NPC-1C: A novel, therapeutic antibody to treat pancreas and colorectal cancers.

1
NPC-1C A novel, therapeutic antibody to treat
pancreas and colorectal cancers.
Nilofer S. Azad, Luis A. Diaz, Daniel Laheru,
Dung T. Le, David Cosgrove, Lei Zheng, Ana De
Jesus-Acosta, Ross Donehower, Leanne Sleer, Craig
Devoe, Michael Morse, Philip M. Arlen, J. A.
Bristol. Sidney Kimmel Comprehensive Cancer
Center at Johns Hopkins University, Baltimore,
MD Johns Hopkins University School of Medicine,
Baltimore, MD Duke University Medical Center
Hofstra University School of Medicine-North
Shore-LIJ, Lake Success, NY Medical Oncology
Branch, National Cancer Institute, Bethesda, MD
Neogenix Oncology, Inc., Rockville, MD
Abstract
The Clinical Trial
Background
Killing Activity of NPC-1 Chimeric mAb
NPC-1C Tissue cross-reactivity and other toxicity
studies suggest a favorable safety profile

• The concept of monoclonal antibody therapy for
  recurrent solid tumor malignancies was derived
  from results obtained in the original Hollinshead
  cancer vaccine trials of the 1970s and 1980s
• Results of these vaccine trials indicated that
  patients responding to therapy had to be capable
  of sustaining an IgG1 antibody response.
• Failure to sustain this antibody response
  resulted in recurrence of the malignancy being
  treated.
• Vaccine Preparation and Screening A Colorectal
  Cancer Study
• Vaccine derived from operative samples form 78
  different individuals with colorectal
  cancervarious stages
• Cell membrane components released using
  sonication techniques
• Components then separated by centrifugation and
  HPLC
• HPLC fractions were tested for immune reactivity
  by DTH in cohorts of BOTH colorectal cancer
  patients and Healthy Volunteers
• Only HPLC fractions reacting in colon cancer
  patients used for vaccine
• FDA allowed human clinical trials in 1970s and
  1980s using this pre-screened biologic material
• Published Phase I Trial Results from Hollinshead
  Colorectal Cancer Study Demonstrated Positive
  Results
• Specific active immunotherapy in patients with
  adenocarcinoma of the colon utilizing tumor
  associated antigens (TAA). A phase I clinical
  trial. Hollinshead A, Elias EG, Arlen M, et al.
  Cancer 56(3)480-9, 1985
• 22 patients with Dukes stage B2 through D Colon
  Cancer underwent surgical resection prior to TAA
  vaccine injection
• No systemic toxicity (hepatic, renal, GI,
  respiratory, or neurologic) was observed with the
  vaccine
• Results 82 survival, 59 disease-free (median
  follow-up 21 months)

