Study of the Therapeutic Vaccine (ISA101/ISA101b) to Treat Advanced or Recurrent Cervical Cancer
Study of the Therapeutic Vaccine (ISA101/ISA101b) to Treat Advanced or Recurrent Cervical Cancer
The purpose of the study is to assess the safety, tolerability and the HPV-specific immune
 responses of different doses of ISA101 vaccine with or without pegylated IFNα as combination
 therapy with carboplatin and paclitaxel.

 To qualitatively assess the safety profile and the HPV-specific immune responses of ISA101b
 vaccine compared to ISA101 at the same dose levels.

 To assess the safety and the HPV-specific immune responses of ISA101b vaccine with
 carboplatin, paclitaxel with or without bevacizumab.
A majority of cervical carcinomas are caused by an uncontrolled, persistent infection with
 high risk Human Papilloma Virus (HPV). ISA101/ISA101b is a novel therapeutic synthetic long
 peptide (SLP) vaccine targeting HPV16 which is being developed and has shown efficacy in
 patients with high-grade premalignant vulvar lesions caused by HPV with only minor toxicity.
 For most advanced cancers, chemotherapy remains the treatment modality of choice but has been
 considered to be immunosuppressive. However, accumulating evidence indicates that many
 modalities of conventional chemotherapy not only are less immunosuppressive than previously
 thought but in fact can exert favorable effects on the tumor micro-environment by interfering
 with suppressive immune cells and by stimulating the release of immune activating molecules
 by tumor cells. Thus chemotherapy may enhance tumor-specific immunity and synergize with
 cancer immunotherapy. Addition of pegylated interferon alpha (IFNα) two-b (IIb) to
 vaccination might even further improve the immune response. This multicenter, open label,
 non-randomized Phase I/II study will be performed to assess the safety and tolerability of
 the ISA101/ISA101b vaccine, and the immune modulating effects of ISA101 (with or without
 pegylated IFNα)/ISA101b when combined with carboplatin and paclitaxel, with or without
 bevacizumab.
Inclusion Criteria:

 1. Women ≥ 18 years of age.

 2. Cervical cancer confirmed by histology.

 3. Advanced or metastatic or recurrent cervical cancer confirmed by clinical and/or
 radiological proof with no curative treatment options.

 4. For cohort 10 (and 12), i.e. patients eligible to receive bevacizumab at each site per
 standard of care, patients may be primary stage IVB (including persistent) or first
 recurrent carcinoma of the uterine cervix (squamous cell carcinoma, adenocarcinoma, or
 adenosquamous carcinoma). Prior treatment with chemotherapy for recurrent disease is
 not permitted. However, one prior line of chemotherapy with platinum during primary
 radio-chemotherapy or platinum-base chemotherapy as neoadjuvant chemotherapy prior to
 surgery is permitted

 5. Tumour must be HPV16 positive.

 6. Patients should be eligible for chemotherapy with carboplatin and paclitaxel, and have
 consented with chemotherapy with carboplatin and paclitaxel, before the start of the
 informed consent procedure for the study.

 7. Performance status (WHO scale/ECOG) 1.

 8. Written informed consent according to local guidelines.

 9. Written approval by the treating physician/investigator of his/her clinical judgment
 that the patient has a reasonable life expectancy and is sufficiently fit and
 motivated to complete the study treatment and comply to all study procedures conform
 the protocol.

 Exclusion Criteria:

 Treatment:

 1. Prior treatment with anti-HPV agents.

 2. Chronic systemic steroid use. Local application (i.e. stable doses of topical or
 inhaled corticosteroids) is allowed.

 3. Less than 4 weeks since the last treatment with other cancer therapies, (i.e.
 endocrine therapy, immunotherapy, radiotherapy, chemotherapy, etc), less than 8 weeks
 for cranial radiotherapy, and less than 6 weeks for nitrosoureas and mitomycin C.

 4. Toxicities resulting from previous anti-cancer therapy must be resolved to ≤ grade 2.

 5. Recent treatment (within 30 days of first study treatment) with another
 investigational drug.

 6. Patients with known hypersensitivity to any component of the Investigational Medicinal
 Product.

 7. Any contraindication to the use of authorized applied products (i.e. paclitaxel,
 carboplatin or bevacizumab).

 Haematology and biochemistry:

 8. Inadequate bone marrow function: Absolute Neutrophil Count (ANC) < 1.5 x 109/L, or
 platelet count < 100 x 109/L or hemoglobin < 6 mmol/L.

 9. Inadequate liver function, defined as:

 -  Serum (total) bilirubin > 2 x upper normal limit (ULN);

 -  Aspartate Aminotransferase (ASAT) or Alanine Aminotransferase (ALAT) > 2.5 x ULN
 (> 5 x ULN in patients with liver metastases);

 -  Alkaline phosphatase levels > 2.5 x ULN (> 5 x ULN in patients with liver
 metastases, or > 10 x ULN in patients with bone metastases).

 Other:

 10. Clinical suspicion or radiological evidence of brain or leptomeningeal metastases.

 11. Previous or current malignancies at other sites, with the exception of basal or
 squamous cell carcinoma of the skin and with the exception of other malignancies from
 which the patient may be considered cured as evidenced by complete regression of all
 lesions >10 years ago.

 12. Active HIV, chronic hepatitis B or C infection.

 13. Patients of childbearing potential not willing to consistently and correctly us a
 contraceptive method according to ICH (M3) resulting in low failure rate, i.e. less
 that 1% per year such as oral contraceptives or use of effective means of
 contraception.

 14. Pregnancy or lactation. Serum pregnancy test to be performed within 7 days prior to
 study treatment start in patients of childbearing potential.

 15. Major surgical procedure within 28 days prior to the first study treatment.

 16. Uncontrolled sustained hypertension (systolic > 180 mm Hg and/or diastolic > 110mm
 Hg).

 17. Clinically significant (i.e. active) cardiovascular disease defined as:

 -  Stroke within ≤ 6 months prior to day 1;

 -  Transient Ischemic Attack (TIA) within ≤ 6 months prior to day 1;

 -  Myocardial infarction within ≤ 6 months prior to day 1;

 -  Unstable angina;

 -  New York Heart Association (NYHA) Grade II or greater Congestive Heart Failure
 (CHF);

 -  Serious cardiac arrhythmia requiring medication;

 18. History of severe bronchial asthma and/or severe allergy.

 19. Evidence of any other medical conditions that may interfere with the planned
 treatment, affect patient compliance or place the patient at high risk from
 treatment-related complications.