Pulsing Crizotinib like Tarceva? Has anyone done it?

There has been some discussion about pulsing high dose Tarceva at spaced intervals for effectiveness in brain metastasis (not sure, maybe mostly for Leptomeningeal disease?). Has this ever been tried with Crizotinib? Asked our doctor and they had no idea, except a bit worried that it may impact WBC.

Tarceva pulsing article links:
http://www.springerlink.com/content/26kq3282500846w0/
http://www.medscape.com/viewarticle/738089

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Good subject cjvil.

There has been more effective treatment for leptomeningeal metastases using small molecule drugs that may be able to penetrate the blood-brain barrier (BBB). Small molecule intervention can be beneficial by dissolving through the capillary cell membranes and absorbed into the brain.

What may be another alternative is high doses of two small molecule EGFR pathway drugs, Tarceva (erlotnib) and Iressa (gefitinib), given together. It might cross the blood-barin barrier and some patients may get a long-lived remission with these drugs.

In different tumors, either Tarceva or Iressa might get inside the cells, better or worse than the other. And the drugs may also be inactivated at different rates, also contributing to sensitivity versus resistance.

The efficacy of high-dose (1250 mg/d) of Iressa (gefitinib) for the treatment of leptomeningeal metastasis in a patient with lung cancer harboring a mutation in the epidermal growth factor receptor (EGFR) gene has previously be reported.

It is speculated that Tarceva (erlotinib), instead of high-dose Iressa (gefininib) may be also effective for the treatment of central nervous system (CNS) lesions, as trough serum concentration of Tarceva is nine times higher than that of Iressa.

High-dose Tamoxifen could then be given continuously as a potentiator and an anti-angiogenic effect. These novel protocols have been used in cell function analysis.

Drugs like high-dose Tamoxifen (2.5 micromolar or greater) that significantly inhibit the P-glycoprotein (gatekeeper in the blood brain barrier) multidrug resistant membrane pump, as well as inhibiting protein kinase C (preventing the increase in vascular resistance).

http://cancerfocus.org/forum/showthread.php?t=3500

I believe it could be possible using Xalkori (crizotinib) for brain metastses, as it is a small molecule drug. I have to see if any of the cell-based assay labs have tried it yet.

Greg

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Let's first clarify where we are.

Tarceva is an effective drug for EGFR positive patients. For that group it is probably the treatment of choice with a response rate of about 60%. I do not know of post-approval studies comparing dosages, but certainly dosage would be based on study results.

Crizotinib is the same thing; it is an effective drug with patients who have the mutation and questionable with those who don't.

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Greg, thank very much for the insight. If you see or hear of anything from cell assay labs, please let me know.

Howian1 - Yes, We've got an ALK mutation NSCLC and have the odd situation of having no systemic disease detectable now, except metastasis to brain keep occurring from an unknown source. We keep zapping w/ gamma, but wondering if there are any preventative measures like pulsing Crizotinib that could help.

Has anyone tried this or heard of it being done?
Thanks!

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So you are taking Crizotinib already and are evaluating changing the dose. Do we have a cite for the article gpawelski mentioned,

"The efficacy of high-dose (1250 mg/d) of Iressa (gefitinib) for the treatment of leptomeningeal metastasis in a patient with lung cancer harboring a mutation in the epidermal growth factor receptor (EGFR) gene has previously be reported."

The first inclination for any doctor will be to adhere to standard practices and recommended doses. Unless there were an emergency situation, a very courageous doctor, or compelling data,one would think he would be reluctant to substantially alter recommended dosage.

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I'm going to just jump in because I also find this a compelling idea (sorry to say, just for speculation at this point, not answers).

I do wonder if at some point they will discover that administration of targeted therapies should not in fact be daily, but rather 'pulsed' or until a therapeutic response is arrived at. Taking an ALK (my mutation as well) daily would only seem to increase selective pressure for the cancer to mutate...

As for your particular situation, the absence of systemic disease is great, but the brain mets frustrating. I would look into a different treatment that crizotinib at any rate, as it is know to cross the blood brain barrier in only very small concentrations, and so maybe not the best choice to battle brain mets.

I can't check your profile without leaving this page, but have you considered traveling to Boston for a second opinion with Dr. Alice Shaw (certainly one of, if not the leading expert on ALK mutations).


Best, Linnea

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Yes, in the url thread posting above.

Greg

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@Cjvil
I am in your same situation. For now dr says just stay with the xalkori. I have been growing a new brain tumor every four months. Hoping sept will prove otherwise. My alternative oncologist wants to give me weekly dose of a hemoplathic level of tremodor. Will speak to my main oncologist about it in september. Until than hoping for the best. Best to you, Sean

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FYI -- Very good question.

