-- All varlilumab dose levels showed acceptable
tolerability/safety in combination regimen; Phase 2 portion of
study now open to enrollment --
Celldex Therapeutics, Inc. (NASDAQ:CLDX) announced today new safety
and immune response data from the Phase 1 portion of a Phase 1/2
dose escalation and cohort expansion study examining the
investigational combination of varlilumab, Celldex's CD27 targeting
investigational immune-activating antibody, and Bristol-Myers
Squibb's anti-PD-1 immunotherapy Opdivo® (nivolumab). The data were
presented today in a poster at the American Association for Cancer
Research (AACR) Annual Meeting 2016 in New Orleans. The Phase 1
portion of the study, conducted in patients with solid tumors, has
completed enrollment (n=36) and primarily enrolled patients with
colorectal (n=20) and ovarian cancer (n=8). The primary objective
of the Phase 1 portion of the study was to evaluate the safety and
tolerability of the combination. The Phase 2 portion of the study
is open to enrollment.
Key Highlights:
- Combining the potent immune activator, varlilumab, with the
PD-1 inhibitor, nivolumab, showed acceptable tolerability and
safety across all dose levels without any evidence of increased
autoimmunity or inappropriate immune activation.
- Combination therapy led to marked changes in the tumor
microenvironment including increased infiltrating CD8+ T cells and
increased PD-L1 expression, which have been shown to correlate with
a greater magnitude of treatment effect from checkpoint inhibitors
in other clinical studies.
- Additional favorable immune biomarkers, such as increase in
inflammatory chemokines and decrease in T regulatory cells, were
also noted.
- In a subset of patients (n=17) on study who had both pre- and
post-tumor biopsies available, preliminary evidence suggest a
correlation between biomarker data and stable disease or better in
seven of these patients (4 ovarian cancer, 2 colorectal cancer, 1
squamous cell carcinoma of the head and neck).
“The combination of varlilumab and nivolumab demonstrated
acceptable tolerability across all dose levels of varlilumab,
showing that immune stimulation through CD27 was safely combined
with PD-1 blockade,” said Tibor Keler, Ph.D., Executive Vice
President and Chief Scientific Officer of Celldex Therapeutics. “In
addition, we observed favorable changes in intratumoral immune
biomarkers, most notably an increase in tumor infiltrating
lymphocytes, which is recognized to correlate with improved
clinical outcome. Based on the strong preclinical data, scientific
rationale and these recent results, we are very excited for the
Phase 2 portion of the trial, which is now open to enrollment
across six different indications.”
The Phase 2 portion of the study includes cohorts in advanced
non-small cell lung cancer (n=35), colorectal cancer (n=18),
ovarian cancer (n=18), head and neck squamous cell carcinoma
(n=18), renal cell carcinoma (n=25) and glioblastoma (n=20). The
primary objective of the Phase 2 study is overall response rate for
all cohorts except glioblastoma, where the primary objective is the
rate of 12-month overall survival. Secondary objectives include
pharmacokinetics assessments, determining the immunogenicity of
varlilumab when given in combination with nivolumab and further
assessing the anti-tumor activity of combination treatment,
including duration of response, time to response, progression-free
survival and overall survival. The study is being conducted by
Celldex under a clinical trial collaboration with Bristol-Myers
Squibb Company. The companies are sharing development costs.
Celldex and its collaborating investigators are presenting seven
posters at the AACR Annual Meeting. As of Monday, April 18, four of
these posters have been presented and summaries of these, including
the Phase 1/2 varlilumab/nivolumab combination study, can be found
below.
Title: Phase 1 results from the combination of an immune
activating anti-CD27 antibody (varlilumab) in combination with PD-1
blockade (nivolumab): activation across multiple immune pathways
without untoward immune-related adverse events
The Phase 1, dose-escalation portion of the study assessed the
safety and tolerability of varlilumab at doses ranging from 0.1 to
10 mg/kg when administered with nivolumab (3 mg/kg). Enrollment to
the Phase 1 study portion is complete with a total of 36 patients
treated. Data for 35 patients are included in the poster:
colorectal cancer (n=20), ovarian cancer (n=8), metastatic melanoma
(n=4) and head and neck squamous cell carcinoma (n=3). 69% of
patients had three or more prior therapies.
All dose levels of the combination therapy showed acceptable
tolerability and safety, without identification of a maximum
tolerated dose. In the Phase 2 portion of the study, varlilumab
will be administered at 3 mg/kg, which is based upon cumulative
data across multiple studies.
The safety profile of the varlilumab and nivolumab combination
has been consistent with that of each agent individually, and no
unexpected toxicities have been observed. The most frequent
treatment related adverse events, occurring in more than 10% of
patients, were fatigue (25.7%), lymphopenia (20%), nausea (20%),
chills (17.1%), arthralgia (14.3%), pruritus (14.3%) and rash
(11.4%), the majority of which were grade 1 or 2. Two patients
experienced drug-related serious adverse events. In the 10 mg/kg
cohort, grade 4 hepatitis and grade 3 renal insufficiency was
observed in a patient with ovarian cancer. Also in the 10 mg/kg
cohort, grade 2 paresthesia (tingling/numbness) was observed in a
patient with colorectal cancer.
