Celldex Therapeutics, Inc. (Nasdaq:CLDX) and Bristol Myers-Squibb
(NYSE:BMY) today announced the initiation 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 immunotherapy
Opdivo (nivolumab). The study will be conducted in adult patients
with advanced non-small cell lung cancer (NSCLC), metastatic
melanoma (MEL), colorectal cancer (CRC), ovarian cancer, and head
and neck squamous cell carcinoma (SCCHN). Varlilumab is a fully
human monoclonal antibody that targets CD27, a critical molecule in
the activation pathway of lymphocytes. Opdivo is a human programmed
death receptor-1 (PD-1) blocking antibody that binds to the PD-1
receptor expressed on activated T-cells. This study will evaluate
the safety and tolerability of the combination and address the
hypothesis that the combination of these two mechanisms enhance the
anti-tumor activity compared to either agent alone. Celldex is
responsible for conducting the study and development costs will be
shared. The Phase 1 dose-escalation portion of the study will
assess the safety and tolerability of varlilumab at doses ranging
from 0.1 to 10 mg/kg when administered with Opdivo (3mg/kg).
Following dose escalation, a Phase 2 portion of the study will
include 5 disease specific cohorts, with either 18 (CRC, SCCHN,
ovarian) or 35 (NSCLC and MEL) patients in each cohort. Patients
will be treated with varlilumab until intolerance, disease
progression or completion of up to 4 cycles. There is no limit on
the duration of treatment with Opdivo. The primary objective of the
Phase 2 study is overall response rate. Secondary objectives
include pharmacokinetics assessments, determining the
immunogenicity of varlilumab when given in combination with Opdivo
and further assessing the anti-tumor activity of combination
treatment, including duration of response, time to response,
progression-free survival and overall survival.
About Varlilumab
Varlilumab is a fully human monoclonal antibody that targets
CD27, a critical molecule in the activation pathway of lymphocytes.
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
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. Varlilumab is currently being studied in two Phase 1/2
combination studies and several additional combination studies will
be initiated in 2015.
About OPDIVO (Nivolumab)
The U.S. Food and Drug Administration (FDA) approved Opdivo
(nivolumab) injection, for intravenous use. Opdivo is a PD-1
blocking antibody indicated for the treatment of patients with
unresectable or metastatic melanoma and disease progression
following Yervoy (ipilimumab) and, if BRAF V600 mutation
positive, a BRAF inhibitor. This indication is approved under
accelerated approval based on tumor response rate and durability of
response. Continued approval for this indication may be contingent
upon verification and description of clinical benefit in the
confirmatory trials. Bristol-Myers Squibb has a broad, global
development program to study Opdivo in multiple tumor
types consisting of more than 50 trials – as monotherapy or in
combination with other therapies – in which more than 7,000
patients have been enrolled worldwide.
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.
About Bristol-Myers Squibb
Bristol-Myers Squibb is a global biopharmaceutical company whose
mission is to discover, develop and deliver innovative medicines
that help patients prevail over serious diseases. For more
information, please visit www.bms.com or follow us on Twitter at
http://twitter.com/bmsnews.
OPDIVO IMPORTANT SAFETY INFORMATION
Immune-Mediated Pneumonitis
- Severe pneumonitis or interstitial lung disease, including
fatal cases, occurred with OPDIVO treatment. Across the clinical
trial experience in 574 patients with solid tumors, fatal
immune-mediated pneumonitis occurred in 0.9% (5/574) of patients
receiving OPDIVO; no cases occurred in Trial 1. In Trial 1,
pneumonitis, including interstitial lung disease, occurred in 3.4%
(9/268) of patients receiving OPDIVO and none of the 102 patients
receiving chemotherapy. Immune-mediated pneumonitis occurred in
2.2% (6/268) of patients receiving OPDIVO; one with Grade 3 and
five with Grade 2. Monitor patients for signs and symptoms of
pneumonitis. Administer corticosteroids for Grade 2 or greater
pneumonitis. Permanently discontinue OPDIVO for Grade 3 or 4 and
withhold OPDIVO until resolution for Grade 2.
Immune-Mediated Colitis
- In Trial 1, diarrhea or colitis occurred in 21% (57/268) of
patients receiving OPDIVO and 18% (18/102) of patients receiving
chemotherapy. Immune-mediated colitis occurred in 2.2% (6/268) of
patients receiving OPDIVO; five with Grade 3 and one with Grade 2.
Monitor patients for immune-mediated colitis. Administer
corticosteroids for Grade 2 (of more than 5 days duration), 3, or 4
colitis. Withhold OPDIVO for Grade 2 or 3. Permanently discontinue
OPDIVO for Grade 4 colitis or recurrent colitis upon restarting
OPDIVO.
Immune-Mediated Hepatitis
- In Trial 1, there was an increased incidence of liver test
abnormalities in the OPDIVO-treated group as compared to the
chemotherapy-treated group, with increases in AST (28% vs 12%),
alkaline phosphatase (22% vs 13%), ALT (16% vs 5%), and total
bilirubin (9% vs 0). Immune-mediated hepatitis occurred in 1.1%
(3/268) of patients receiving OPDIVO; two with Grade 3 and one with
Grade 2. Monitor patients for abnormal liver tests prior to and
periodically during treatment. Administer corticosteroids for Grade
2 or greater transaminase elevations. Withhold OPDIVO for Grade 2
and permanently discontinue OPDIVO for Grade 3 or 4 immune-mediated
hepatitis.
