Celldex Therapeutics, Inc. (Nasdaq:CLDX) announced today data from
the Phase 1 portion of a Phase 1/2 dose escalation and cohort
expansion study examining the combination of varlilumab, Celldex's
CD27 targeting investigational immune-activating antibody, and
Bristol-Myers Squibb's anti-PD-1 immunotherapy Opdivo® (nivolumab).
Rachel E. Sanborn, M.D., Co-director of the Providence Thoracic
Oncology Program; and Phase I Clinical Trials Program, at the Earle
A. Chiles Research Institute, Providence Cancer Center, in
Portland, Ore. presented results from the study in an oral
presentation entitled, “Clinical Results with Combination of
Anti-CD27 Agonist Antibody, Varlilumab, with Anti-PD1 Antibody
Nivolumab in Advanced Cancer Patients” at the 2017 American Society
of Clinical Oncology (ASCO) Annual Meeting in Chicago. The primary
objective of the Phase 1 portion (n=36) of the study was to
evaluate the safety and tolerability of the combination. The Phase
2 portion of the study is expected to complete enrollment in early
2018.
“Combining PD-1 inhibition with a potent T cell activating agent
provides the opportunity to broaden the number of patients that
benefit from checkpoint blockade,” said Dr. Sanborn. “While early,
we have evidence that this combination does not add toxicity, can
turn some ‘immune-cold’ tumors hot, and may have clinical benefit,
including in some patients who are not likely to respond to
monotherapy. Further elucidating the role of intermittent versus
chronic T cell activation through the comparison of alternate
varlilumab dosing regimens is an essential component of the ongoing
Phase 2 study and could be important in optimizing the potential of
this combination.”
Key Highlights
• The majority of patients enrolled in the study had PD-L1
negative tumor at baseline and presented with Stage IV,
heavily-pretreated disease. 80% of patients enrolled presented with
refractory or recurrent colorectal (n=21) or ovarian cancer (n=8),
a population expected to have minimal response to checkpoint
blockade.
• Combining the potent immune activator, varlilumab, with the
PD-1 inhibitor, Opdivo, was well tolerated at all varlilumab dose
levels tested without any evidence of increased autoimmunity or
inappropriate immune activation.
• Notable disease control observed (stable disease or better for
at least 3 months), considering the Stage IV patient population,
contained mostly colorectal and ovarian cases (80%).
- 0.1 mg/kg varlilumab + 240 mg Opdivo: 1/5 (20%)
- 1 mg/kg varlilumab + 240 mg Opdivo: 5/15 (33%)
- 10 mg/kg varlilumab + 240 mg Opdivo: 6/15 (40%)
• Three partial responses (PR) observed.
- A patient with PD-L1 negative, MMR proficient colorectal
cancer, typically unlikely to respond to checkpoint blockade
monotherapy, achieved a confirmed PR (presented with metastatic
disease to the liver, adrenal gland, abdomen and mesenteric nodule
and on study experienced a 95% decrease in target lesions,
including resolution of 4/5 target lesions, one 6 mm mesenteric
nodule remains). Following completion of combination treatment, the
patient continues to receive treatment with Opdivo monotherapy at
22 months. The patients previously received two prior
chemotherapy-based regimens, one of which also included
EGFR-targeted therapy.
- A patient with low PD-L1 (5% expression) squamous cell head and
neck cancer achieved a confirmed PR (59% shrinkage) and experienced
progression free survival of 6.7 months.
- A patient with PD-L1 negative ovarian cancer experienced a
single timepoint PR (49% shrinkage) but discontinued treatment to a
dose-limiting toxicity (immune hepatitis, an event known to be
associated with checkpoint inhibition therapy).
• Migration of immune cells to tumor observed.
- Peripheral blood analysis consistent with varlilumab
monotherapy, transient increase in inflammatory chemokines (CXCL10,
MCP-1, MIP-1β and MIG) and prominent decreases in CD4 and Treg
cells without clear association with dose observed.
- Tumor biopsy analysis revealed the majority of patients had
“cold” tumors at baseline (negative or low PD-L1 and low T cell
infiltrate).
- A subgroup analysis was conducted in patients with ovarian
cancer based on an observed increase of PD-L1 and
tumor-infiltrating lymphocytes in this patient population.• In
patients with paired baseline and on-treatment biopsies (n=13),
only 15% were PD-L1 positive (≥ 1% tumor cells) at baseline
compared to 77% during treatment (p=0.015).• Patients with
increased tumor PD-L1 expression and tumor CD8 T cells correlated
with better clinical outcome with treatment (stable disease or
better).
• Continuous activation by immune agonists may not be optimal as
it could lead to immune exhaustion and dampen the effect of
combination therapy. The Phase 2 portion of this study includes
alternate varlilumab dosing regimens to evaluate continuous versus
intermittent immune activation at higher and lower dose levels and
varied frequency.
In April 2016, the trial advanced to the Phase 2 portion of the
study and includes cohorts in colorectal cancer, ovarian cancer,
head and neck squamous cell carcinoma, renal cell carcinoma and
glioblastoma. Varied dosing schedules are being explored in the
ovarian and head and neck cohorts. Celldex plans to complete
enrollment across all cohorts in the first quarter of 2018 and will
work with Bristol-Myers Squibb to present data from the Phase 2
study at a future medical meeting. 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 Opdivo and further assessing the
antitumor 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.
About Varlilumab
Varlilumab 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
antitumor activity in patients with advanced, refractory disease.
No maximum tolerated dose was reached, and minimal toxicities were
observed.
Opdivo® is a registered trademark of Bristol-Myers Squibb.
About Celldex Therapeutics, Inc.
Celldex is developing targeted therapeutics to address
devastating diseases for which available treatments are inadequate.
Our pipeline includes antibodies, antibody-drug conjugates and
other protein-based therapeutics derived from a broad set of
complementary technologies which have the ability to engage the
human immune system and/or directly inhibit tumors to treat
specific types of cancer or other diseases. Visit
www.celldex.com.
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glembatumumab vedotin and other Company drug candidates; our
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Company Contact
Sarah Cavanaugh
Vice President of Investor Relations & Corp Communications
Celldex Therapeutics, Inc.
(781) 433-3161
scavanaugh@celldex.com
Charles Liles
Associate Director of Investor Relations & Corp Communications
Celldex Therapeutics, Inc.
(781) 433-3107
cliles@celldex.com
Media Contact
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(973) 271-6085
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