LOS ANGELES, June 1, 2014 /PRNewswire/ -- ImmunoCellular
Therapeutics, Ltd. ("ImmunoCellular") (NYSE MKT:IMUC) announced
that updated efficacy and safety data from the phase II trial of
dendritic cell-based immunotherapeutic vaccine ICT-107 in patients
with newly diagnosed glioblastoma multiforme (GBM) were presented
at the 2014 American Society for Clinical Oncology (ASCO) annual
meeting in Chicago.
When overall survival (OS) and progression-free survival (PFS)
were assessed in pre-specified patient subgroups, results favored
treatment with ICT-107 over control in HLA-A2 patients within each
of the two major MGMT subgroups (unmethylated and methylated).
While the subgroups were small in size, and not powered to show
statistical significance, the numeric advantages in favor of
ICT-107 treated patients were shown to be large and clinically
meaningful.
HLA (human leukocyte antigens) are cell-surface
antigen-presenting proteins. These molecules are on dendritic cells
and present the tumor-associated antigens to T-cells to induce the
immune response to the ICT-107 vaccine. HLA-A2 was one of two HLA
types that were treated in the phase II trial. Of the two types,
HLA-A2 is twice as common in the population as HLA-A1, and is the
most common HLA type in North
America and the EU.
In the per-protocol (PP) analysis of data from HLA-A2 patients
with unmethylated MGMT:
- The control and treated median OS times were 11.8 and 15.8
months, respectively, indicating about a 4-month or 33% numeric
survival increase for treated patients (HR=0.612, log-rank
p-value=0.175);
- The median PFS times for control and treated patients were 6.0
and 10.5 months, respectively, indicating about a 4.5-month or 75%
numeric PFS increase for treated patients (HR=0.758, log-rank
p-value=0.442);
- There were also signs of a potential long-term survival benefit
for ICT-107-treated patients, with 21% of treated patients still
alive compared to only 7% of controls.
In the PP analysis of data from HLA-A2 patients with methylated
MGMT:
- The control and treated groups had still not reached median
survival times as of the time of data analysis, with the majority
of patients still alive (65% of treated compared to 57% of control
patients);
- However, the median PFS times for control and treated patients
were 8.5 and 24.1 months, respectively, indicating about a
15.6-month or 184% statistically significant PFS increase for
treated patients (HR=0.259, log-rank p-value=0.005).
The updated data from the phase II ICT-107 trial were presented
in an oral session by Patrick Y.
Wen, MD, Director of the Center for Neuro-Oncology at The
Dana Farber Cancer Institute and Professor of Neurology at
Harvard Medical School, and principal
investigator on the trial. The presentation was titled "A
randomized, double‑blind, placebo-controlled phase 2 trial of
dendritic cell (DC) vaccination with ICT-107 in newly diagnosed
glioblastoma (GBM) patients."
"We think that the maturing data from the phase II trial
demonstrate a compelling rationale for phase III development of
ICT-107 in patients with newly diagnosed glioblastoma," said Dr.
Wen. "Standard-of-care chemotherapy, temozolomide, has little or no
treatment benefit for newly diagnosed GBM patients with
unmethylated MGMT, which is the majority of patients. ICT-107 has
shown the potential to meaningfully extend both OS and PFS without
significant side effects in this patient population which has the
poorest prognosis for survival. Furthermore, the early evidence of
a potential long-term survival "tail," even in this small phase II
trial, is promising, and indicative of what we would expect to see
in a highly active immunotherapeutic agent. As the methylated MGMT
group is followed further, I am optimistic that the already very
large increase in PFS for treated patients ultimately may translate
into a survival benefit."
"The pre-specified subgroup analyses in our phase II trial
indicate the potential value of a targeted population approach
going forward, as the demonstration of treatment benefit in HLA-A2
patients presents a favorable case for selecting these patients for
the population to be studied in phase III clinical testing," said
Andrew Gengos, ImmunoCellular's
Chief Executive Officer. "HLA-A2 patients comprise the majority of
the overall GBM patient population in the US and Europe. These new results will provide a
strong basis for conducting registration discussions with US and EU
regulatory authorities, which we intend to start within the next
few months. We want to express our appreciation to the patients,
investigators and clinical teams who have participated in the
ICT-107 phase II trial. We look forward to potentially advancing
this promising cancer vaccine toward the market."
Additional Updated ICT-107 Phase II Results
As reported in December 2013, and
in the updated data presented at ASCO, OS for the ITT and PP
populations showed a numeric, but not statistical, treatment
benefit. PFS for the ITT and PP populations showed a statistical
treatment benefit.
