| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with advanced (Stage IIIb-IVa with involvement of lymph nodes beyond the renal vein) or metastatic (stage IVb )or recurrent HPV16 positive cervical cancer for whom no curative treatment options exist |
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| E.1.1.1 | Medical condition in easily understood language |
| cervical cancer |
| baarmoederhalskanker |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10008229 |
| E.1.2 | Term | Cervical cancer |
| E.1.2 | System Organ Class | 100000004864 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To determine the safety and HPV-specific immune responses of the therapeutic Human Papilloma Virus Type 16 (HPV16) E6/E7 Synthetic Long Peptides Vaccine ISA101b (with or without bevacizumab as combination therapy with carboplatin and paclitaxel) compared to the responses observed at the same dose level(s) of ISA101 in women with HPV16 positive advanced or recurrent cervical cancer who have no curative treatment options |
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| E.2.2 | Secondary objectives of the trial |
| To evaluate the clinical efficacy of immunotherapy with ISA101/ISA101b in combination with standard therapy i.e. carboplatin and paclitaxel with or without bevacizumab. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Women ≥ 18 years of age.
2) Cervical cancer confirmed by histology.
3) Advanced (Stage IIIb/IVa with para-aortic lymph nodes involvement beyond the renal vein) or, metastatic (Stage IVb ) or recurrent cervical cancer confirmed by clinical and/or radiological proof with no curative treatment options.
4) For cohort 10 (and 12), patients should be 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 allowed. 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 (to be determined on archival tumour tissue (≤10 years old); if that is not available a pre-treatment biopsy will be required).
6) Patients should be eligible for chemotherapy with carboplatin and paclitaxel.
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 judgement 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 specified by the protocol.
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| E.4 | Principal 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 (radiation, chemotherapy or surgery) must be resolved to ≤ grade 2 as defined by CTCAE version 4.0.
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 (e.g. ISA101/ISA101b, Montanide, dimethylsulfoxide, Macrogolglycerol Ricinoleate, also known as cremophore, or pegylated IFNα for those subjects assigned to pegylated IFNα cohorts).
Haematology and biochemistry:
7) 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.
8) Inadequate liver function, defined as:
• Serum (total) bilirubin > 2 x upper normal limit (ULN); or
• ASAT or ALAT > 2.5 x ULN (> 5 x ULN in patients with liver metastases); or
• 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:
9) Clinical suspicion or radiological evidence of brain or leptomeningeal metastases. A CT/MRI scan should be performed if there is any clinical evidence of brain metastases.
10) 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.
11) Active HIV, chronic hepatitis B or C infection.
12) Patients of childbearing potential (defined as < 2 years after last menstruation and having an intact reproductive system), not willing to consistently and correctly use a contraceptive method according to ICH (M3) resulting in low failure rate, i.e. less than 1% per year such as oral contraceptives or use of effective means of contraception (intrauterine contraceptive device, barrier method of contraception in conjunction with spermicidal gel).
13) Pregnancy or lactation. Serum pregnancy test to be performed within 7 days prior to study treatment start in patients of childbearing potential.
14) Major surgical procedure within 28 days prior to the first study treatment.
15) Uncontrolled sustained hypertension (systolic > 180 mm Hg and/or diastolic > 110mm Hg).
16) 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;
17) History of severe bronchial asthma and/or severe allergy.
18) Evidence of any other medical conditions (such as psychiatric illness, infectious diseases, auto-immune diseases) that may interfere with the planned treatment, affect patient compliance or place the patient at high risk from treatment-related complications.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Safety will be determined by the incidence rate at each dose level based on the following safety parameters: adverse events (AE) and serious adverse events (SAEs), changes in haematology and chemistry values, including those associated with hepatic and renal function, and assessment of physical examinations, vital signs and performance status. NCI-CTCAE version 4.0 will be used.
The safety profile of ISA101b in the bridging cohort(s) will be qualitatively compared to the safety profile observed at the same dose level(s) of ISA101.
HPV-specific immune responses: HPV-specific immune responses to the ISA101 vaccine with or without pegylated IFNα in combination with carboplatin and paclitaxel will be determined by the quality, breadth and magnitude of the HPV16 E6/E7-specific T-cell responses as measured by a validated assay (IFNγ-ELISPOT) following injection of the different doses of the ISA101 vaccine.
The HPV-specific immune responses to ISA101b in the bridging cohort(s) will be qualitatively compared to the responses observed at the same dose level(s) of ISA101.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| during 18 weeks of duration of treatment |
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| E.5.2 | Secondary end point(s) |
Antitumor efficacy according to RECIST 1.1:
o Objective Response Rate (ORR) will be calculated as the proportion of patients with a best overall response of confirmed Complete Response (CR) or Partial Response (PR).
o Disease Control Rate (DCR) will be calculated as the proportion of patients with a best overall response of confirmed CR, PR or Stable Disease (SD).
o Progression Free Survival (PFS) is defined as the time from start of carboplatin and paclitaxel (with or without bevacizumab) treatment to the documented progression or death from any cause
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| At 9 weeks, 18 weeks, and a follow up at 30 weeks, 42 weeks and 52 weeks excluding patients with confirmation of progressive disease |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Assessment of HPV-specific immune responses |
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| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 11 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
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