trials so I can bring them along to the appt with her oncologist tomorrow.

I have discovered 2 trials that she seems to be eligible for (I hope), but I would like to make sure we are strategic in which we decide to choose (does trial phase matter?). I am very new to this topic and was hoping to get some of your thoughts on which might be more beneficial for my aunt based on previous studies etc. I did not see any info in the library about Avelumab (I think it is an immune checkpoint inhibitor) or Marizomib.
Also, in some trials there is the risk of being put in a control group, while it seems in the first trial below, all participants receive the new drug.

1. Avelumab in Patients With Newly Diagnosed Glioblastoma Multiforme (SEJ)
http://www.neuro-outaouais.com/glioblastoma-multiforme-clinical-trial/
https://clinicaltrials.gov/ct2/show/study/NCT03047473?show_desc=Y

2. A Phase III Trial of With Marizomib in Patients With Newly Diagnosed Glioblastoma
https://www.uhn.ca/PrincessMargaret/Research/cancer_clinical_research/Pages/clinical_trial.aspx?clinicalTrialID=8447#tab1

Any other trials or treatment options in Canada that may be worth looking at?

Any input is greatly appreciated,
Thank you,
Palma

Phase II Results: TMZ with DISULFIRAM and COPPER (SNO 2018)

The disappointing results of this study are published in the SNO 2018 brochure:

http://sci-hub.tw/https://academic.oup.com/neuro-oncology/article-abstract/20/suppl_6/NP/5154662?redirectedFrom=fulltext

"ACTR-19. A MULTICENTER PILOT PHASE II STUDY OF CONTINUING TMZ WITH THE ADDITION OF DISULFIRAM AND COPPER FOR REFRACTORY GLIOBLASTOMA"

BACKGROUND: Preclinical studies have suggested promising activity for the combination of disulfiram and copper (DSF/Cu) against glioblastoma (GBM) including re-sensitization to temozolomide (TMZ). A previous phase I study demonstrated the safety of combining DSF/Cu with adjuvant TMZ for newly diagnosed GBM. This pilot phase II study aimed to estimate the potential effectiveness of DSF/Cu to re-sensitize recurrent GBM to TMZ. METHOD: This open-label, single-arm phase II study treated recurrent TMZ-refractory GBM patients with TMZ 150mg/m2 on days 1–5 of every 28-day cycle with concurrent daily DSF 80mg TID and Cu 1.5mg TID. Eligible patients must have progressed after standard chemoradiotherapy and within 3 months of the last dose of TMZ. Known IDH-mutant or secondary GBMs were excluded. The primary endpoint was objective response rate (ORR), and the secondary endpoints included progression-free survival (PFS), overall (OS), clinical benefit (stable disease for at least 6  months), and safety. Evaluable patients must have received at least 28 days of DSF/Cu unless stopped due to progression, toxicity, or death.

RESULTS: From March 2017 to January 2018, 23 TMZ-refractory GBM patients were enrolled across seven centers in the United States, and 22 patients were evaluable. The median DSF/Cu duration was 48 days (range: 12–246 days). After a median follow-up of 4.4 months, there were no objective responses, with 6-month PFS of 14% and 6-month OS of 55%. Among 17 patients who had at least 28 days of DSF/Cu, 3 patients (18%) had clinical benefit. Grade 3 toxicities that were possibly related to DFS/Cu included fatigue, headache, anxiety, and elevated alanine transaminase (5% for each).

CONCLUSION: Addition of DSF/Cu to TMZ for TMZ-refractory GBM yielded minimal ORR but demonstrated clinical benefit for a subset of patients. DSF/Cu may have modest TMZ re-sensitization or single-agent activity for recurrent GBM.

Sulbutiamine or / and DCA

DCA is known to be associated with toxicity and neuropathy. For example, in this study (https://www.ncbi.nlm.nih.gov/pubmed/16476929), a dose of 25 mg / kg / day of DCA caused neuropathy in all participants in the study!

Recently this article caught my attention:

High Dose Vitamin B1 Reduces Proliferation in Cancer Cell Lines Analogous to Dichloroacetate

2014 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3963161/

"Inhibition of PDKs by dichloracetate (DCA) exhibits a growth suppressive effect in many cancers. Recently it has been shown that the thiamine co-enzyme, thiamine pyrophosphate reduces PDK mediated phosphorylation of PDH. Therefore, the objective of this study was to determine if high dose thiamine supplementation reduces cell proliferation through a DCA like mechanism.

