AbraxaneTM (ABI-007)
Introduction
AbraxaneTM , is albumin nanoparticle paclitaxel
(Taxol). It is billed by the manufacturer as the next generation taxane.
It is a solvent-free, albumin(protein)-bound paclitaxel (taxol®).
It is stated to allow a shorter infusion time with no need for
predmedication to prevent possible severe hypersensitivity reactions.
So far, Abraxane has only been approved for metastatic
breast cancer. The phase III trial that led to this approval had the
following treatment comparison:
Phase 3 Trial Treatment
Regimen Overview1
Abraxane was compared with Taxol in a randomized, multicenter trial:
- Abraxane at 260 mg/m2 given as a
30-minute infusion every 3 weeks (n=233)1
; elimination of corticosteroid premedication was not a problem.
- Taxol at 175 mg/m2 given as a 3-hour
infusion every 3 weeks (n=227)1
- Abraxane nearly doubled the tumor response seen
with Taxol. There also was a
prolongation of time to tumor progression in first and second line
patients
with metastatic breast cancer.
Phase I Dose-Escalation study of Abraxane
Abraxane can be given on a weekly basis and
there has been a study of this to find the maximum tolerated dose in
breast cancer. In an open-label study, 39 patients received doses of
Abraxane ranging
from 80 mg/m2/day to 200 mg/m2/day as a 30 minute infusion 3 weeks out of
4. One half of the patients had previously received minimal chemotherapy
and the others had received extensive prior chemotherapy. Abraxane was well tolerated
when administered over 30 minutes, with no severe hypersensitivity
reactions
observed in this study without the need for premedication with steroids or
G-CSF support. Abraxane demonstrated significant antitumor activity (5 PRs)
including responses in patients previously treated with taxanes. The
maximum
tolerated dose (MTD) of Abraxane was 100 mg/m2/week in those patients who
had
previously received heavy doses of chemotherapy and 150 mg/m2/week in the
group that had previously received minimal amounts of chemotherapy.
Recent Results Presented at the 29th San
Antonio Breast Cancer Symposium (added 2/5/07).
At the 29th SABC Symposium (Dec. 2006), preliminary results of a
randomized phase II clinical trial2 in 300 metastatic breast
cancer patients compared Abraxane given weekly or every 3 weeks vs
taxotere given every 3 weeks were presented. The doses used were: ABX
300mg/m2 every 3 weeks; ABX 100mg/m2 or 150mg/m2 on days 1, 8, 15
every 28 days; or Taxotere(TXT) 100 mg/m2 every 3 weeks.
210 patients were evaluated
by the time the abstract was submitted. The response rates were
comparable for the every 3 week doses whether ABX or TXT. However,
weekly ABX was (they used the word "may be more") more active (RR 58%
for 100mg/m2 and RR 62% for 150mg/m2) than TXT(RR 36%) given every 3
weeks and there was an indication of a dose-response rate for ABX given
weekly. As far as toxicity was concerned, ABX resulted in less
neutropenia and febrile neutropenia than TXT. Furthermore, "to
date, twice as many patients on TXT have progressed and/or died compared
to each ABX arm." (a phase 3 trial is planned using ABX 100mg/m2 weekly
vs TXT 100mg/m2 every 3 weeks).
Abraxane and Hormone Refractory
Prostate Cancer
Taxol is often used for treating hormone refractory prostate cancer.
The response rate with single agent taxol in hrpca patients is low --
the PSA RR (greater than 50% decrease in PSA) is 25-30%. This
increases to 48% when estramustine phosphate (emcyt) is added. The taxol
only performance status improvement is 8% at 12 months (29% when emcyt
is added) and survival is
12.9 months (15.1 months with emcyt added) (Berry et al, Proc. ASCO 2001,
abstract 696). This study used 100mg/m2 3 weeks out of 4.
Taxol also carries
some risks associated with the Cremophor EL
(a polyoxyethylated castor oil) -- see taxol vs
taxotere. Abraxane doesn't have the cremophor(hence none of
the asthmatic/ anaphylactic-type reactions,) but the chemotherapy is
still taxol -- which begs the question as to just how effective would
single agent Abraxane be in HRPCa?
So far, there is only 1 small clinical trial(3) that has been
reported on with HRPC patients, but there are supposedly about 5 trials that have started or
will be starting. This trial was 1st line chemotherapy with Abraxane. 15
patients were enrolled and all were evaluated for toxicity and is
described as "very well tolerated so far by this population...."
Response Evaluation (12 of
15)
-
2 - too early in treatment
to evaluate
-
1 - elevated LFT toxicity
so d/c after 1 infusion
-
1 - completed 11 cycles,
maintained SD, PSA PR.
-
10 - off study due to
rising PSA or radiological progression.
-
4 - # of patients actively
receiving treatment.
Basically, response was 1 out
of 12. They indicated in the abstract that updated results would
be presented at the ASCO annual meeting. No dose or schedule information
was included in the abstract. We'll have to see if they every
publish this.
Abraxane can be given at a much higher dose than taxol
and perhaps that is the key to having an improved or continued taxane
response. Another question is can Abraxane be combined with emcyt
or carboplatin? Is Abraxane better when given as a weekly infusion
or as an every 3 week treatment? So there are more questions than
answers to date (but reference (2) may indicate weekly is the best
choice.)
NET
So just what is a patient supposed to do if he decides to
use Abraxane instead of Taxol? Unfortunately, there are more
questions than answers, but perhaps the way it is being used in breast
cancer on an every 3 week basis is the best choice for now(but see below.)
(2/5/07 update): Based on the results in reference (2),
weekly Abraxane might be the better choice starting at the 100mg/m2 dose
and perhaps escalating to the higher dose if warranted. The actual
benefit for HRPC patients won't be known until clinical trials in HRPC are
conducted.
Author: Howard Hansen 9/5/05 with updates made 19 October
2007.
References
American BioScience Inc. (ABI) and American Pharmaceutical Partners (APP) are strategic partners in the
development, manufacture and marketing of Abraxane . ABI is responsible for
the clinical development and registration of Abraxane . APP has licensed
the
exclusive North American manufacturing and marketing rights for Abraxane . Abraxis
Oncology is a division of American Pharmaceutical Partners. Information on
Abraxane can be found at
www.abraxane.com
1.
William J. Gradishar *, Sergei Tjulandin , Neville Davidson , Heather Shaw
, Neil Desai , Paul Bhar , Michael Hawkins , and Joyce O'Shaughnessy,
Superior Efficacy of Albumin-Bound Paclitaxel, ABI-007, Compared With
Polyethylated Castor Oil-Based Paclitaxel in Women With Metastatic Breast
Cancer: Results of a Phase III Trial, JCO Early Release, published online
ahead of print Sep 19, 2005.
Journal of Clinical Oncology, 10.1200/JCO.2005.04.937.
2. Gradishar W, Krasnojon D, Cheporov S, Makhson A, Manikhas G, Hawkins MJ,
A randomized phase 2 trial of qw or q3w ABI-007 (ABX) vs. q3W
solvent-based docetaxel (TXT) as first-line therapy in metastatic breast
cancer (MBC), 29th Annual San Antonio Breast Cancer Symposium, December
14-17, 2006, abstract 46.
3. T. Kolevska, D. Goldstein, C. Davis, L.
Fehrenbacher, Phase II trial of paclitaxel in front-line therapy of
hormone refractory metastatic prostate cancer, Journal of Clinical
Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S
(June 20 Supplement), 2007: 15628.