A Phase 1/2A Therapeutic, Open Label,
Multi-Center Clinical Trial of NPC-1C, a Chimeric
Monoclonal Antibody, in Adults with Recurrent,
Locally Advanced Unresectable or Metastatic
Pancreatic and Colorectal Cancer After Standard
Therapy
Background NPC-1C (Ensituximab) is a chimeric
monoclonal antibody being developed as a novel
biological treatment for pancreatic and
colorectal cancers. This antibody was selected
from a panel of hybridomas generated from mice
immunized with semi-purified membrane-associated
proteins derived from biologically screened,
pooled human allogeneic colon cancer tissues.
The NPC-1C epitope appears to be a variant of
MUC5AC that is expressed specifically by human
colon and pancreatic tumor tissues and cell lines
with only minimal and weak cross-reaction
occasionally to certain GI tract tissues. The
NPC-1C antibody shows ADCC activity against human
colon and pancreatic tumor cells, but not control
tumor cell lines. Human pancreatic tumor
xenograft models showed significant, and
reproducible, anti-tumor action, including some
complete tumor regressions. Several examples of
human tumor tissues stained with NPC-1C showed a
strong correlation of NPC-1C staining against
pancreatic and colon tumors (45 of tumors
strongly positive). The staining pattern was
typical of elaborated mucin expression, but also
showed cytoplasmic and cell membrane
staining. Methods A Phase I open label,
multi-center dose escalation clinical trial with
NPC-1C is currently accruing patients with
advanced pancreatic and colorectal cancer who are
refractory to standard therapy. A standard 33
design with an expansion cohort of 10 pancreatic
cancer patients is planned. Patients were treated
with NPC-1C starting at 1 mg/kg IV q2wks cohort
1 has been completed without DLT but cohort 2
did have DLT cohort 1.5 is being accrued during
which patients are hospitalized for 48 hours for
observation after cycle 1 doses of NPC-1C .
Eligibility criteria included good end organ
function and performance status, gt20 of tumor
tissue staining positive for MUC5AC, and an
exclusion for QTc prolongation or history of
hemolytic episodes. Objectives The primary
objectives of the Phase I clinical trial are to
determine the safety and tolerability of
escalating doses of NPC-1C monoclonal antibody
therapy and to assess pharmacokinetics and
select immune responses to the antibody at each
dose level. Secondary objectives are to evaluate
evidence of clinical benefit and to explore the
immunologic correlates associated with
administration of NPC-1C. Results from this trial
will determine the minimum standard dosage levels
to be used in further trials.

• Primary Objectives
• Determine the safety and tolerability of
  escalating doses NPC-1C monoclonal antibody
  therapy in subjects with metastatic, locally
  advanced unresectable or recurrent pancreatic
  cancer or metastatic colorectal cancer that
  express NPC-1C target on tumor and
• Assess pharmacokinetics and select immune
  responses to the antibody at each dose level
• Secondary Objectives
• Evaluate evidence of clinical benefit, as
  measured by RECIST criteria
• Explore the immunologic correlates associated
  with administration of NPC-1C monoclonal antibody
  therapy in subjects with metastatic, locally
  advanced unresectable or recurrent pancreatic
  cancer or metastatic colorectal cancer that
  express NPC-1C target on tumor

NPC-1C Binds to a Variant of MUC5AC
NPC-1C Anti-Tumor efficacy data

• Study Design Phase 1
• 33 dose escalation with an expansion cohort of
  10 pancreatic cancer patients
• NPC-1C will be given IV every 2 weeks for 4 doses
  (one course).
• To establish the MTD, 3-6 subjects with recurrent
  or metastatic colorectal or pancreatic cancer
  will be enrolled in the following cohorts
• Cohort of patients Dose
• Cohort 1 3 patients 1 mg/kg (COMPLETED)
• Cohort 1.5 4 of 6 patients 1.5 mg/kg ? (ONGOING)
• Cohort 2 3 patients 2 mg/kg (COMPLETED)
• Cohort 3 N/A 4 mg/kg
• Cohort 4 N/A 8 mg/kg

MUC5AC 11kb gene gt90 exons 5,500 amino acids Mr
1,000,000 Da

• NPC-1C Pre-Clinical In Vivo Studies
• Pre-clinical animal pharmacokinetic testing
  supports dosing every two weeks.
• Biodistribution studies indicate that NPC-1C can
  traffic to the tumor site following intravenous
  administration and potentially effect an
  anti-tumor effect.
• Animal toxicity studies did not identify
  toxicities associated with the administration of
  NPC-1C.

• Eligibility criteria of interest
• Good end organ function and performance status
• gt 20 of tumor tissue staining positive for
  MUC5AC
• No QTc prolongation
• No history of hemolytic episodes

• Correlative studies
• Pharmacokinetics
• Human Antibody to chimeric monoclonal antibody
  testing on C1d4, C1d15, and C1d57 and final
  follow-up visit by ELISA
• Th1 and Th2 cytokine analysis (IL-1b, IL-2, IL-6,
  IL-8, IL-10, IL-12p70, GM-CSF, TNF-a, IFN-?) at
  same time points