- The data presentation from the 124-patient randomized,
controlled phase II trial was based on about 17.6 and 16.2 months
of median follow-up for ICT-107 and control patients, respectively.
As of April, a total of 79 events (patient deaths) had been
recorded, representing 12 additional events since the top-line data
from the phase II trial were reported in December 2013. 30 active and 15 control patients
were alive for a total of 45 patients available for additional
follow-up.
- Median OS in the ITT updated results was 18.3 months for
ICT-107 and 16.7 months for control, representing a numeric
advantage for the treatment group of 1.6 months (HR=0.89,
p-value=0.643). In the PP population, median OS was 18.6 months for
ICT-107 and 16.7 months for control, representing a numeric
advantage for the treatment group of 1.9 months (HR=0.84,
p-value=0.477).
- Median PFS in the ITT updated results was 11.2 months for
ICT-107 and 9.0 months for control, representing a statistically
significant advantage for the treatment group of 2.2 months
(HR=0.57, p-value=0.011). In the PP population, median OS was 11.4
months for ICT-107 and 9.0 months for control, representing a
statistically significant advantage for the treatment group of 2.4
months (HR=0.54, p-value=0.006).
- Both the OS and PFS median results in the ICT-107 phase II
trial were measured from the time of randomization (i.e., at the
start of vaccination after standard-of-care surgery and
chemoradiation). In historical studies of newly diagnosed GBM
patients (e.g., Stupp, et al.), OS and PFS measurements were likely
assessed from the time of surgery. In the ICT-107 phase II trial,
there was an average of about 83 days from surgery to
randomization.
- Vaccine potency was assessed via measurements of key dendritic
cell indicators of cell maturity and activation and their
correlation with survival time. Two key indicators relating to
IL-12 secretion and HLA-DR expression were predictive of survival
in all treated patients in the results announced in December. In
the updated results, IL-12 secretion and HLA-DR expression were
again correlated with treated patient survival time in Cox
Proportionate Hazards models, with p-values of 0.048 and 0.006,
respectively.
Assessment of Additional Trial Parameters
Data on quality of life as well as certain immunological
parameters, including vaccine potency and antigen expression, were
also presented.
- Quality of life was assessed in the phase II trial both by
using the FACT-BR assessment tool and through monitoring patient
performance levels according to the Karnofsky Performance Status
(KPS). For the FACT-BR, there was no difference in the overall
assessment between the treated and control groups from baseline
through progression. Because treated patients had a statistically
longer PFS, this means that they had more months of similar quality
of life compared to the control group prior to progression. Treated
patients also maintained a higher KPS from immediately before
vaccination started through 19 weeks. The signed rank test p-value
was less than 0.05 for each of four KPS assessments between these
time points.
- Patients were assessed for vaccine response at baseline
(pre-vaccination) and at three time points during vaccination.
Response was assessed via Elispot, and patients were deemed
responders if their T-cells (from blood samples) reacted to any of
the six antigens used to challenge the samples. 27% of treated
patients were responders as compared with 15% of controls. In the
HLA-A2 subgroup, 33% of treated patients were responders as
compared with 15% of controls.
- The primary tumors of patients were assessed for expression of
the six vaccine antigens via qPCR. In all treated patients, 75%
expressed at least one antigen and 51% expressed at least four
antigens. In the control group, 93% expressed at least one antigen
and 65% expressed at least four antigens. In the HLA-A2 subgroup
for treated patients, 94% expressed at least one antigen and 85%
expressed all four HLA-A2 antigens. For the control patients, 100%
expressed at least one antigen and 97% expressed all four HLA-A2
antigens.
Next Steps in the ICT-107 Program
ImmunoCellular plans to consult further with the international
neuro-oncology community, and to hold regulatory agency discussions
in both the US and EU concerning ICT-107.
The Company is in the process of finalizing the design of the
phase III protocol, in anticipation of discussions with the FDA and
the European Medicines Agency, or EMA. Plans are underway to
request an end-of-phase II meeting with the FDA, anticipated to
take place during the summer. Following typical European protocol
in preparation for meeting with the EMA, ImmunoCellular has
requested advice meetings at the national level in Germany, the UK and the Netherlands to discuss ICT-107. These
meetings are scheduled to take place later in June. In the third or
fourth quarter of 2014, the Company plans to seek advice from the
EMA on the approval process for ICT-107.
ImmunoCellular also plans to continue to monitor patients in the
phase II trial and update the data analysis at upcoming scientific
meetings, such as potentially the Society for Neuro-Oncology (SNO)
meeting in November.
