The Colon Club

Hey Everyone-

I know I have been quiet lately - frankly there hasn't been a lot of news to report... Current trials are in progress, not too many new ones opening lately. But I continue to watch closely I expect the news-flow to increase when we hit the big news engines: the AACR & ASCO cancer conferences (especially ASCO) later this spring.

I posted a blog today that talks about a crowdfunding effort for a new CRC trial at UCSD. It is based upon a good scientific idea and should be eligible to both KRAS-wt and KRAS-mut. It doses the EGFR inhibitor "erlotinib" at very high doses but only 2 days a week, the rest of the week is no treatment. The hypothesis (supported by data so far) is that this "Cmax drive dosing" may increase activity as well as decrease skin toxicity - but only doing the CRC trial will tell for sure. I plan to enter it as needed!

Crowdfunding is being used to help pay for the trial start since the drug is almost off-patent.

More details at the blog (second half): http://adventuresinlivingterminallyopti ... cal-trial/

Cheers,
-DK

Really good info and an interesting take on this pulse dose / pause idea…. AND funding !!!!!

I think if we understand the science, the "loading dose" idea is workable for many applications whereas the sustained "AUC" is more valid for others … BUTT … the true Genius is in knowing which is which and where to use it !!!!

Thanks for the update buddy
Cheers
CRguy

Thanks again DK

CRguy wrote:
I think if we understand the science, the "loading dose" idea is workable for many applications whereas the sustained "AUC" is more valid for others … BUTT … the true Genius is in knowing which is which and where to use it !!!!

That's exactly right CR. "Most drugs" work through something call "sustained AUC" which is kept above a certain drug threshold level necessary for activity via e.g. once a day dosing. The problem with some drugs like EGFR-inhibitors is that they have "on-target tox" (e.g. skin rash) which limits how high they can push dosing to maximize AUC.

It was hypothesized (and preliminary data supports) that you may be able to disconnect the anti-cancer effects of an EGFR-inhibitor and its toxic side effects by hitting the tumor with a very high dose but for only 2 days - then have a rest period without any dosing. Skin is hypothesized to maintain health due to this rest period but it appears that there may be a disconnect and tumors have a really hard time dealing with that short term EGFR-inhibitor sledghammer dose and can't recover during the rest period.

In effect it is treating a targeted therapy (erlotinib) more like a chemotherapy & less like a targeted therapy in terms of dose schedule. It is similar to FOLFIRI dosing. You dose high & hard in an infusion which hits the tumor hard. Then you rest ~2 weeks, to allow normal tissue to recover but the tumors selectively have more trouble rebuilding. This would now be tried using a drug (erlontinib) with less intrinsic overall toxicity than irinotecan (because it is a targeted agent) - thus improving side effect profile. By hitting the cancer with high doses/sledgehammer - it is believed that responses in even KRAS-mut patients may occur.

Unproven yet in a CRC clinical trial - but all the data in hand right now supports these ideas, so the trial should be tried!

-DK

The dosing schedule sounds similar to what my wife's current trial is attempting to do with Irinotecan, Erbitux, with or without Avastin (or placebo). They dropped the 5-FU from the previous FOLFIRI and added Erbitux. She thinks she is still getting the Avastin based on previous experience with it (She is still on the ACE inhibitor they use with Avastin use though her BP is usually low to begin with). She has only the infusion on Mondays, then nothing again until day 14 when she gets hit again. Problem is I don't know if they are using a higher dosage of Erbitux or not. She is tolerating this very well and the rash came on after a week, not right away, but she thinks it was subsiding prior to yesterdays infusion (which was #2).

I am of course interested in the UCSD trial as I contributed research to these class of drugs - particularly CI-1033, and Dacomitinib. I still believe despite the failure of Dacomitinib against Erlotinib in the big Pfizer NSCLC trial (ARCHER 1009) that Dacomitinib is still a superior EGFR family inhibitor. The UCSD trial looks promising. We know that EGFr inhibitors once they become resistant, that if one lays off them for a while the pathway that was diverted and make the tumors resistant will revert and EGFr inhibitors become effective again. So I wonder also if this dosing schedule and concentration used in the trial isn't working similarly. Hitting the tumor hard, relaxing, and not enabling the tumor to slide into the alternative signaling pathway. Many questions that hopefully this trial will answer. I wonder if they would consider using Dacomitinib in an arm of the crowd funded trial also?

Regards,

GrouseMan

GrouseMan wrote:The dosing schedule sounds similar to what my wife's current trial is attempting to do with Irinotecan, Erbitux, with or without Avastin (or placebo). They dropped the 5-FU from the previous FOLFIRI and added Erbitux. She thinks she is still getting the Avastin based on previous experience with it (She is still on the ACE inhibitor they use with Avastin use though her BP is usually low to begin with). She has only the infusion on Mondays, then nothing again until day 14 when she gets hit again. Problem is I don't know if they are using a higher dosage of Erbitux or not. She is tolerating this very well and the rash came on after a week, not right away, but she thinks it was subsiding prior to yesterdays infusion (which was #2).

I am of course interested in the UCSD trial as I contributed research to these class of drugs - particularly CI-1033, and Dacomitinib. I still believe despite the failure of Dacomitinib against Erlotinib in the big Pfizer NSCLC trial (ARCHER 1009) that Dacomitinib is still a superior EGFR family inhibitor. The UCSD trial looks promising. We know that EGFr inhibitors once they become resistant, that if one lays off them for a while the pathway that was diverted and make the tumors resistant will revert and EGFr inhibitors become effective again. So I wonder also if this dosing schedule and concentration used in the trial isn't working similarly. Hitting the tumor hard, relaxing, and not enabling the tumor to slide into the alternative signaling pathway. Many questions that hopefully this trial will answer. I wonder if they would consider using Dacomitinib in an arm of the crowd funded trial also?

Regards,

GrouseMan

Good points and questions GrouseMan, thanks-

First of all, I wish you wife good results on her trial!

In terms of your points;
- I think a mechanistic goal of delaying resistance via pulse dosing is very much on their minds.
- You raise an interesting question re: Dacomitinib. The final trial protocol has not been written yet - I will discuss it with the PI!
- I think they are intentionally focusing on using a LMW EGFR inhibitor to have a better dosing controlled PK (cetuximab's PK is quite variable between people and can have a very long half-life).

I am a big fan of alternative dose schedules in general when there is a strong scientific basis to try.

Cheers,
-DK