Primary objectives of the study are to assess whether the administration of p53-SLP together with the local administration of IFNα is safe and able to induce a strong (directly ex-vivo detectable) p53-specific CD4+ T-cell response. Secondary…
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Brief title
Condition
- Gastrointestinal neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Safety will be assessed during the whole study by collecting all adverse events
according CTC version 3.0 (with a focus on administration site reactions),
vital signs, blood-chemistry and haematological parameters. Immunogenicity will
be assessed by an array of complementary immunological assays which focus on
p53-specific T-cell proliferation, enumeration of circulating IFNγ-producing
T-cells, Th1/Th2 cytokine production, and p53 protein recognition by
circulating and vaccine-site-homing T-cells. However, the primary endpoint is
determined by the directly ex-vivo detectable p53-specific CD4+ T-cell response
and is defined by the percentage of CD3+CD4+ T cells that up-regulate the
activation markers CD154 and CD137 upon stimulation with p53 antigen in freshly
tested PBMC as measured by multiparameter flowcytometry. The immunological
endpoint is successful if a combination of the p53-SLP vaccine combined with
subcutaneous injection of IFN* is capable of inducing a directly ex-vivo
detectable p53-specific CD4+ T-cell response in at least 70% of the vaccinated
patients.
Secondary outcome
The secondary endpoint is successful if a combination of the p53-SLP vaccine
combined with subcutaneous injection of interferon-alfa is capable of inducing
a more pronounced Th1 response in the vaccinated patients. Th1 response is
defined as the number of IFNγ producing T-cells in ELISPOT, the proportion of
IFNγ producing cells in the total population of p53-specific T-cells measured
by multiparameter flow cytometry, as well as the amount of IFNγ in the
supernatant of proliferation assays. All which were low in our previous trial.
Background summary
Colorectal cancer is the second most frequent cancer in the Netherlands.
Despite treatment 45% of all colorectal cancer patients die within 5 years.
Efforts to improve survival in patients with advanced colorectal cancer have
had only limited success. P53, is due to a mutation a frequently over-expressed
protein in colorectal cancer patients. This over-expression provides an
immunological window for immunotherapy of colorectal cancer. In a recent phase
I study we showed that vaccination with p53 synthetic long peptides (p53-SLP)
is capable to induce a systemic p53 specific T-cell response in the majority of
patients. Despite the induction of p53-specific T-cell immunity in vaccinated
patients, the p53-specific T helper responses are probably too weak to become
truly effective as they were not associated with a good Th1 polarization. Most
likely this is due to the fact that the p53-SLP vaccine did not contain a
compound to activate dendritic cells (DC). DC-activating agents, including
Interferon-alfa (IFNα), are known for their capacity to strongly enhance
Th1-associated T-cell responses.
Study objective
Primary objectives of the study are to assess whether the administration of
p53-SLP together with the local administration of IFNα is safe and able to
induce a strong (directly ex-vivo detectable) p53-specific CD4+ T-cell
response.
Secondary objective is to assess whether the administration of p53-SLP together
with the local administration of IFNα is able to induce an overall
significantly stronger p53-specific Th1 response than observed in the group of
patients vaccinated in our previous trial.
Study design
Exploratory phase I trial
Intervention
Eligible patients will receive 2 vaccinations consisting of 9 synthetic long
peptides, 300 µg per peptide, emulsified in DMSO / 20 mM PBS / Montanide ISA 51
20/30/50 v/v/v by subcutaneous injection in one of the arms. Vaccinations will
be given with a three week interval. Pegylated IFNα (Pegintron,
Schering-Plough) will be injected in close proximity of the vaccination site
one hour afterwards.
Study burden and risks
Patient will visit the clinic during the trial five times more compared to
routine follow up in a period of four months. During the visits, patients are
two times vaccinated in combination with application of the adjuvant, blood is
drawn (2 times 215 mL, 3 times 15 mL), a skin biopsy from the second
vaccination site is punched. Results from two previous phase I/II trial with
both colorectal and ovarian cancer patients showed that the p53-SLP vaccine is
safe. We expect that adverse events in this trial mainly consist of swelling
and redness of the vaccination site, due to the vaccine induced immune
response.
Postbus 9600
2300 RC Leiden
NL
Postbus 9600
2300 RC Leiden
NL
Listed location countries
Age
Inclusion criteria
- Willing and able to comply with the protocol and to provide informed consent in accordance with institutional and regulatory guidelines
- Patients must be 18 years or older.
- Histological proven colorectal carcinoma
- At least one month after last treatment
- Life expectance of more than 6 months
- Patients of child-bearing potential should test negative using a serum pregnancy test and agree to utilize effective contraception during the entire treatment and follow-up period of the study
- Patients must be ambulatory, with an WHO performance status of 0 to 1
- Absence of any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; conditions should be discussed with the patient before registration in the trial
- Baseline laboratory findings; haemoglobin > 6.0mmol/L, white blood cells (WBC) > 3,000 x 109/L, lymphocytes > 1,000 x 109/L, platelets > 100 x 109/L, HIV- and HBV-negative
Exclusion criteria
- History of an autoimmune disease or other systemic intercurrent disease that might affect the immunocompetence of the patient, or patients receiving immunosuppressive therapy including transplant recipients
- History of a second malignancy except curatively treated low-stage tumours with a histology that can be differentiated from colorectal cancer
- Any condition that in the opinion of the investigator could interfere with the conduct of the study
- Radiotherapy, chemotherapy or other potentially immunosuppressive therapy administered within 4 weeks prior to the enrolment visit
- Receipt of another investigational product within the previous 4 weeks or at any time during the study period
- Receipt of prior P53 directed immunotherapy
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2008-004611-35-NL |
| CCMO | NL24089.000.08 |