I don't have an answer, but it might depend on
(a) whether as much Xalkori crosses the BBB as Tarceva (might be much less) and
(b) whether 4x dose every 4 days is tolerable and
(c) whether the mets are Xalkori-sensitive.

re: how to grow resistance, the technique used in lab experiments is to start with a very diluted amount of the drug and gradually increase it so there's time for natural selection and mutations to occur and survive as the concentration of the drug rises. That makes me assume that the best defense would be to not let the level of the drug dip below what it is with normal dosing every day.

BTW, some researchers have been trying to solve the ALK brain mets problem. I'm optimistic they'll find something helpful eventually new but assume not anytime soon. In the meanwhile, there's radiation, surgery, infusion of chemo directly into a brain met using a port, and experimental drugs like GRN1005.

Best hopes,

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Cjvil

From the cell assay labs: it could work, not just that it's a small molecule but, more importantly, because it's a lipid soluble molecule (better at crossing the blood brain barrier). A few brain diseases consistently respond to lipid-soluble small molecules.

Greg

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Thanks everyone for the insights. With no systemic disease and recurring brain mets we felt it was important enough to try (but not with an official stamp of approval from our doctor, who understood the logic but said that as a licensed doctor they could not recommend an alternate dosing from what has been tested previously, so we would need to do it on our own if we felt it was best). We'll see how it goes. Did some calculations based on 42 hr half life (pls correct me if I am wrong) with 12 hr 250 mg doses, vs 4 day dose of 2000 mg all at once with a 4 day interval, and it looks like approximately 80% boost in level of medication on the first day, down to 50% below normal by the 4th day. Not as much variance as I had expected, and actually a bit less variance than Tarceva due to Xalkori's slightly longer half life.
We think it may also be important to de-load a bit before starting or the incremental dose at the beginning will be much higher than 80%. To test safety we started with skipping one day to deload and then taking a 1000mg dose. That should give a moderate dose increase of 27% from normal levels if a simplistic half life calc is correct. But the dose was actually a bit hard on the digestive track and diarrhea resulted after 3 hrs. We'll need to figure out a solution for that, maybe preemptive anti diarrhea medication. Any thoughts? Thanks!

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immodium worked for me when I needed it initially. (Too well -- got worried after a few days but a small bucket of prunes did the trick.)

I'd be concerned with the effect on the heart. At normal dose, my resting heart rate is suppressed by 10pbm. Would 4x that drop it by 40bpm and be life-threatening, or does it not get worse than 10bpm??? I can't guess. I'd recommend very close monitoring (incl. when sleeping) and being quick to rush to the hospital if it becomes an issue.

Best hopes,

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Thanks for the advice. We'll keep an eye (or ear) on the heart beat. Also, the 4x dose does not actually result in 4x extra load in the body. With nearly a 2 day half life, we have a stable state load of the equivalent of almost 3 days worth (1400 mg) in us on a daily basis (although much of the 1400 won't make it to our plasma). So the 4x dose of 2000 mg with 4 day spacing may only succeed in getting the load up 80% higher to 2500 mg equivalent (500 remaining by the time we take dose again). Big caveat that this is just calculations on a spreadsheet based on half life. I really have no idea what the dose does in a complex human body, so we will watch carefully.

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You could also have one of the heart monitors that you wear for a few days. That is what they were going to do with me before we decided to lower the dose. Because when I was on a 250x 2. I was passing out. Sean

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I do know that diarrhea can be followed by constipation and that constipation may actually be worse and prophylactic anti-diarrheals may make the constipation much worse. Sometimes it's better to just deal with the diarrhea, which is usually self limited, than to overtreat it.

Greg

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I would also see thatfrequent monitoring of liver enzymes is done--I believe with the higher doses liver toxicity could be a potential issue, and if you notice a spike in values, you want to catch and discontinue as soon as possible.

Linnea

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Tried the full 4 day 2000 mg dose yesterday. My wife paced it through the day with 250 mg every 2 hours and was able to avoid diarrhea without taking any immodium, so hopefully she got the full dose impact. But this morning she's feeling very tired and a bit nauseous, had one bout of diarrhea as well. Heart rate appears to be normal. She will rest up today.

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cjvil,

Thank you for sharing that info. Glad to hear it's managable so far. It could become important info for some of us. Keep us posted. (As you know, sometimes side effects can take weeks to become apparent.)

Best hopes,

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FYI, another old half-thought, for later. I ran across this article some time ago:
http://www.lungcancerjournal.info/article/S0169-5002(12)00063-3

Best hopes,

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