A Pilot Study to Test the Feasibility of the Combination of Gemcitabine and Anti-PD1 Monoclonal Antibody (CT-011) in the Treatment of Resected Pancreatic Cancer
- In 2009, 49,096 patients were diagnosed with pancreatic cancer. Pancreatic cancer
carries a poor prognosis with an overall 5-year relative survival rate of 5.6%.
- One of the leading causes for immune suppression in cancer patients was suggested to be
associated with the elevated expression of programmed cell death 1 ligand 1 (PD-L1)
human B7 homolog 1 (B7-H1) at tumor-involved sites, either by the tumor itself or by
surrounding cells like regulatory immune cells, resulting in the local suppression and
apoptosis of tumor infiltrating effector lymphocytes.
- CT-011 is a humanized immunoglobulin G 1 (IgG1) kappa recombinant monoclonal antibody
against PD-1 receptor that blocks the interaction of PD-L1 with PD-1. CT-011
specifically binds to an epitope that is shared between the murine and the human PD-1
receptors on activated T cells, B cells, natural killer (NK) cells, and myeloid cells
(CD14+ cells) and primarily functions in effector/memory T lymphocytes and in NK cells.
In a functional bioassay, CT-011 was demonstrated to block the activity of PD-1 and to
operate on CD4+CD45RO+ effector/memory T lymphocytes leading to attenuation of
- CT-011 was studied in experimental murine tumor models of melanoma, lung cancer,
fibrosarcoma, leukemia/lymphoma and colorectal carcinoma and was shown to inhibit tumor
growth and extend the survival of tumor-bearing nude mice, and to generate
tumor-specific protection against tumor re-challenge.
- Recent findings have demonstrated that chemotherapies like paclitaxel, etoposide or
fluorouracil (5-FU) induce the expression of the PD-L1 on tumor cell lines leading to
an immune-suppressive environment and promoting PD-L1-mediated T cell apoptosis
- Primary endpoint: To determine the feasibility and safety of the combination of CT-011
and Gemcitabine in patients after primary macroscopic resection of pancreatic
- Secondary endpoint: To determine if the addition of CT-011 to Gemcitabine can improve
the median disease-free survival in resected pancreatic cancer.
- Adult patients with histologic verification of adenocarcinoma of the pancreas (T1-3,
N0-1) who have undergone surgical resection within the past 4-8 weeks.
- Must meet all laboratory safety criteria and not have active or history of autoimmune
disease or conditions, be treated with immunosuppressive drugs, or require the use of
- Pregnant or nursing women will be excluded. Subjects with active infection, human
immunodeficiency virus (HIV), Hepatitis B or C will be excluded.
- Eligible subjects will receive adjuvant combination CT-011 and Gemcitabine.
- Gemcitabine will be given at a dose of 1000mg/m^2 by intravenous infusion over 30
minutes on Days 8, 15 and 22 of each cycle.
- CT-011 will be given at a dose of 3mg/kg by intravenous infusion over 2 hours on day 1,
one week prior to the first Gemcitabine infusion of each cycle.
- Treatment will be continued for a total of 6 cycles or until disease recurrence or
grade IV non-hematological toxicity if occurred before the completion of 6 cycles.
- The study will be conducted as an optimal two-stage phase II trial, in order to rule
out an unacceptably low 50% of patients who do not receive the full dose of CT-011
(p0=0.50) in favor of a modestly high 80% fraction who receive the full dose of CT-011
(p1=0.80). It is anticipated that up to 32 patients may be enrolled onto this trial.
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
To determine the feasibility and safety of the combination of CT-011 and Gemcitabine in patients after primary macroscopic resection of pancreatic adenocarcinoma.
Samir N. Khleif, MD
Georgia Regents University
United States: Food and Drug Administration
|Georgia Health Sciences University||Augusta, Georgia 30912|