Data Reported at ASCO Confirm a Statistically Significant
Improvement in Both Time to Tumor Progression and Overall Survival
in the Perifosine + Capecitabine Arm Versus Placebo + Capecitabine
Arm
QUEBEC CITY, June 8
/PRNewswire-FirstCall/ - Aeterna Zentaris Inc. (NASDAQ: AEZS, TSX:
AEZ) (the "Company"), a late-stage drug development company
specialized in oncology and endocrine therapy, today reported final
results on the clinical activity of perifosine (KRX-0401), the
Company's novel, potentially first-in-class, oral anticancer agent
that inhibits Akt activation in the phosphoinositide 3-kinase
(PI3K) pathway, in combination with capecitabine (Xeloda(R)) as a
treatment for advanced, metastatic colorectal cancer. Abstract
#3531, entitled, "Final results of a randomized Phase 2 study of
perifosine in combination with capecitabine (P-CAP) versus
capecitabine plus placebo (CAP) in patients with second- or
third-line metastatic colorectal cancer (mCRC)" is being presented
today in a poster discussion held during the 2010 Annual Meeting of
the American Society of Clinical Oncology (ASCO) held in
Chicago.
Study Design
In this randomized, double-blind, placebo-controlled study
conducted at 11 centers across the United
States, heavily pre-treated patients with second- or
third-line metastatic colorectal cancer were randomized to receive
capecitabine (a chemotherapy used in advanced metastatic colorectal
cancer which is marketed by Roche as Xeloda(R)) at 825 mg/m2 BID
(total daily dose of 1650 mg/m2) on days 1 - 14 every 21 days plus
either perifosine or placebo at 50 mg daily. The study enrolled a
total of 38 patients, 34 of which were third-line or greater.
Median age of patients was 65 (32-83); 61% of the patients were
male. Of the 38 patients enrolled, 35 patients were evaluable for
response (20 patients on the perifosine + capecitabine arm and 15
patients on the placebo + capecitabine arm). Three patients on the
placebo + capecitabine arm were not evaluable for response (2
patients were inevaluable due to toxicity (days 14, 46) and 1 was
inevaluable due to a new malignancy on day 6). All patients in the
perifosine + capecitabine arm were evaluable for response.
The patients in the study were heavily pre-treated, with the
arms well-balanced in terms of prior treatment regimens. The prior
treatment regimens for all 38 patients are shown in the table
below. Notably, all of the patients (with the exception of one CAP
arm patient) had been treated with FOLFIRI and/or FOLFOX, almost
80% treated with Avastin(R), and half treated with an EGFR
antibody:
-------------------------------------------------------------------------
P-CAP CAP All Patients
Prior RX (n(equals)20) (n(equals)18) (n(equals)38)
-------------------------------------------------------------------------
FOLFIRI 18 (90%) 16 (89%) 34 (89%)
-------------------------------------------------------------------------
FOLFOX 15 (75%) 13 (72%) 28 (74%)
-------------------------------------------------------------------------
FOLFIRI & FOLFOX 13 (65%) 12 (67%) 25 (66%)
-------------------------------------------------------------------------
Avastin(R) 15 (75%) 15 (83%) 30 (79%)
-------------------------------------------------------------------------
EGFR Antibody(1) 9 (45%) 10 (56%) 19 (50%)
-------------------------------------------------------------------------
5-FU Refractory Status 14 (70%) 13 (72%) 27 (71%)
-------------------------------------------------------------------------
Third Line or (greater) 18 (90%) 16 (89%) 34 (89%)
-------------------------------------------------------------------------
(1) Prior treatment with Erbitux(R) and/or Vectibix(R)
The primary endpoint of this study was to measure Time to
Progression (TTP). Overall Response Rate (ORR), defined as Complete
Response (CR) + Partial Response (PR) by RECIST, and Overall
Survival (OS) were measured as secondary endpoints.
