Study of the Therapeutic Vaccine (ISA101/ISA101b) to Treat Advanced or Recurrent Cervical Cancer

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/orradiological proof with no curative treatment options.

4. For cohort 10 (and 12), i.e. patients eligible to receive bevacizumab at each site perstandard of care, patients may be primary stage IVB (including persistent) or firstrecurrent carcinoma of the uterine cervix (squamous cell carcinoma, adenocarcinoma, oradenosquamous carcinoma). Prior treatment with chemotherapy for recurrent disease isnot permitted. However, one prior line of chemotherapy with platinum during primaryradio-chemotherapy or platinum-base chemotherapy as neoadjuvant chemotherapy prior tosurgery is permitted

5. Tumour must be HPV16 positive.

6. Patients should be eligible for chemotherapy with carboplatin and paclitaxel, and haveconsented with chemotherapy with carboplatin and paclitaxel, before the start of theinformed 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 judgmentthat the patient has a reasonable life expectancy and is sufficiently fit andmotivated to complete the study treatment and comply to all study procedures conformthe protocol.

Exclusion Criteria: Treatment:

1. Prior treatment with anti-HPV agents.

2. Chronic systemic steroid use. Local application (i.e. stable doses of topical orinhaled 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 weeksfor 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 anotherinvestigational drug.

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

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, orplatelet 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 livermetastases, 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 orsquamous cell carcinoma of the skin and with the exception of other malignancies fromwhich the patient may be considered cured as evidenced by complete regression of alllesions >10 years ago.

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

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

14. Pregnancy or lactation. Serum pregnancy test to be performed within 7 days prior tostudy 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 > 110mmHg).

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 plannedtreatment, affect patient compliance or place the patient at high risk fromtreatment-related complications.