Biomarker data from all varlilumab dose levels indicate
increases in inflammatory chemokines and decreases in circulating T
regulatory cells, which is generally consistent with varlilumab
monotherapy. Importantly, in tissue biopsies from patients, the
authors noted, where pre-treatment and on-study specimens were
available (n=17), a marked increase of tumor infiltrating
lymphocytes and an increase in PD-L1 expression. Although the Phase
1 portion of the study was focused on immune response and safety, a
correlation between this biomarker readout and stable disease or
better (n=7) was observed in this preliminary dataset.
The poster is available on the "Publications" page of the
"Science" section of the Celldex website.
Title: In situ Vaccine for Low-Grade Lymphoma:
Combination of Intratumoral Flt3L and Poly-ICLC With Low-Dose
Radiotherapy
The potential activity of CDX-301 (recombinant human Flt3
ligand) is being explored in an investigator-sponsored, Phase 1/2
study of CDX-301 and poly-ICLC in combination with low-dose
radiotherapy in patients with low-grade B-cell lymphomas conducted
by the Icahn School of Medicine at Mount Sinai. CDX-301 is a potent
hematopoietic cytokine that uniquely expands dendritic cells and
hematopoietic stem cells. To date, the study has enrolled 12
patients with indolent non-Hodgkin lymphoma. The authors presented
flow cytometry and mass cytometry data from selected patients,
which demonstrate the ability of CDX-301 to induce dendritic cell
mobilization.
The poster is available on the "Publications" page of the
"Science" section of the Celldex website.
Title: IHC and RT-PCR Assays for Detection of Cancer
Antigen NY-ESO-1 in Human Tissues
The Company presented data from the development of diagnostic
assays for NY-ESO-1, the target of CDX-1401, an antibody-based
NY-ESO-1-specific therapeutic vaccine for multiple solid tumors.
Samples from 75 solid tumor types and 38 normal adjacent tissue
samples were analyzed by immunohistochemistry (IHC) and
quantitative RT-PCR assays, which were developed to determine
NY-ESO-1 expression. The validated diagnostic tests for use in the
clinical development of CDX-1401 and preliminary screening suggest
that several cancers, including non-small cell lung cancer (NSCLC),
melanoma and ovarian cancer, express NY-ESO-1, which is consistent
with published literature.
The poster is available on the "Publications" page of the
"Science" section of the Celldex website.
Title: Targeting the melanosome: overcoming
MAPK-inhibitor resistance in melanoma Abstract: 296
Research collaborators examined the role of MiTF-regulated
melanosomal differentiation antigens (MDAs), such as gpNMB, as
potential therapeutic targets that could potentially overcome MAPK
inhibitor resistance in melanoma. MiTF is a transcription factor
that has been identified as an indicator of melanoma resistance,
and through the interrogation of the TCGA melanoma database, the
authors found it to be strongly correlated with MDAs, including
gpNMB. In a preclinical study investigating resistance mechanisms
in melanoma, glembatumumab vedotin, an antibody-drug conjugate that
targets gpNMB, demonstrated synergies with therapies for BRAF
mutated melanoma and overcame phenotypes associated with
resistance, suggesting use of glembatumumab vedotin may be
particularly effective as a single-agent or in combination in this
refractory patient population.
About VarlilumabVarlilumab is a fully human
monoclonal agonist antibody that binds and activates CD27, a
critical co-stimulatory molecule in the immune activation cascade.
CD27 can be effectively manipulated with activating antibodies to
induce potent anti-tumor responses and may result in fewer
toxicities due to its restricted expression and regulation.
Varlilumab is a potent anti-CD27 agonist that induces activation
and proliferation of human T cells when combined with T cell
receptor stimulation. In lymphoid malignancies that express CD27 at
high levels, varlilumab may have an additional mechanism of action
through a direct anti-tumor effect. Varlilumab has completed a
single-agent Phase 1 dose-escalation study, demonstrating potent
immunologic activity consistent with its mechanism of action and
anti-tumor activity in patients with advanced, refractory disease.
No maximum tolerated dose was reached and minimal toxicities were
observed. Celldex has initiated a broad development program for
varlilumab to explore its role as an immune activator in
combination with a number of complementary investigational and
approved oncology drugs.
About CDX-301CDX-301 (Flt3L) is a potent
hematopoietic cytokine that has demonstrated a unique capacity to
increase the number of circulating dendritic cells in both
laboratory and clinical studies. In addition, CDX-301 has shown
impressive results in models of cancer, infectious diseases and
inflammatory/autoimmune diseases. Celldex believes this ligand may
hold significant opportunity for synergistic development in
combination with other proprietary molecules in the Company's
portfolio.
