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

Primary Purpose

Cervical Cancer

Status
Completed
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
ISA101/ISA101b
Sponsored by
ISA Pharmaceuticals
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Cervical Cancer focused on measuring Advanced or recurrent cervical cancer, HPV16 positive, No curative treatment options

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)FemaleDoes not accept healthy volunteers

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.

Sites / Locations

  • UZA
  • Chirec Cancer Institute
  • UZG
  • UZL
  • CHU of Liege Site Citadelle
  • Universitätsklinikum Düsseldorf - Frauenklinik
  • Universitätsklinikum Essen - Klinik für Frauenheilkunde
  • Medizinische Hochschule Hannover - Klinik für Frauenheilkunde
  • Universitätsklinikum Heidelberg
  • NKI/AVL
  • AMC
  • UMCG
  • LUMC
  • MUMC
  • Radboud UMC

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

ISA101/ISA101b

Arm Description

The maximum total treatment duration for a patient is six cycles (1 cycle is 21 days) for a total of 18 weeks. On day 15 of cycles 2, 3 and 4 patients are to receive the vaccination scheme of ISA101/ISA101b. Patients will be vaccinated with a fixed dose of ISA101/ISA101b every three weeks for a total of three rounds of vaccination. Four dose levels of ISA101 have been tested. ISA101b will be tested in bridging cohorts.

Outcomes

Primary Outcome Measures

HPV-specific immune responses
HPV-specific immune responses to different doses of the ISA101 vaccine with or without pegylated interferon alpha (INFα) as combination therapy with carboplatin and paclitaxel will be determined. The HPV-specific immune responses to ISA101b will be qualitatively compared to the responses at the same dose level(s) of ISA101.

Secondary Outcome Measures

Evaluate the clinical efficacy by antitumor efficacy according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1

Full Information

First Posted
April 18, 2014
Last Updated
March 5, 2019
Sponsor
ISA Pharmaceuticals
Collaborators
Dutch Cancer Society
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1. Study Identification

Unique Protocol Identification Number
NCT02128126
Brief Title
Study of the Therapeutic Vaccine (ISA101/ISA101b) to Treat Advanced or Recurrent Cervical Cancer
Acronym
CervISA
Official Title
A Multicenter, Open Label Phase I/II Study to Determine the Safety and Immune Modulating Effects of the Therapeutic Human Papilloma Virus 16 (HPV16) E6/E7 Long Peptides Vaccine (ISA101/ISA101b) Immunotherapy in Combination With Standard of Care Therapy (Carboplatin and Paclitaxel With or Without Bevacizumab) in Women With HPV16 Positive Advanced or Recurrent Cervical Cancer Who Have no Curative Treatment Options
Study Type
Interventional

2. Study Status

Record Verification Date
March 2019
Overall Recruitment Status
Completed
Study Start Date
September 2013 (undefined)
Primary Completion Date
August 2018 (Actual)
Study Completion Date
August 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
ISA Pharmaceuticals
Collaborators
Dutch Cancer Society

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.
Detailed Description
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Cervical Cancer
Keywords
Advanced or recurrent cervical cancer, HPV16 positive, No curative treatment options

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
93 (Actual)

8. Arms, Groups, and Interventions

Arm Title
ISA101/ISA101b
Arm Type
Experimental
Arm Description
The maximum total treatment duration for a patient is six cycles (1 cycle is 21 days) for a total of 18 weeks. On day 15 of cycles 2, 3 and 4 patients are to receive the vaccination scheme of ISA101/ISA101b. Patients will be vaccinated with a fixed dose of ISA101/ISA101b every three weeks for a total of three rounds of vaccination. Four dose levels of ISA101 have been tested. ISA101b will be tested in bridging cohorts.
Intervention Type
Drug
Intervention Name(s)
ISA101/ISA101b
Other Intervention Name(s)
HPV Type 16 E6/E7 Synthetic Long Peptides Vaccine
Intervention Description
Four dose levels ISA101/ISA101b
Primary Outcome Measure Information:
Title
HPV-specific immune responses
Description
HPV-specific immune responses to different doses of the ISA101 vaccine with or without pegylated interferon alpha (INFα) as combination therapy with carboplatin and paclitaxel will be determined. The HPV-specific immune responses to ISA101b will be qualitatively compared to the responses at the same dose level(s) of ISA101.
Time Frame
4 months
Secondary Outcome Measure Information:
Title
Evaluate the clinical efficacy by antitumor efficacy according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
Time Frame
one year
Other Pre-specified Outcome Measures:
Title
Evaluate the general responsiveness of the immune system as measured by explorative assays.
Description
General responsiveness of the immune system as measured by explorative assays in particular: Lymphocyte proliferation Antigen Presenting Cell (APC) function tests Assay of myeloid and lymphoid cell composition Recall proliferative responses of Peripheral Blood Mononuclear Cells(PBMCs) in response to common microbial antigens
Time Frame
4 months