Immune-Mediated Nephritis and Renal
Dysfunction
- In Trial 1, there was an increased incidence of elevated
creatinine in the OPDIVO-treated group as compared to the
chemotherapy-treated group (13% vs 9%). Grade 2 or 3
immune-mediated nephritis or renal dysfunction occurred in 0.7%
(2/268) of patients. Monitor patients for elevated serum creatinine
prior to and periodically during treatment. For Grade 2 or 3 serum
creatinine elevation, withhold OPDIVO and administer
corticosteroids; if worsening or no improvement occurs, permanently
discontinue OPDIVO. Administer corticosteroids for Grade 4 serum
creatinine elevation and permanently discontinue OPDIVO.
Immune-Mediated Hypothyroidism and
Hyperthyroidism
- In Trial 1, Grade 1 or 2 hypothyroidism occurred in 8% (21/268)
of patients receiving OPDIVO and none of the 102 patients receiving
chemotherapy. Grade 1 or 2 hyperthyroidism occurred in 3% (8/268)
of patients receiving OPDIVO and 1% (1/102) of patients receiving
chemotherapy. Monitor thyroid function prior to and periodically
during treatment. Administer hormone replacement therapy for
hypothyroidism. Initiate medical management for control of
hyperthyroidism.
Other Immune-Mediated Adverse Reactions
- In Trial 1, the following clinically significant,
immune-mediated adverse reactions occurred in less than 1% of
OPDIVO-treated patients: pancreatitis, uveitis, demyelination,
autoimmune neuropathy, adrenal insufficiency, and facial and
abducens nerve paresis. Across clinical trials of OPDIVO
administered at doses 3 mg/kg and 10 mg/kg, additional clinically
significant, immune-mediated adverse reactions were identified:
hypophysitis, diabetic ketoacidosis, hypopituitarism,
Guillian-Barré syndrome, and myasthenic syndrome. Based on the
severity of adverse reaction, withhold OPDIVO, administer high-dose
corticosteroids, and, if appropriate, initiate hormone-replacement
therapy.
Embryofetal Toxicity
- Based on its mechanism of action, OPDIVO can cause fetal harm
when administered to a pregnant woman. Advise pregnant women of the
potential risk to a fetus. Advise females of reproductive potential
to use effective contraception during treatment with OPDIVO and for
at least 5 months after the last dose of OPDIVO.
Lactation
- It is not known whether OPDIVO is present in human milk.
Because many drugs, including antibodies, are excreted in human
milk and because of the potential for serious adverse reactions in
nursing infants from OPDIVO, advise women to discontinue
breastfeeding during treatment.
Serious Adverse Reactions
- Serious adverse reactions occurred in 41% of patients receiving
OPDIVO. Grade 3 and 4 adverse reactions occurred in 42% of patients
receiving OPDIVO. The most frequent Grade 3 and 4 adverse drug
reactions reported in 2% to <5% of patients receiving OPDIVO
were abdominal pain, hyponatremia, increased aspartate
aminotransferase, and increased lipase.
Common Adverse Reactions
The most common adverse reaction (≥20%) reported with OPDIVO was
rash (21%).
Please see US Full Prescribing
Information for
OPDIVO.
Celldex Forward Looking Statement
This 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 rindopepimut ("rindo"; CDX-110),
glembatumumab vedotin ("glemba"; CDX-011), varlilumab ("varli";
CDX-1127), CDX-1401, CDX-301 and other products and our goals for
2015. 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 rindopepimut, 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; 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 our 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.
BMS Forward Looking Statement
This press release contains "forward-looking statements" as that
term is defined in the Private Securities Litigation Reform Act of
1995 regarding the research, development and commercialization of
pharmaceutical products. Such forward-looking statements are based
on current expectations and involve inherent risks and
uncertainties, including factors that could delay, divert or change
any of them, and could cause actual outcomes and results to differ
materially from current expectations. No forward-looking statement
can be guaranteed. Among other risks, there can be no guarantee
that this investigational combination regimen will receive
regulatory approval, or, if approved, that it will become a
commercially successful product. Forward-looking statements in this
press release should be evaluated together with the many
uncertainties that affect Bristol-Myers Squibb's business,
particularly those identified in the cautionary factors discussion
in Bristol-Myers Squibb's Annual Report on Form 10-K for the year
ended December 31, 2013 in our Quarterly Reports on Form 10-Q and
our Current Reports on Form 8-K. Bristol-Myers Squibb undertakes no
obligation to publicly update any forward-looking statement,
whether as a result of new information, future events or
otherwise.
CONTACT: Celldex Company Contacts:
Investors:
Sarah Cavanaugh
Vice President of Investor Relations &
Corp Communications
Celldex Therapeutics, Inc.
(781) 433-3161
scavanaugh@celldex.com
or
Media:
Dan Budwick
Pure Communications, Inc.
(973) 271-6085
dan@purecommunicationsinc.com
BMS Company Contacts:
Media:
Ken Dominski, 609-252-5251
ken.dominski@bms.com
or
Investors:
Ranya Dajani, 609-252-5330
ranya.dajani@bms.com
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