An open-label, dose escalation, safety, and pharmacokinetic study of
ENMD-2076 administered orally to patients with advanced cancer.
Sub-category: Other Novel Agents
Category: Developmental Therapeutics: Molecular Therapeutics
Meeting: 2009 ASCO Annual Meeting
Citation: J Clin Oncol 27:15s, 2009 (suppl; abstr 3520)Abstract No: 3520
Author(s):
Background: ENMD-2076, a novel, orally-active antimitotic and antiangiogenic molecule inhibits Aurora A as well as tyrosine kinases that drive tumor vascularization, including VEGFR2 (KDR), PDGFR and the FGF receptors. This Phase 1 study was designed to evaluate the safety, pharmacokinetics (PK) and preliminary efficacy of ENMD-2076 administered once daily to patients (pts) with advanced cancer. Methods: The dose escalation scheme utilizes 3 (or 4) + 3 (or 2) design. Pts receive ENMD-2076 once daily in 28-day cycles (followed by 7-14 days of rest between cycles 1 and cycle 2 only). Results: 14 pts have been enrolled in 3 dose cohorts (range 60 to 120 mg/m2/d). Median age/performance status is 62/1. The total number of treatment cycles to date is 45, with a median of 3 cycles (range <1 n="14)">2/d. Following drug interruption, the pt restarted at 30 mg/m2/d and continued for 4 additional cycles before being removed for progressive disease. Noncompartmental PK analysis of the first two dose levels shows that the plasma concentration of ENMD-981693 (the active free base of ENMD-2076) is dose- linear, as reflected in AUC and Cmax. The estimated terminal half-life (t1/2) is unaltered regardless of dose; however, t1/2 is approximately 50% greater at steady state than following single dose administration. Four ovarian cancer and 2 colon cancer pts have achieved decreases ranging from 11-61% in either CA125 or CEA, respectively (4 are associated with stable disease at Cycle 2 by modified RECIST criteria). Serum KDR concentrations assayed by ELISA decreased from baseline in all patients on treatment from a mean of 9153 pg/mL (SEM 464.2) at D1 to 6987 pg/mL (SEM 460.0) at D28 (p <0.05).>Conclusions: ENMD-2076 is a small molecule kinase inhibitor with acceptable toxicity and preliminary evidence of antitumor activity in pts with ovarian and colorectal cancers.
(The final bold is mine.)
If this is true, this could be HUGE!!!!!!!!! This is on actual patients, people!!
I love you, Entremed researchers and docs involved with this clinical trial. With all my heart.
Tune in to the annual ASCO meeting on May 30, 2009 for the actual presentation of trial results. Or my blog.John Crewdson, are you still out there?
NOTE: So I am not accused of going all New York Times, May 3, 1998 on you (here), I would like to point out that this is just a Phase I trial.
11 comments:
Just to be clear: This was primarily a study of a drug's safety and metabolism, not its effectiveness. A clinical trial of a new treatment consists of four phases. This one was a Phase 1 study.
Where effectiveness WAS measured, it showed that by the end of the study, 6 of the 14 patients enrolled had lower levels of a tumor-associated protein in their blood, and 4 of those 6 had, in the researchers' words, "stable disease"--their cancer had neither grown nor shrunk.
When you see "Phase 3" or "Phase 4" in a study's title or abstract, you know they are concentrating primarily on actual effectiveness--tumor shrinkage.
I've been through this drill with my own family, so I appreciate your hopefulness, and support it.
Hope that it is an effective treatment. After all this time maybe they are on the right track! Great news, HD, thanks for this information.
Anon: I understand and was really reluctant to post this, having lived through it myself with my first husband.
He was one of the first patients in Entremed's clinical trial for Endostatin.
However, this is very exciting news. What they were seeing in the lab is translating to patients so far. And you rarely see regression in tumor markers at this stage. Not trying to go all New York Times, May 3, 1998 on anybody, but you'll understand my hope and excitement.
Hey Anon:
Your points are well-taken, of course.
I go back with this more than a decade. The pharmacological thesis is elegant and to some extent has been vindicated by other molecules. The initial AI's, angoistatin and endostatin, fragments of plasminogen and collagen XVIII, while potent, were large molecules that were very difficult to express recombinantly. The scientists have spent a decade pulling these molecules apart in an effort to determine the component parts that are responsible for the inhibition of the angiogenisis upon which tumor growth depends. A few months ago they halted work on all of the candidates except for this one (ENMD-2076). So I am pretty excited over here that 2076 is looking good at least thus far. I had the honor of knowing Judah (Folkman) personally, and he would be mighty proud. I know that it is only a first inning run, but it is a run nevertheless.
This would be a godsend, let's all keep every bit on our bodies crossed.
Couldn't understand much of that gobledy-gook ... but it must be a good thing! *crosses fingers*
First let me say that so far I like the content of your blog.
Oh, I should say hello to Pilot and Lori, Spudlysma.
OK!!!
Let me start by saying that the abstract submission deadline was(January 6, 2009) for this years Annual ASCO Meeting.
http://www.ascocancerfoundation.org/anf/Past+Issues/October+2008/Call+for+Abstracts
So let's say that the abstract was written almost 5 months ago.
