Gemcitabine and CT-011 for Resected Pancreatic Cancer
| Status: | Suspended |
|---|---|
| Conditions: | Cancer, Cancer, Pancreatic Cancer |
| Therapuetic Areas: | Oncology |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 6/30/2016 |
| Start Date: | September 2012 |
| End Date: | February 2018 |
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
Background:
- 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%.
- Many doctors believe that individuals who have had surgery to remove pancreatic cancer
should receive additional treatment, known as adjuvant therapy or adjuvant treatment,
to prevent the cancer from returning. One chemotherapy drug that has been found to be
effective in some patients with pancreatic cancer is called gemcitabine; it has been
shown to improve patient survival by 6 months. Researchers are searching for new drugs
or drug combinations to improve on these results.
- One of the leading causes for immune suppression in cancer patients was suggested to be
associated with the elevated expression of programmed cell death 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.
- Some chemotherapy drugs kill cancer cells directly, but appear to prevent the immune
system from helping in that fight. The experimental drug CT-011 is designed to help the
immune system remain active to fight cancer cells. CT-011 has been tested in
laboratories and studied for use with a number of other cancers, but it has not been
given in combination with gemcitabine as a treatment for pancreatic cancer.
Objective:
- To test the safety and effectiveness of chemotherapy drugs gemcitabine and CT-011 as a
follow-up treatment for pancreatic cancer that has been surgically removed.
Eligibility:
- Individuals at least 18 years of age who have had surgery to remove pancreatic cancer and
have not had other types of follow-up treatments.
Design:
- Participants will receive gemcitabine and CT-011 in 28-day cycles of treatment, and
will be monitored throughout their treatment.
- Participants who do not have serious side effects and remain cancer-free may receive
this drug combination every 28 days for a total of 6 cycles.
- Participants will have follow-up visits with additional blood tests every 2 months
after stopping treatment for up to 2 years.
- 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%.
- Many doctors believe that individuals who have had surgery to remove pancreatic cancer
should receive additional treatment, known as adjuvant therapy or adjuvant treatment,
to prevent the cancer from returning. One chemotherapy drug that has been found to be
effective in some patients with pancreatic cancer is called gemcitabine; it has been
shown to improve patient survival by 6 months. Researchers are searching for new drugs
or drug combinations to improve on these results.
- One of the leading causes for immune suppression in cancer patients was suggested to be
associated with the elevated expression of programmed cell death 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.
- Some chemotherapy drugs kill cancer cells directly, but appear to prevent the immune
system from helping in that fight. The experimental drug CT-011 is designed to help the
immune system remain active to fight cancer cells. CT-011 has been tested in
laboratories and studied for use with a number of other cancers, but it has not been
given in combination with gemcitabine as a treatment for pancreatic cancer.
Objective:
- To test the safety and effectiveness of chemotherapy drugs gemcitabine and CT-011 as a
follow-up treatment for pancreatic cancer that has been surgically removed.
Eligibility:
- Individuals at least 18 years of age who have had surgery to remove pancreatic cancer and
have not had other types of follow-up treatments.
Design:
- Participants will receive gemcitabine and CT-011 in 28-day cycles of treatment, and
will be monitored throughout their treatment.
- Participants who do not have serious side effects and remain cancer-free may receive
this drug combination every 28 days for a total of 6 cycles.
- Participants will have follow-up visits with additional blood tests every 2 months
after stopping treatment for up to 2 years.
RATIONALE:
- 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
apoptotic processes.
- 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
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.
OBJECTIVES:
- Primary endpoint: To determine the feasibility and safety of the combination of CT-011
and Gemcitabine in patients after primary macroscopic resection of pancreatic
carcinoma.
- Secondary endpoint: To determine if the addition of CT-011 to Gemcitabine can improve
the median disease-free survival in resected pancreatic cancer.
DESIGN:
- Eligible subjects will be screened with a full medical history and physical
examination, blood and urine tests, and imaging studies.
- Participants will receive adjuvant combination CT-011 and Gemcitabine in 28-day cycles.
- 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.
- 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.
- 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.
- Participants will be monitored with frequent blood and urine tests throughout their
treatment visits. Every other cycle (about every 2 months), participants will also have
imaging studies to evaluate the experimental treatment.
- Participants will have follow-up visits with additional blood tests every 2 months
after stopping treatment for up to 2 years.
- 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
apoptotic processes.
- 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
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.
OBJECTIVES:
- Primary endpoint: To determine the feasibility and safety of the combination of CT-011
and Gemcitabine in patients after primary macroscopic resection of pancreatic
carcinoma.
- Secondary endpoint: To determine if the addition of CT-011 to Gemcitabine can improve
the median disease-free survival in resected pancreatic cancer.
DESIGN:
- Eligible subjects will be screened with a full medical history and physical
examination, blood and urine tests, and imaging studies.
- Participants will receive adjuvant combination CT-011 and Gemcitabine in 28-day cycles.
- 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.
- 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.
- 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.
- Participants will be monitored with frequent blood and urine tests throughout their
treatment visits. Every other cycle (about every 2 months), participants will also have
imaging studies to evaluate the experimental treatment.
- Participants will have follow-up visits with additional blood tests every 2 months
after stopping treatment for up to 2 years.
- Adult patients with histologic verification of carcinoma of the pancreas (T1-3, N0-1)
who have undergone surgical resection within the past 4 - 12 weeks. Patients with R1
resections are excluded.
- 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
systemic steroids. Primary intraoperative chemotherapy will be allowed.
- Pregnant or nursing women will be excluded. Subjects with active infection, HIV,
Hepatitis B or C will be excluded.
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