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Celldex Therapeutics,
Inc.
today reported data from its ongoing Phase 1
dose-escalation study of the fully human monoclonal antibody CDX-1127. The
results suggest an excellent safety profile and demonstrate clear biologic
activity and promising signs of clinical activity in an advanced, refractory
patient population. No maximum tolerated dose has been reached to date. The
data will be presented in two poster sessions (poster #144 and 146) at the
2013 Society for Immunotherapy of Cancer (SITC) Annual Meeting, November 7
-- 10, 2013. In addition, a third poster (#85) will be presented on
preclinical combination studies of CDX-1127 with chemotherapies and
checkpoint inhibitors. The Company will host a webcast/conference call at
8:30 am ET today to discuss the results (details provided below).
"CDX-1127 has exceeded our expectations thus far in this ongoing Phase 1
dose-escalation study," said Thomas Davis, MD, Senior Vice President and
Chief Medical Officer of Celldex Therapeutics. "Our primary goal was to
establish a favorable safety profile, a challenge that other agonist
antibodies in this class have not been able to meet. To date, CDX-1127 has
demonstrated minimal toxicity and, importantly, no evidence of worrisome
overlap with toxicities seen with other immunotherapies--a critical hurdle
for combination therapy. We were also very pleased to see clear evidence of
biologic and anti-cancer activity in a heavily pretreated patient
population. While future data from the expansion cohorts will be important
to understanding single-agent activity, we are confident based on the
dose-escalation data we have seen to date that we are well positioned to
initiate combination studies of CDX-1127, with a particular interest in
immune modulators."
"We are encouraged by the initial safety and activity profile observed to
date and believe CDX-1127 could play an important role in the field of
cancer immunotherapy," said Howard A. "Skip" Burris, III, MD, Chief Medical
Officer and Executive Director of the Drug Development Program at Sarah
Cannon Research Institute and a lead investigator of the Phase 1 CDX-1127
study. "An agonist with this safety and biologic activity profile has
potential, particularly in combination with checkpoint inhibitors, where the
ability to mount an immune response could expand the effectiveness of these
compounds for more patients."
CDX-1127 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 less toxicities due to its restricted
expression and regulation. CDX-1127 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, CDX-1127 has an additional mechanism through a direct
anti-tumor effect.
Study Overview:
The Phase 1 dose-escalation study of CDX-1127 includes two arms--solid
tumors and lymphoid malignancies and is designed to evaluate five doses
(0.1, 0.3, 1, 3, 10 mg/kg). Enrollment is complete in the solid tumor
dose-escalation arm (n=25) and expansion cohorts are ongoing in metastatic
melanoma and renal cell carcinoma. In the dose-escalation lymphoid
malignancies arm (n=17), enrollment recently initiated in the 10 mg/kg
cohort and expanded development is being planned. Currently, first response
assessments are pending for four patients across the 1 and 3 mg/kg cohorts
and all patients in the 10 mg/kg cohort in the lymphoid malignancies arm.
Patients enrolled in the study across both arms had advanced disease and
most were heavily pretreated. Patients progressed on previous therapies and
had no remaining approved treatment options before study entry. The median
number of prior therapies is 5 anti-cancer (3 cytotoxic) for solid tumors
and 4 anti-cancer (3 cytotoxic) for lymphoid malignancies.
Safety and Immune Monitoring Overview:
In the solid tumor dose-escalation phase, CDX-1127 was associated with
minimal toxicity including at the highest dose levels through multiple
cycles. No maximum tolerated dose was reached. The most common
treatment-related adverse events were decreased appetite (12%) and fatigue
(12%). One patient experienced a dose limiting toxicity (DLT), a Grade 3
transient asymptomatic hyponatremia 14 days after a single 1.0 mg/kg dose of
CDX-1127. Hyponatremia has not been attributed to CDX-1127 in any other
patient. The safety data from the lymphoid malignancies arm also show that
CDX-1127 has been well tolerated with no DLTs to date.
