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A Phase II Clinical Trial of Chemo-radiotherapy in Combination With INO-3112 in Patients With Locally Advanced Cervical Cancer

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ClinicalTrials.gov Identifier: NCT02501278
Recruitment Status : Withdrawn (company (Inovio) is no longer able to support the study)
First Posted : July 17, 2015
Last Update Posted : May 13, 2016
Sponsor:
Collaborators:
Inovio Pharmaceuticals
Centre Hospitalier Universitaire Vaudois
Information provided by (Responsible Party):
European Organisation for Research and Treatment of Cancer - EORTC

Brief Summary:

The aim of this study is to assess the potential benefit of the addition of immunotherapy with VGX-3100 and INO-9012 (i.e. INO-3112) to concomitant CRT or, to concomitant CRT and continued as adjuvant in patients with locally advanced cervical cancer.

Safety run-in: To test the safety of CRT combined with immunotherapy with INO-3112. This safety run-in phase will include the first 3 patients treated in each of the two INO-3112 combination arms who are exposed to at least two immunotherapy doses and evaluate whether the combination does not pose undue immediate risks to the patients further enrolled in the trial.

Phase II:To demonstrate sufficient activity in the experimental combination arms to warrant a further phase III conclusive trial based on progression free survival (PFS) at 18 months assessed by RECIST by the local investigator. The efficacy will be assessed within each experimental arm while the standard arm will serve as a reference arm to check the reliability of the results.


Condition or disease Intervention/treatment Phase
Uterine Cervical Neoplasms Biological: INO-3112 vaccine Radiation: Radiotherapy (Extrernal beam radiotherapy + brachytherapy) Drug: Cisplatin chemotherapy Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 0 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Clinical Trial of Chemo-radiotherapy in Combination With INO-3112 in Patients With Locally Advanced Cervical Cancer
Study Start Date : May 2016
Estimated Primary Completion Date : May 2019
Estimated Study Completion Date : May 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Cervical Cancer

Arm Intervention/treatment
Experimental: Arm A: Immunotherapy during and after CRT + vaccine boost
INO-3112 dosing during chemoradiotherapy plus immunotherapy dosing after chemoradiotherapy in an adjuvant setting and vaccine boost one year after last vaccine dosing.
Biological: INO-3112 vaccine

INO-3112 i.e. the combination of VGX-3100 and INO-9012, specifically:

  • VGX-3100 (HPV16 and HPV18 E6-E7 DNA vaccine) will be administered at 3 mg per plasmid (6 mg total DNA)
  • INO-9012 (IL-12 DNA plasmid) will be administered at 1 mg per dose will be administered using the CELLECTRA® electoporation device

Radiation: Radiotherapy (Extrernal beam radiotherapy + brachytherapy)

The whole pelvis will be irradiated with 45 - 50.4 Gy in 25-28 fractions in fractions of 1.8 Gy over 5 weeks daily.

Those patients with pelvis positive and/or para-aortic positive lymph nodes should be treated with an elective dose to the para-aortic area of 45 Gy in fractions of 1.6-1.8 Gy in 25-28 fractions.

Pelvic and para-aortic nodes known to contain gross/macroscopically visible disease and heavily involved parametria or tumor areas that may lie beyond the high-dose range of brachytherapy should be treated with additional small volume boost of EBRT to a total dose of 60-65 Gy using a combination of either sequential and/or concomitant boost. Fractions of 1.8-2 Gy can be used in the sequential boost.


Drug: Cisplatin chemotherapy
Cisplatin chemotherapy will be administered i.v. at a dose of 40 mg/m2 (total 5 cycles during week 1-5) weekly in concomitance with RT with the total dose not to exceed 70 mg per week.

Experimental: Arm B: Immunotherapy during CRT + vaccine boost
INO-3112 dosing during chemoradiotherapy, and vaccine boost one year after last vaccine dosing.
Biological: INO-3112 vaccine

INO-3112 i.e. the combination of VGX-3100 and INO-9012, specifically:

  • VGX-3100 (HPV16 and HPV18 E6-E7 DNA vaccine) will be administered at 3 mg per plasmid (6 mg total DNA)
  • INO-9012 (IL-12 DNA plasmid) will be administered at 1 mg per dose will be administered using the CELLECTRA® electoporation device

Radiation: Radiotherapy (Extrernal beam radiotherapy + brachytherapy)

The whole pelvis will be irradiated with 45 - 50.4 Gy in 25-28 fractions in fractions of 1.8 Gy over 5 weeks daily.

Those patients with pelvis positive and/or para-aortic positive lymph nodes should be treated with an elective dose to the para-aortic area of 45 Gy in fractions of 1.6-1.8 Gy in 25-28 fractions.

Pelvic and para-aortic nodes known to contain gross/macroscopically visible disease and heavily involved parametria or tumor areas that may lie beyond the high-dose range of brachytherapy should be treated with additional small volume boost of EBRT to a total dose of 60-65 Gy using a combination of either sequential and/or concomitant boost. Fractions of 1.8-2 Gy can be used in the sequential boost.


Drug: Cisplatin chemotherapy
Cisplatin chemotherapy will be administered i.v. at a dose of 40 mg/m2 (total 5 cycles during week 1-5) weekly in concomitance with RT with the total dose not to exceed 70 mg per week.