10. Eligibility

Sex
Female
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Women ≥ 18 years of age. Cervical cancer confirmed by histology. Advanced or metastatic or recurrent cervical cancer confirmed by clinical and/or radiological proof with no curative treatment options. 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 Tumour must be HPV16 positive. 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. Performance status (WHO scale/ECOG) 1. Written informed consent according to local guidelines. 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: Prior treatment with anti-HPV agents. Chronic systemic steroid use. Local application (i.e. stable doses of topical or inhaled corticosteroids) is allowed. 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. Toxicities resulting from previous anti-cancer therapy must be resolved to ≤ grade 2. Recent treatment (within 30 days of first study treatment) with another investigational drug. Patients with known hypersensitivity to any component of the Investigational Medicinal Product. Any contraindication to the use of authorized applied products (i.e. paclitaxel, carboplatin or bevacizumab). Haematology and biochemistry: 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. 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: Clinical suspicion or radiological evidence of brain or leptomeningeal metastases. 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. Active HIV, chronic hepatitis B or C infection. 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. Pregnancy or lactation. Serum pregnancy test to be performed within 7 days prior to study treatment start in patients of childbearing potential. Major surgical procedure within 28 days prior to the first study treatment. Uncontrolled sustained hypertension (systolic > 180 mm Hg and/or diastolic > 110mm Hg). 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; History of severe bronchial asthma and/or severe allergy. 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Winald Gerritsen, Oncologist
Organizational Affiliation
Radboud University Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
UZA
City
Antwerp
ZIP/Postal Code
2650
Country
Belgium
Facility Name
Chirec Cancer Institute
City
Brussels
ZIP/Postal Code
1180
Country
Belgium
Facility Name
UZG
City
Gent
ZIP/Postal Code
B-9000
Country
Belgium
Facility Name
UZL
City
Leuven
ZIP/Postal Code
3000
Country
Belgium
Facility Name
CHU of Liege Site Citadelle
City
Liege
ZIP/Postal Code
B-4000
Country
Belgium
Facility Name
Universitätsklinikum Düsseldorf - Frauenklinik
City
Düsseldorf
ZIP/Postal Code
40225
Country
Germany
Facility Name
Universitätsklinikum Essen - Klinik für Frauenheilkunde
City
Essen
ZIP/Postal Code
45147
Country
Germany
Facility Name
Medizinische Hochschule Hannover - Klinik für Frauenheilkunde
City
Hannover
ZIP/Postal Code
30625
Country
Germany
Facility Name
Universitätsklinikum Heidelberg
City
Heidelberg
ZIP/Postal Code
69120
Country
Germany
Facility Name
NKI/AVL
City
Amsterdam
ZIP/Postal Code
1066 CX
Country
Netherlands
Facility Name
AMC
City
Amsterdam
ZIP/Postal Code
1105 AZ
Country
Netherlands
Facility Name
UMCG
City
Groningen
ZIP/Postal Code
9713 GZ
Country
Netherlands
Facility Name
LUMC
City
Leiden
ZIP/Postal Code
2333 ZA
Country
Netherlands
Facility Name
MUMC
City
Maastricht
ZIP/Postal Code
6229 HX
Country
Netherlands
Facility Name
Radboud UMC
City
Nijmegen
ZIP/Postal Code
6525 GA
Country
Netherlands

12. IPD Sharing Statement

Citations:
PubMed Identifier
31060612
Citation
Domingos-Pereira S, Galliverti G, Hanahan D, Nardelli-Haefliger D. Carboplatin/paclitaxel, E7-vaccination and intravaginal CpG as tri-therapy towards efficient regression of genital HPV16 tumors. J Immunother Cancer. 2019 May 6;7(1):122. doi: 10.1186/s40425-019-0593-1.
Results Reference
derived

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

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