Now let's look at the data from 5 months ago.
14 total patients were treated at the time. At that time four ovarian cancer and 2 colon cancer pts have achieved decreases ranging from 11-61% in either CA125 or CEA, respectively (4 are associated with stable disease at Cycle 2 by modified RECIST criteria). So let's say that at that time a minimum of 6 patients out of 14 patients were showing anti-cancer responses. At that time the positive response rate was 42.9%. That sounds great to me especially for relatively low doses of an oral anti-cancer drug.
The abstract written in December 2008 or early January 2009 said "...The total number of treatment cycles to date is 45, with a median of 3 cycles (range <1 to 9 cycles)." So at least one patient was in the trial for 9 months (a cycle is 4 weeks) That means that at least one patient had been on trial since the very first dose cohort. Remember these patients were advanced cancer patients. On average the 14 patients had been through three months of treatment.
The median age of patients was at the time 62 years of age, which means that half the paients were 62 years old or older.
There has been some adverse side effects reported "...most frequent, related toxicities (all grades, n=14) were hypertension (29%), fatigue (21%), proteinuria and diarrhea (both 14%). One pt experienced dose limiting toxicity of Grade 4 hypertension and Grade 3 cholecystitis in the first dose cohort of 60 mg/m2/d. Following drug interruption, the pt restarted at 30 mg/m2/d and continued for 4 additional cycles before being removed for progressive disease..." "...Conclusions: ENMD-2076 is a small molecule kinase inhibitor with acceptable toxicity and preliminary evidence of antitumor activity in pts with ovarian and colorectal cancers."
Good luck and God bless,
George
Sorry this is a part two:
Now even the side effects particularly hypertension and proteinuria are common of angiogenesis inhibitors and may actually not be too bad. It may be a sign that ENMD-2076 is a very potent oral angiogenesis inhibitor.
See the second paragraph under Conclusions on page 521
http://books.google.com/books?id=bSHef8z0cb4C&pg=RA1-PA521&lpg=RA1-PA521&dq=proteinuria+%22shrinkage+of+tumors%22&source=bl&ots=Q9aiMvCFxb&sig=Hf3qgT4cFZNtNJWO9i2722nTGJ4&hl=en&ei=7j0QSqrdB5-stge8x7z5Bw&sa=X&oi=book_result&ct=result&resnum=1
Hypertension could be a sign that ENMD-2076 is showing efficacy.
See the following abstrat from this years ASCO that has come to a similar conclusion for another drug. dystolic blood pressure ≥90 mmHg during therapy is a strong predictor of clinical efficacy. "...An 82% increase in probability of a partial response was predicted for a 10 mmHg higher dBP during therapy...."
Treatment of hypertension when using angiogenesis inhibitors is very common.
"...In conclusion the hypertension associated with angiogenesis
inhibition can be exquisite responsive to longacting oral
nitrates with prompt return of pre-treatment blood pressure in
spite of continuous anti-VEGF treatment...."
http://annonc.oxfordjournals.org/cgi/reprint/18/6/1121
More up to date interim results will be reported on May 29, 2009 at the Annual ASCO Meeting. Notice that no dose limiting toxicities were reported therefore the dose escalation continues.
I don't want to hog this space.
I do want to leave one last link of a video regarding ENMD-2076.
http://app2.capitalreach.com/esp1204/servlet/tc?cn=aacr&c=10165&s=20385&e=9605&&
We all miss Dr. Moses Judah Folkman. I never met the man but I have the utmost repect for him. He was a true Rabbi like doctor. He has taught many people and he has left a never ending legacy. Others now see farther because they stand on the shoulders of a giant like Dr. Moses Judah Folkman.
Good luck and God bless,
George
Hey George:
So good to hear from you! Long time no see...
I ran all of this by Golfdad down in Texas (now retired from MDACC), but he is to busy entertaining grandchildren and growing vegetables to comment. I have been out of the game now too long to know a DF or a MDACC PhD who could offer a even a minimally competent opinion, so, anymore, I am just along for the ride. I am concerned, of course, about the durability of the response, but the response sounds kick-*ss thus far.
All the best,
Pilot
Georgejjl!! I knew you would find me. You know, the government needs some helping finding Osama bin Laden. See what you can do about that. ;-)
I was checking on ASCO results for the first time in years and ran across this abstract.
It makes me so happy to see they are making real progress. I am excited to hear results of early PhI trials in a week or so.
Is there still a Yahoo Group? Please feel free to email me about it.
Thanks, Georgie, and take care.
For old time's sake, Spudlysma
A relative of mine went through treatment with a then-new drug that had gotten a lot of exuberant coverage: a monoclonal antibody linked to a conventional cancer drug. The idea was that the combo molecule would be ultra-targeted, sparing the non-cancer cells and really whamming just the cancer cells.
It's been well over a decade. The combo-drug proved not a roaring success but not a complete washout. The last time I checked, a small biotech company had picked up the patent on it and was starting a new round of testing, with a different group of cancers.
I think with cancer drugs, this is a common story: Some success, some disappointment, usually nothing huge or radical but rather incrementally helpful.
I don't know why, at this late date, so many illnesses (not just cancers) still cannot be cured by medication. It's widly frustrating (understatement).
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