Active Comparator: CRT without immunotherapy
Standard chemoradiotherapy without immunotherapy
Radiation: Radiotherapy (Extrernal beam radiotherapy + brachytherapy)

The whole pelvis will be irradiated with 45 - 50.4 Gy in 25-28 fractions in fractions of 1.8 Gy over 5 weeks daily.

Those patients with pelvis positive and/or para-aortic positive lymph nodes should be treated with an elective dose to the para-aortic area of 45 Gy in fractions of 1.6-1.8 Gy in 25-28 fractions.

Pelvic and para-aortic nodes known to contain gross/macroscopically visible disease and heavily involved parametria or tumor areas that may lie beyond the high-dose range of brachytherapy should be treated with additional small volume boost of EBRT to a total dose of 60-65 Gy using a combination of either sequential and/or concomitant boost. Fractions of 1.8-2 Gy can be used in the sequential boost.


Drug: Cisplatin chemotherapy
Cisplatin chemotherapy will be administered i.v. at a dose of 40 mg/m2 (total 5 cycles during week 1-5) weekly in concomitance with RT with the total dose not to exceed 70 mg per week.




Primary Outcome Measures :
  1. Occurence of Adverse Events [ Time Frame: 6 months ]

    In order to ensure adequate safety of the combination treatment, a safety run-in will be performed. This safety run-in phase will include the first 3 patients treated in each of the experimental arms (arms A & B) exposed to at least two immunotherapy doses. The acute safety of the combination of INO-3112 with concomitant CRT will be evaluated similar to a phase I "3+3" safety design. The safety evaluation will be done by the Data Safety Monitoring Board who will invoke an IDMC evaluation of the whole study if undue safety signals are observed.

    Acute toxicity is defined as a grade 3 or more related AEs occurring between the first dose of vaccine administration and up to 14 days after the second dose of immunotherapy. Adverse events are graded according to the NCI CTCAE v4.0. Use of narcotics will be reviewed on case-to-case basis by a medical review team to assess its relevance towards the safety evaluation


  2. Progression free survival (PFS) at 18 months assessed by RECIST [ Time Frame: 18 months ]
    Progression Free Survival at 18 months assessed by local investigator



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Main inclusion criteria:

Registration step

  • Age 18 years or older;
  • Newly diagnosed locally advanced cervical cancer defined as FIGO 2009: stage IB2, IIA&IIB, IIIA&IIIB or IVA disease;
  • No evidence of distant metastases (Stage IVB);
  • Histological diagnosis of squamous cell carcinoma, adenocarcinoma or adenosquamous cell carcinoma of the cervix is accepted. Not accepted are small cell, clear cell and other rare variants of the classical adenocarcinoma;
  • Availability of HPV 16 and HPV 18 testing;
  • No HIV seropositive, Hepatitis B or C (unless sustained virologic response achieved by anti-HCV therapy);
  • Written informed consent must be given according to ICH/GCP, and national/local regulations

Randomization step

  • Positive for HPV 16 and/or HPV 18 as assessed by central lab;
  • WHO/ECOG performance status 0 - 2
  • Adequate hematological, liver and renal functions
  • ECG with no clinically significant findings as assessed by the investigator performed within 30 days of signing the informed consent form
  • Absence of current malignancies at other sites, with the exception of adequately treated basal or squamous cell carcinoma of the skin. Cancer survivors, who have undergone potentially curative therapy for a prior malignancy, who have no evidence of that disease for five years and are deemed at low risk for recurrence, are eligible for the study;
  • No prior history of clinically significant autoimmune disease, Crohn's disease, ulcerative colitis;
  • No history of previous therapeutic HPV vaccination (individuals who have been immunized with licensed prophylactic HPV vaccines (e.g. Silgard®, Cervarix®, Gardasil®) are not excluded);
  • No known or suspected hypersensitivity to component(s) of investigational product or cisplatin contraindication (e.g. peripheral neuropathy ≤ grade 2 or ototoxicity ≤ grade 2 as per CTCAE v4);
  • No previous pelvic RT;
  • No previous chemotherapy for this tumor;
  • No patients who have undergone a previous hysterectomy or will have a hysterectomy as part of their initial cervical cancer therapy;
  • No receipt of any immunotherapy within 4 weeks of start of protocol treatment;
  • No prior major surgery within 4 weeks of randomization from which the patient has not recovered.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02501278


Locations
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Switzerland
Centre Hospitalier Universitaire Vaudois
Lausanne, Switzerland
Sponsors and Collaborators
European Organisation for Research and Treatment of Cancer - EORTC
Inovio Pharmaceuticals
Centre Hospitalier Universitaire Vaudois
Investigators
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Study Chair: Fernanda Herrera Centre Hospitalier Universitaire Vaudois - Lausanne
Study Chair: George Coukos Centre Hospitalier Universitaire Vaudois - Lausanne

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Responsible Party: European Organisation for Research and Treatment of Cancer - EORTC
ClinicalTrials.gov Identifier: NCT02501278     History of Changes
Other Study ID Numbers: EORTC-1411
2015-004602-42 ( EudraCT Number )
First Posted: July 17, 2015    Key Record Dates
Last Update Posted: May 13, 2016
Last Verified: May 2016
Additional relevant MeSH terms:
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Uterine Cervical Diseases
Vaccines
Uterine Cervical Neoplasms
Uterine Neoplasms
Genital Neoplasms, Female
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Uterine Diseases
Genital Diseases, Female
Cisplatin
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents