p53 synthetic long peptides vaccine with cyclophosphamide for ovarian cancer, a phase II trial.

Ovarian cancer is considered a silent lady killer. Due to the absence of
specific symptoms, the majority of patients present with advanced stage
disease. Although the incidence of ovarian cancer is low, the mortality rate is
high. The standard treatment consists of a combination of surgery and platinum
based chemotherapy. Despite this treatment, 80% of the patients die within 5
years after the diagnosis has been made.
Progress in the fight against ovarian cancer has been hampered by the lack of
highly effective therapy to permanently eradicate disseminated intraperitoneal
metastases, present in most patients at the time of diagnosis. In order to
improve the poor outcome for ovarian cancer patients old and new treatment
modalities, such as targeted or biologic agents and immunotherapy should be
combined. Recent data show the importance of the immune response in the course
of ovarian cancer as well as the negative influence of Tregs. The availability
of new potent immunization strategies urge further exploration of immunotherapy
as adjuvant treatment modality in ovarian cancer patients.

Primary objectives:
- To improve the clinical effectiveness of the p53 synthetic long peptides
vaccine by pre-administration of cyclophosphamide.
- To evaluate the immunogenicity of a p53 synthetic long peptide vaccine when
preceded by administration of cyclophosphamide.

Secondary objective:
To evaluate the safety of the p53 synthetic long peptide vaccine when preceded
by administration of cyclophosphamide.

This is an uncontrolled, mono-centre, phase II study, investigating the
clinical effectiveness, immunogenicity and safety of four vaccinations with the
p53 synthetic long peptide vaccine, with each vaccination preceded by
administration of cyclophosphamide i.v.

The vaccine consists of 10 synthetic p53 peptides in dimethylsulfoxide (DMSO) /
phosphate buffer 20mM (PBS) / Montanide ISA51 (20/30/50 v/v/v-%). The vaccine
will be administered by subcutaneous injection at a dose of 300 µg per peptide.
Patients will be vaccinated four times at three week intervals. Vaccinations
are given in four different sites: left upper arm, left thigh, right upper arm,
right thigh.

Cyclophosphamide will be administered intravenously, in a dose of 300mg/m2, two
days prior to each peptide vaccination.

Burden and risks:
Based on the results from the previous phase I/II study with the p53 synthetic
long peptides vaccine, little toxicity is anticipated from peptide vaccination.
The peptide components in the vaccine are designed to be non-toxic. Experienced
toxicity so far using this vaccine was local pain, redness, pruritis and
swelling of the local skin, grade I/II according to the Common Terminology
Criteria for Adverse Events.
Cyclophosphamide may cause nausea and vomiting as a side effect of treatment.
Premedication for nausea will be administered prior to infusion of the drug.
With the specified dose, hematologic toxicity is not expected.
Anemia caused by blood sampling may occur, but is not expected as this was not
observed in the previous phase I/II study (with a higher total volume of blood
taken).
At two times during the study a skin biopsy will be taken from the vaccination
site under local anesthesia, where after the wound is closed with stitches.

Benefit and group relatedness:
Immunotherapy is one of the novel therapeutic strategies under investigation in
ovarian cancer. In theory, immunotherapy directed at tumor specific antigens,
administered after standard therapy, provides an ideal tool to consolidate
anti-tumor effects of standard therapy, and to delay and possibly prevent
progression of disease.
There are indications that chemotherapy after vaccination might be more
effective in patients who showed an immunological response after vaccination.