Safety and Immunogenicity Study of the New dHER2 Vaccine to Treat HER2-positive Metastatic Breast Cancer
Safety and Immunogenicity Study of the New dHER2 Vaccine to Treat HER2-positive Metastatic Breast Cancer
Patients will receive a maximum of 18 injections of dHER2 vaccine in a treatment schedule
 that will last for up to about a year, and thereafter there will be a follow-up period of
 about one more year.
This Phase I/II study will be conducted according to a multicenter, open-label design. At
 least 20 patients will receive the vaccine as first-line and at least 20 as second-line
 treatment. The treatment will comprise a maximum of 18 injections of dHER2 vaccine. Follow-up
 phase: This will commence with the end-of-treatment examination, followed by examinations
 three months, six months and twelve months after the last study vaccination. The Protocol
 Posting has been updated in order to comply with the FDA Amendment Act, Sep 2007.
Inclusion criteria:

 -  Female.

 -  At least 18 years of age.

 -  Written informed consent to participate in the study.

 -  Diagnosis of advanced breast cancer. Furthermore, for patients being considered for
 second-line study treatment only: The patient has received a first-line chemotherapy
 together with Herceptin - or Herceptin alone - for her metastatic breast disease
 meeting all of the following conditions:

 i) For patients who have received a first-line chemotherapy together with Herceptin:

 -  The administration of chemotherapeutic agent(s) has been stopped for at least 3
 months, or will have been stopped for at least 3 months by the time of the first study
 vaccination, and

 -  The administration of Herceptin alone was maintained after chemotherapy.

 ii) The last dose of Herceptin was given not less than 3 weeks before the study
 vaccination.

 iii) The patient will not be given Herceptin during the trial.

 -  A tumor lesion from the patient biopsied before or during screening, shows either i)
 overexpression of the HER2 protein, as determined by IHC (result: IHC 3+), or ii)
 amplification of the HER2 gene as determined by FISH (at least 4-fold, i.e., at least
 8 copies).

 -  For patients being considered for first-line study treatment only: The patient's
 metastatic disease affects the skin and/or the lymph nodes and/or the lungs, but no
 other organ (with the exception of asymptomatic bone lesions). For patients being
 considered for second-line study treatment only: The patient's metastatic disease may
 affect any organ(s) with the exception of the central nervous system (CNS).

 -  At least one measurable lesion.

 -  ECOG status of 0 or 1.

 -  Agree to use effective contraception for the duration of the study and statement not
 to plan to bear children in the future.

 -  Result of serum β-HCG pregnancy test at the screening visit is negative. (This does
 not apply to patients who are not of child-bearing potential)

 -  Adequate bone marrow reserve.

 -  Adequate renal function.

 -  Adequate hepatic function.

 -  Baseline LVEF measured by MUGA scan equal to or greater than the lower limit of normal
 for the radiology facility.

 -  Results of a viral screening tests (HCV, and HBV surface antigen) on samples taken at
 the screening visit are both negative.

 -  Investigator believes that the patient can and will comply with the requirements of
 the protocol.

 The following condition applies to centers in France only: A subject will be eligible for
 inclusion in this study if he/she is either affiliated to or a beneficiary of a social
 security category. It is the investigator's responsibility to ensure and to document (in
 source document - patient notes) that the patient is either affiliated to or a beneficiary
 of a social security category.

 Exclusion criteria:

 For patients being considered for first-line study treatment only:

 -  Received any chemotherapy for metastatic breast disease.

 -  Received >300 mg/m2 doxorubicin (cumulative dose) or >600 mg/m2 epirubicin (cumulative
 dose).

 -  Although hormone therapy as a first-line therapy for metastatic disease is accepted,
 it must NOT have been started or modified (in nature or dosage) within the 12 weeks
 before the first study vaccination, and NO such change during the study period may be
 anticipated.

 -  Treatment with bisphosphonate UNLESS the bisphosphonate treatment was initiated more
 than 3 months before first study vaccination.

 -  Received any investigational or non-registered drug or vaccine other than the study
 vaccine within the 30 days preceding the first dose of study vaccine, or plans to
 receive such a drug during the study period.

 -  For patients being considered for first-line study treatment, any of the following
 will result in exclusion of the patient:

 1. Any organ other than skin, lymph nodes, bone and lung is affected by the
 metastatic disease.

 2. If the lung is affected: >3 lung lesions have been detected.

 3. If the lung is affected: Any lesion measures 30 mm or more (longest diameter).

 4. If the lung is affected: The lung metastases cause any functional impairment.

 5. The sponsor may during the study instruct sites that no further patients with
 lung metastases are to be included. Receipt of such instructions from the sponsor
 constitutes an exclusion criterion for all further patients with lung
 metastases.For patients being considered for second-line study treatment, the
 presence of lung metastases that cause any functional impairment following will
 result in exclusion of the patient.

 -  The patient has a history of congestive heart failure or difficult-to-control
 hypertension, hypercholesterolemia or diabetes.

 -  The patient has known coronary artery disease, arrhythmia requiring treatment,
 clinically significant valvular disease, cardiomegaly on chest X-ray, ventricular
 hypertrophy (found by ECG) or previous myocardial infarction.

 -  The patient has any acute or chronic, clinically significant pulmonary,
 cardiovascular, hepatic or renal functional abnormality, as determined by physical
 examination or laboratory screening tests.

 -  The patient presents with autoimmune disease.

 -  The patient requires chronic administration of immunosuppressive drugs including
 corticosteroids.

 -  Medical history includes splenectomy or irradiation to the spleen.

 -  Known family history of congenital or hereditary immunodeficiency.

 -  Received major organ graft (including bone-marrow transplantation).

 -  Any uncontrolled bleeding disorder or coagulation disorder or thrombocytopenia or
 prothrombotic disorder.

 -  History of anaphylaxis or severe allergic reaction to vaccines or unknown allergens.

 -  HIV positive.

 -  Previous or concomitant malignancies at other sites, except (i) effectively treated
 non-melanoma skin cancers or carcinoma in situ of the cervix, and (ii) effectively
 treated malignancy that has been in remission for >2 years and which is considered
 highly likely to have been cured.

 -  Pregnant or lactating.

 -  Any psychiatric or addictive disorder that may compromise ability to give informed
 consent, or to comply with the trial procedures.

 -  Any history of alcohol or drug abuse.

 -  Any other condition is present that in the opinion of the investigator might
 jeopardize the patient's safety or ability to comply with requirements of the study

 -  Received any commercial vaccine within one week before the first study vaccination.