Results: Thiamine exhibited a lower IC50 value in both cell lines compared to DCA. Both thiamine and DCA reduced the extent of PDH phosphorylation, reduced glucose consumption, lactate production, and mitochondrial membrane potential.
...Although our findings demonstrate that doses of thiamine (mM) required to reduce cancer cell proliferation are similar to DCA, thiamine has few dose limiting toxicities."

According to the authors, the proliferation of cancer cells decreased by 50% at thiamine levels of 4.9 and 5.4 mM. While DCA was required 10.3 and 23.8mM. The question is, is it possible to reach a thiamine level of 4.9-5.4 mM in glioblastoma cells in the brain?

"Thiamine reduces cancer cells proliferation.
The IC50 values for DCA were 23.8 for SK-N-BE and 10.3 mM Panc-1. Comparatively, the IC50 of thiamine was lower than DCA for both cell lines with values of 4.9 for SK-N-BE and 5.4 mM for Panc-1."

The effects of Thiamine on PDH phosphorylation, glucose consumption and lactate production, mitochondrial polarization, ROS production, caspase-3 activity were estimated at 25 mM and therefore are probably not easily achievable.

Sulbutiamine is a synthetic thiamine derivative designed to overcome thiamine’s inherently poor bioavailability. It was designed in the 70’s in Japan in response to widespread thiamine deficiency.

I also found some studies that sulbutiamine penetrates the brain better than benfotiamine and thiamine. It also seems that sulbutiamine is safe in large doses.

 

2017 https://www.ncbi.nlm.nih.gov/pubmed/28755683

"Sulbutiamine shows promising results in reducing fatigue in patients with multiple sclerosis. Sulbutiamine is a lipophilic compound that crosses the blood-brain barrier more readily than thiamine and increases the levels of thiamine and thiamine phosphate esters in the brain."

2008 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2435522/
"...We previously found that sulbutiamine treatment significantly increases thiamine, ThMP, ThDP and ThTP content of rat brain, while the present results show that benfotiamine, at a twice higher dose, is unable to raise the levels of intracerebral thiamine phosphate derivatives.

...Furthermore our results on cultured neuroblastoma cells show that benfotiamine, in contrast to sulbutiamine, does not easily cross cell membranes.

...Our results show that oral administration of benfotiamine leads to significant increases in thiamine, ThMP and ThDP levels in blood, liver but not in the brain. This difference is in agreement with the known pharmacological profile of benfotiamine, i.e. the beneficial effects of the drug concern peripheral tissues but not the central nervous system."

1999 https://www.ncbi.nlm.nih.gov/pubmed/12973384
"Sulbutiamine, a highly lipophilic thiamine derivative, is the only antiasthenic compound known to cross the blood-brain barrier and to be selectively active on specific brain structures directly involved in asthenia."

Sulbutiamine is available as a dietary supplement. Unfortunately, there is not enough information about the risk of its effect on tumor growth at low and medium doses and what should be the high dose for an effect similar to DCA.

Irina’s mom healing cocktail

Dear Stephen, dear all!

I want to apologize in advance for the mistakes, because I have not practiced English for a long time.

Some history:

My mom’s tumor was found on MRI in 2011, doctors did not operate it because it was inconveniently located. One of the best Russian surgery said that we just have to watch it and do MRI each year. Seven years it did not interfere, but gradually grew and changed boundaries, in 2018 epileptic seizures started and appeared contrast on MRI.

07/17/2018 85% of the tumor was removed.

Three courses of TMZ (5/23) and 6 courses of Avastin. After the first course of TMZ and Avastin, MRI showed a reduction in the tumor and a decrease in contrast. Doctors said that radiation therapy should not be done because of the location of the tumor.

Histology results: 

- glioblastoma;

- MGMT methylated;

- no mutation was detected in 599-601 codons of the BRAF gene;

- diffuse expression of GFAP;

- p53 (norm);
- Ki-67 index - 25%;
- expression of synaptophysin;
- IDH1, NF, CD34 (in the tumor endothelium) was not detected in the tumor cells;
- mutations in 4 exogenes of the IDH11 and IDH2 genes were not detected;
- the deletion of the 19q13 locus was not found (the ratio of the number of signals 19q: 19p is 1.34);
- a deletion of the 1p36 locus was detected (the ratio of the number of signals to 1p: 1q is 0.70;
- in the nuclei of tumor cells a tri-, tetrasomy 19 chromosome is detected;
- microsatellite instability by markers NR-21, BAT-25, NR-24, NR-27 was not detected (tumor phenotype with a stable repair system - MSS);
- PD-L1 expression is not determined;

- BRCA1, BRCA2, CHEK2 not found.

My mom's cocktail (weight 63 kg, height 172 cm):

Coriolus versicolor	3150 mg. Better take on empty stomach or with meal?
Nexium (esomeprazole)	60 mg 2 times a day. Two days before chemo, one day after chemo. Or she should take it constantly?
DCA	12 / mg per kilogram 2 times a day and than increasing (ordered but not arrived yet)
Hydroxycitrate (Garcinia cambogia extract) + Lipoic acid + Low Dose Naltrexone (protocol METABLOC)	Hydroxycitrate: 500 mg thrice daily; Sodium R Lipoate: 800 mg twice daily + 5mg before bed time
ECGC and Sulfofran	Could you please advice on dosage of ECGC? And should she take ECGC and sulfofran only during 5 days of TMZ or all course of TMZ?
Boswellia (wokvel)	Should be taken only during radiation? If my mom doesn't have radiation can boswellia affect the tumor positively, or it just reduce edema and that is all?
Ashwagandha	What dosage and best trade mark?
Aged Garlic	What dosage?
Maitake	Mom takes this mushroom supplement: https://ru.iherb.com/pr/Fungi-Perfecti-Host-Defense-MyCommunity-120-Veggie-Caps/21448 (Maitake (Grifola frondosa) mycelium - 142 mg) Is it enough or I better buy Maitake D-fraction?
Perillyl alcohol

I understand that my mom's cocktail is very far from the ideal, but I'm trying to improve it every day.

Questions:   

1. Which mutations do we still need to pass to choose the most effective treatment tactics and select the optimal cocktail? I read on the forum about EGFR, EGFR III and many other mutations, but I have never heard about it from mom’s oncologist.

2. What drugs should I add to my mom’s cocktail that will be maximum effective in her case (Actuante during 23 days off TMZ, disulfiram with copper during 5 days of TMZ, Artemether during 5 days of TMZ, Captopril, Tagamet, Celebrex, Minocycline or other)?

I got a bit confused in such a huge amount of drugs in the Stephen’s library, because in Russia there was absolutely no one to consult on this topic, 3 chemotherapists refused to even listen about such methods.

3. My mom also takes Valproic acid against epilepsy after surgery, but she doesn’t have radiation. Probably we should change it on Keppra, because she is still on TMZ? Or there is no need, because her MGMT is methylated?

4. Are there any drugs - MGMT inhibitors, that can possibly change the status of MGMT methylated to unmethylated?

5. How do you think, should we go from only TMZ to TMZ + lomustine? And make 12 courses (3 TMZ have already done)?

6. Do I understand correctly that I should limit mom’s protein intake to 0.83 grams protein per kilogram body weight?

I want to thank Stephen for the blog! I can’t even express how useful this resource is!

I wish all of you and your loved ones good health!

Irina

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!

Rovalpituzumab Tesirine (DLL3 antibody-drug conjugate) for IDH1-mutant glioma

Cell surface Notch ligand DLL3 is a therapeutic target in isocitrate dehydrogenase mutant glioma

pubmed link

full article download

"DLL3 immunostaining was intense and homogeneous in IDH mutant gliomas, retained in all recurrent tumors, and detected in only 1 of 20 non-tumor brains. Patient-derived IDH mutant glioma tumorspheres overexpressed DLL3 and were potently sensitive to Rova-T in an antigen-dependent manner."

This is particularly interesting because the therapy is currently available in a clinical trial for recurrent GBM and other solid tumors recruiting at multiple locations across the USA.

https://clinicaltrials.gov/ct2/show/study/NCT02709889?show_locs=Y#locn

CDK4/6 inhibitors

My father was diagnosed with GBM a few months ago and a recent molecular screening suggests that CDK4/6 inhibitors may be of use as a form of therapy due to evidence of 'CDK4 amplification'.  

Following my own research, there seem to be three CDK4/6 inhibitor drugs available:

1) ribociclib (Kisqali) 

2) palbociclib (lbrance) 

3) abemaciclib

Does anyone have any experience with the above drugs in terms of toxicity, side effects, dose etc?

Are there any drugs that are known to, or have some evidence to suggest that they may work synergistically (or to have negative interactions) with these three? 

Apart from the three drugs above, does anyone know of any other CDK4/6 inhibitors?

Any inputs would be much appreciated! Thanks!