Study Results
The P-CAP arm demonstrated a statistically significant advantage
for TTP and OS, as well as for the percentage of patients achieving
Stable Disease (SD) or better lasting 12 or more weeks, as compared
to the CAP arm. The P-CAP arm demonstrated a greater than 60%
improvement in OS, a more than doubling of median TTP, and almost a
doubling of the percentage of patients achieving SD or better. In
addition, the ORR was 20% (including one CR, and durable responses)
in the P-CAP arm versus 7% in the CAP arm.
The final efficacy results are as follows:
All evaluable patients (n=35):
-------------------------------------------------------------------------
(greater
than) SD PD(less
Duration (min 12 wks) than)
CR PR of n (%) 12 wks
Group n n (%) n (%) Response p(equals)0.036 n (%)
-------------------------------------------------------------------------
P-CAP 20 1 3 CR: 36 m 11 (55%) 5 (25%)
(5%) (15%) ----------------
PR: 21, 19, 11 m
-------------------------------------------------------------------------
CAP 15 0 1 PR: 7 m 5 (33%) 9 (60%)
(7%)
-------------------------------------------------------------------------
-------------------------------------------------------------------------
Median TTP Median OS*
Wks Months
Group p(equals)0.0012 p(equals)0.0161
-------------------------------------------------------------------------
P-CAP 28 17.7
(95% CI (12-48)) (95% CI (8.5-24.6))
-------------------------------------------------------------------------
CAP 11 10.9
(95% CI (9-15.9)) (95% CI (5.-16.9))
-------------------------------------------------------------------------
* Survival is calculated from date of randomization until the date of
death from any cause, whether or not additional therapies were
received after removal from treatment.
Of notable interest were the patients who were previously
refractory to a 5-FU based regimen. The P-CAP arm again
demonstrated a statistically significant increase in both TTP and
OS compared to the CAP arm. The final data is illustrated
below:
5-FU refractory patients (n=25):
-------------------------------------------------------------------------
(greater than
or equal to) SD PD(less
Duration (min 12 wks) than)
PR of n (%) 12 wks
Group n (%) n (%) Response p(equals)0.066 n (%)
-------------------------------------------------------------------------
P-CAP 14 1 19 m 11 (55%) 5 (25%)
(70%) (7%)
-------------------------------------------------------------------------
CAP 11 0 - 8 (57%) 5 (36%)
(73%)
-------------------------------------------------------------------------
-------------------------------------------------------------------------
Median TTP Median OS
Wks Months
Group p(equals)0.0004 p(equals)0.0112
-------------------------------------------------------------------------
P-CAP 18 15.1
(95% CI (12-36)) (95% CI (7.3-22.3))
-------------------------------------------------------------------------
CAP 10 6.6
(95% CI (6.6-11)) (95% CI (4.7-11.7))
-------------------------------------------------------------------------
All 38 patients were evaluable for safety. The P-CAP combination
was well-tolerated with Grade 3 and 4 adverse events of (greater
than) 10% incidence for the P-CAP arm versus CAP arm as follows:
hand-foot syndrome (30% vs. 0%), anemia (15% vs. 0%), fatigue (0%
vs. 11%) and abdominal pain (5% vs.11%). Of note, incidence of
Grade 1 and 2 hand-foot syndrome was similar in both the P-CAP and
CAP arms (25% vs. 22%, respectively). Hand-foot syndrome is a
reported adverse event with capecitabine monotherapy. Patients who
remained on treatment longer in the Phase 2 study had a greater
chance to develop hand-foot syndrome, as illustrated by a median
time to onset of Grade 3 and 4 hand-foot syndrome in the P-CAP arm
of 19 weeks.
Based on the Phase 2 data, a Phase 3 randomized double-blind
trial comparing perifosine + capecitabine vs. placebo +
capecitabine in patients with advanced refractory colorectal cancer
(X-PECT trial : Xeloda(R) + Perifosine Evaluation in Colorectal
cancer Treatment), under Special Protocol Assessment (SPA) from the
FDA, is open and enrolling patients at multiple centers throughout
the US.
Juergen Engel, Ph.D., President
and Chief Executive Officer of AEterna Zentaris, commented, "We are
very pleased with the positive final data of this Phase 2 study, as
they continue to demonstrate perifosine's potential as novel agent
for the treatment of colorectal cancer. They are also encouraging
regarding our current Phase 3 trial in this same indication, since
its design is based on results of this Phase 2 trial."