About the ICT-107 Phase II Trial
The ICT-107 phase II trial is a randomized, double-blind,
placebo-controlled phase II study of the safety and efficacy of
ICT-107 in newly diagnosed patients with glioblastoma multiforme
following resection and chemoradiation. ICT-107 is an intradermally
administered autologous vaccine consisting of the patient's
dendritic cells pulsed with six synthetic tumor-associated
antigens: AIM-2, MAGE-1, TRP-2, gp100, HER-2, IL-13Rα2. The control
consists of the patient's unpulsed dendritic cells.
A total of 124 patients were randomized at 25 clinical trial
sites in the US. One third of the patients or 43 patients were
treated with placebo (their own dendritic cells not exposed to
antigen), and the treatment arm included two thirds or 81 patients
who received the ICT-107 vaccine. All patients in the trial
received standard-of-care temozolomide. The regimen is four
induction doses of ICT-107 after chemoradiation, and then
maintenance doses until the patient progresses. The primary
endpoint of the trial is OS, defined as the time from randomization
until date of death or the last date the patient is known to be
alive. Secondary endpoints include PFS, defined as the time from
randomization until the date of documented progressive disease or
death, whichever occurs first, or the last date the patient is
known to be alive and progression-free if progression or death is
not observed. Other secondary endpoints include the rates of OS and
PFS at six months after surgery, then assessed every three months
until the end of the study. Safety and immune response are
additional secondary endpoints.
The subgroups analyzed in the phase II trial were based on age,
gender, HLA type, MGMT status, performance status and resection
status.
HLA-A2 patients comprised about 62% of all patients randomized
in the trial, meaning that these numeric and statistical outcome
benefits were conveyed to a majority of treated patients.
MGMT status has been demonstrated to be predictive of response
to radiation or chemotherapy. The O(6)-methylguanine-DNA
methyltransferase, or MGMT, gene is responsible for a DNA repair
mechanism in cells. Methylation of MGMT impedes the DNA repair
mechanism in cancer cells, making them susceptible to radiation or
chemotherapy, such as temozolomide. The DNA repair mechanism in
cancer cells with unmethylated MGMT is intact, enabling them to
survive and proliferate. GBM is the most common and aggressive
primary cancer of the brain. Patients with this disease have
few therapeutic options; temozolomide is currently the only
FDA-approved systemic chemotherapy for newly diagnosed GBM.
For patient-related information about the ICT-107 clinical
program in glioblastoma, please visit the ImmunoCellular website at
www.imuc.com and access the ICT-107 "Frequently Asked Questions."
The email address to contact the company directly is
clintrials@imuc.com.
About ImmunoCellular Therapeutics, Ltd.
ImmunoCellular Therapeutics, Ltd. is a Los Angeles-based clinical-stage company that
is developing immune-based therapies for the treatment of brain and
other cancers. ImmunoCellular is conducting a phase II trial of its
lead product candidate, ICT-107, a dendritic cell-based vaccine
targeting multiple tumor-associated antigens for glioblastoma.
ImmunoCellular's pipeline also includes ICT-121, a dendritic cell
vaccine targeting CD133, and ICT-140, a dendritic cell vaccine
targeting ovarian cancer antigens and cancer stem cells. To learn
more about ImmunoCellular, please visit www.imuc.com.
Forward-Looking Statements for ImmunoCellular Therapeutics
This press release contains certain forward-looking statements
that are subject to a number of risks and uncertainties, including
the risk that ICT-107 can be further successfully developed or
commercialized, the timing and outcome of the post-phase II meeting
with the FDA and EU regulatory authorities, the status of the
current data and whether further analyses or later studies may
confirm the successful PFS results to date, the potential for
initiation of phase III trials and possibility of successful
results from such studies. Additional risks and uncertainties are
described in IMUC's most recently filed quarterly report on Form
10-Q and annual report on Form 10-K. Except as permitted by law,
IMUC undertakes no obligation to update or revise any
forward-looking statements, whether as a result of new information,
future events or otherwise. In this press release, you can identify
forward-looking statements by terms such as "may," "will,"
"should," "could," "would," "expect," "plan," "anticipate,"
"believe," "estimate," "project," "predict," "potential," "future,"
"intend," "certain," and similar expressions intended to identify
forward-looking statements.
Contact:
ImmunoCellular Therapeutics, Ltd.
Investor Relations
Jane Green
415.348.0010 direct
415.652.4819 mobile
jane@jmgcomm.com
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SOURCE ImmunoCellular Therapeutics, Ltd.