The preliminary assessment of pharmacokinetics demonstrates significant
exposure to CDX-1127 throughout the duration of the study period. Immune
monitoring assessments conducted in the solid tumor arm support the overall
safety profile and also demonstrate that CDX-1127 induces immunologic
activity in patients that is consistent with both its mechanism of action
and preclinical models, including an increase in Natural Killer cells and in
T cells that express the activation marker, HLA-DR. The study also
identified the serum chemokine, interferon-gamma inducible protein 10
(IP-10) as a significant biomarker for CDX-1127 treatment. Of note, the
study confirms that CDX-1127 does not induce major lymphocyte depletion, but
does reduce the number of regulatory T cells, which are thought to have
immune suppressive activity. Taken together, these markers demonstrate clear
evidence of lymphocyte activation--the direct purpose of CDX-1127 therapy.
Clinical Activity Overview:
Across both arms, eight patients experienced stable disease or better with a
PFS range of 3.0 to 14+ months. In addition, three patients experienced
significant tumor shrinkage, including a complete response as outlined
below.
-- A 28 year old female with Stage IV Hodgkin lymphoma achieved a complete
response, including complete resolution of B symptoms (drenching sweats,
pruritus and weight loss)--an important marker of disease activity in
Hodgkin disease, after three cycles of CDX-1127 (0.3 mg/kg). The patient
remains in remission at 8.6+ months. During treatment, the area of
measurable lesions first increased and then regressed. This pattern is
consistent with the current perception of an immune mediated response.
The patient was heavily pretreated, including high dose chemotherapy
with
autologous marrow transplantation, and most recently had progressed
after
less than one month on Adcetris(TM) plus chemotherapy.
-- A 69 year old male with Stage IV colorectal cancer metastatic to the
liver, lung and peritoneum was treated with CDX-1127 (1 mg/kg) and had a
33% unidimensional shrinkage of measurable disease and a PFS of 5.7
months. The shrinkage was associated with small, new lesions
representing
a mixed response. The patient had previously received multiple agents,
including Avastin(R) and most recently had progressed through
Xeloda(R)/radiation at two weeks.
-- A 67 year old male with Stage III marginal zone B-cell lymphoma who
received CDX-1127 (0.3 mg/kg) experienced a 36% shrinkage of measurable
disease, including complete disappearance of disease in the inguinal and
iliac regions and had a PFS of 5.6 months. The patient was very heavily
pretreated with 10 prior regimens of cytotoxic, radiation and Rituxan(R)
therapy.
Two patients received all five cycles of treatment and were on trial for
greater than a year, including:
-- An 83 year old male with Stage IV renal cell carcinoma metastatic to
liver and lung who remains progression-free at 14+ months after study
entry, and
-- A 52 year old male with Stage IV follicular lymphoma who had a PFS of 14
months.
The Company also reported very early data from the solid tumor expansion
cohorts, where CDX-1127 has been well-tolerated to date. The melanoma cohort
has accrued 14 patients at 3 mg/kg with eight patients continuing treatment,
seven who have not yet been seen for the first assessment of response. One
patient with uveal melanoma who is entering the third round of treatment has
experienced a 12% shrinkage of measurable disease by RECIST and stable
disease is ongoing at 5.7 months. The renal cell carcinoma arm has accrued
eight patients at 3 mg/kg with seven continuing treatment, all of whom have
not yet been seen for the first assessment of response.
In a separate poster, the Company reported new data of CDX-1127 in
combination therapy using mouse tumor models. Agents that induce tumor
killing to provide a source of antigen and agents that block T cell
inhibitory molecules were chosen for their potentially complementary
mechanisms of action. Employing challenging treatment settings where single
agent activity is limited, a clear survival benefit was observed with
CDX-1127 combinations of cyclophosphamide or checkpoint blockade. These
studies, together with the favorable safety profile and activity data from
the Phase 1 trial with CDX-1127, support the initiation of combination
trials with conventional and immune-based therapies.
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