About CDX-1401CDX-1401 is a next-generation,
off-the-shelf cancer vaccine designed to activate the patient's
immune system against cancers that express the tumor marker,
NY-ESO-1. CDX-1401 consists of a fully human monoclonal antibody
with specificity for the dendritic cell receptor DEC-205
genetically linked to the NY-ESO-1 tumor antigen. Celldex has
accessed NY-ESO-1 through a licensing agreement with the Ludwig
Institute for Cancer Research. By selectively delivering the
NY-ESO-1 antigen to dendritic cells in the body, CDX-1401 is
intended to induce robust immune responses against the
antigen-expressing cancer cells.
About Glembatumumab VedotinGlembatumumab
vedotin is a fully-human monoclonal antibody-drug conjugate (ADC)
that targets glycoprotein NMB (gpNMB). gpNMB is a protein
overexpressed by multiple tumor types, including breast cancer,
melanoma, lung cancer, uveal melanoma and osteosarcoma. gpNMB has
been shown to be associated with the ability of the cancer cell to
invade and metastasize and to correlate with reduced time to
progression and survival in breast cancer. The gpNMB-targeting
antibody, CR011, is linked to a potent cytotoxic, monomethyl
auristatin E (MMAE), using Seattle Genetics' proprietary
technology. Glembatumumab vedotin is designed to be stable in the
bloodstream but to release MMAE upon internalization into
gpNMB-expressing tumor cells, resulting in a targeted cell-killing
effect. Glembatumumab vedotin is in development for the treatment
of locally advanced or metastatic breast cancer with an initial
focus in triple negative disease, stage III and IV melanoma, uveal
melanoma and osteosarcoma.
Opdivo® is a registered trademark of Bristol-Myers Squibb
Company.
About Celldex Therapeutics, Inc.Celldex is
developing targeted therapeutics to address devastating diseases
for which available treatments are inadequate. Our pipeline is
built from a proprietary portfolio of antibodies and
immunomodulators used alone and in strategic combinations to create
novel, disease-specific therapies that induce, enhance or suppress
the body's immune response. Visit
www.celldex.com.
Forward Looking StatementThis release contains
"forward-looking statements" made pursuant to the safe harbor
provisions of the Private Securities Litigation Reform Act of 1995,
including those related to the Company's strategic focus and the
future development and commercialization (by Celldex and others) of
glembatumumab vedotin ("glemba"; CDX-011), varlilumab, and other
products and our goals for 2016. Forward-looking statements reflect
management's current knowledge, assumptions, judgment and
expectations regarding future performance or events. Although
management believes that the expectations reflected in such
statements are reasonable, they give no assurance that such
expectations will prove to be correct and you should be aware that
actual results could differ materially from those contained in the
forward-looking statements. Forward-looking statements are subject
to a number of risks and uncertainties, including, but not limited
to, our ability to successfully complete research and further
development and commercialization of glembatumumab vedotin and
other drug candidates; our ability to obtain additional capital to
meet our long-term liquidity needs on acceptable terms, or at all,
including the additional capital which will be necessary to
complete the clinical trials that we have initiated or plan to
initiate; the uncertainties inherent in clinical testing and
accruing patients for clinical trials; our limited experience in
bringing programs through Phase 3 clinical trials; our ability to
manage and successfully complete multiple clinical trials and the
research and development efforts for our multiple products at
varying stages of development; the availability, cost, delivery and
quality of clinical and commercial grade materials produced by our
own manufacturing facility or supplied by contract manufacturers,
who may be our sole source of supply; the timing, cost and
uncertainty of obtaining regulatory approvals; our ability to
maintain and derive benefit from the Fast Track designation for
glembatumumab vedotin which does not change the standards for
regulatory approval or guarantee regulatory approval on an
expedited basis, or at all; the failure of the market for the
Company's programs to continue to develop; our ability to protect
the Company's intellectual property; the loss of any executive
officers or key personnel or consultants; competition; changes in
the regulatory landscape or the imposition of regulations that
affect the Company's products; and other factors listed under "Risk
Factors" in our annual report on Form 10-K and quarterly reports on
Form 10-Q.
All forward-looking statements are expressly qualified in their
entirety by this cautionary notice. You are cautioned not to place
undue reliance on any forward-looking statements, which speak only
as of the date of this release. We have no obligation, and
expressly disclaim any obligation, to update, revise or correct any
of the forward-looking statements, whether as a result of new
information, future events or otherwise.
Contact:
Sarah Cavanaugh
Vice President of Investor Relations & Corp Communications
(781) 433-3161
scavanaugh@celldex.com
Charles Liles
Manager of Investor Relations & Corp Communications
(781) 433-3107
cliles@celldex.com
Media Contact:
Dan Budwick
Pure Communications, Inc.
(973) 271-6085
dan@purecommunicationsinc.com
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