A copy of the abstract can be accessed through the ASCO website,
www.asco.org
About Perifosine
Perifosine, a novel, potentially first-in-class, oral Akt
inhibitor, is currently in Phase 3 trials for advanced colorectal
cancer and multiple myeloma, under Special Protocol Assessment and
Fast Track designation granted by the Food and Drug Administration
(FDA) for both indications. FDA has also granted perifosine
orphan-drug status for multiple myeloma. Furthermore, the European
Medicines Agency (EMA) has issued a positive Scientific Advice, as
well as a positive opinion for Orphan Medicinal Product designation
for perifosine in multiple myeloma. Perifosine is also in a Phase 1
trial in pediatric patients, as well as in other Phase 1 and Phase
2 trials for several other tumor types.
Perifosine is licensed to Keryx Biopharmaceuticals Inc. (Keryx)
(Nasdaq: KERX), in the United
States, Canada and
Mexico. Aeterna Zentaris has also
out-licensed perifosine to Handok in South Korea, while retaining rights for the
rest of the world.
About Colorectal Cancer
According to the American Cancer Society, colorectal cancer is
the third most common form of cancer diagnosed in the United States. It is estimated that over
146,000 people were diagnosed with some form of colorectal cancer
with over 49,000 patients dying from colorectal cancer in 2009.
Surgery is often the main treatment for early stage colorectal
cancer. When colorectal cancer metastasizes (spreads to other parts
of the body such as the liver) chemotherapy is commonly used.
Treatment of patients with recurrent or advanced colorectal cancer
depends on the location of the disease. Chemotherapy regimens (i.e.
FOLFOX or FOLFIRI either with or without bevacizumab) have been
shown to increase survival rates in patients with
metastatic/advanced colorectal cancer. Currently, there are seven
approved drugs for patients with metastatic colorectal cancer:
5-fluorouracil (5-FU), capecitabine (Xeloda(R)), irinotecan
(Camptosar(R)), oxaliplatin (Eloxatin(R)), bevacizumab
(Avastin(R)), cetuximab (Erbitux(R)), and panitumumab
(Vectibix(R)). Depending on the stage of the cancer, two or more of
these types of treatment may be combined at the same time or used
after one another. For example, FOLFOX combines 5-FU, leucovorin
and oxaliplatin and FOLFIRI combines 5-FU, leucovorin and
irinotecan. Bevacizumab, a VEGF monoclonal antibody, is commonly
administered with chemotherapy. Typically, patients who fail 5-FU,
oxaliplatin, irinotecan, and bevacizumab-containing therapies, and
who have wild-type KRAS status receive EGFR monoclonal antibody
therapy with either cetuximab or panitumumab. Once patients
progress on these agents, there are no further standard treatment
options.
About Aeterna Zentaris Inc.
Aeterna Zentaris Inc. is a late-stage drug development company
specialized in oncology and endocrine therapy. News releases and
additional information are available at www.aezsinc.com.
Forward-Looking Statements
This press release contains forward-looking statements made
pursuant to the safe harbor provisions of the U.S. Securities
Litigation Reform Act of 1995. Forward-looking statements involve
known and unknown risks and uncertainties, which could cause the
Company's actual results to differ materially from those in the
forward-looking statements. Such risks and uncertainties include,
among others, the availability of funds and resources to pursue
R&D projects, the successful and timely completion of clinical
studies, the ability of the Company to take advantage of business
opportunities in the pharmaceutical industry, uncertainties related
to the regulatory process and general changes in economic
conditions. Investors should consult the Company's quarterly and
annual filings with the Canadian and U.S. securities commissions
for additional information on risks and uncertainties relating to
the forward-looking statements. Investors are cautioned not to rely
on these forward-looking statements. The Company does not undertake
to update these forward-looking statements. We disclaim any
obligation to update any such factors or to publicly announce the
result of any revisions to any of the forward-looking statements
contained herein to reflect future results, events or developments
except if we are required by a governmental authority or applicable
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SOURCE AETERNA ZENTARIS INC.