Clinical Trials /

Ovarian Cancer Treatment With a Liposome Formulated mRNA Vaccine in Combination With (Neo-)Adjuvant Chemotherapy

NCT04163094

Description:

This is a first-in-human, open label phase I study in ovarian cancer patients with primary disease eligible for standard-of-care treatment with neo-adjuvant chemotherapy, i.e. 3 cycles carboplatin/paclitaxel, interval surgery and 3 additional cycles carboplatin/paclitaxel. Eight doses of the W_ova1 vaccine will be administered prior and in combination with the (neo-)adjuvant chemotherapy to induce an anti-tumor immune response. Systemic immune responses are determined using peripheral blood mononuclear cells collected before, during and after vaccinations. Intratumoral accumulation of T-cells recognizing vaccine-encoded TAAs will be determined before vaccination in a tumor biopsy and after the 3 cycles of chemotherapy and the 5th vaccination using tumor tissue derived from interval surgery. [18F]FB-IL2 PET-CT will be used for the non-invasive assessment of T-cell activation and correlated to immunohistochemistry tumor tissue data from pre-treatment biopsy and interval debulking surgery

Related Conditions:
  • Ovarian Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Ovarian Cancer Treatment With a Liposome Formulated mRNA Vaccine in Combination With (Neo-)Adjuvant Chemotherapy
  • Official Title: Ovarian Cancer Treatment With a Liposome Formulated mRNA Vaccine in Combination With (Neo-)Adjuvant Chemotherapy

Clinical Trial IDs

  • ORG STUDY ID: OLIVIA-UMCG-01
  • SECONDARY ID: 2017-004585-10
  • NCT ID: NCT04163094

Conditions

  • Ovarian Cancer

Interventions

DrugSynonymsArms
W_ova1 VaccineTreatment arm

Purpose

This is a first-in-human, open label phase I study in ovarian cancer patients with primary disease eligible for standard-of-care treatment with neo-adjuvant chemotherapy, i.e. 3 cycles carboplatin/paclitaxel, interval surgery and 3 additional cycles carboplatin/paclitaxel. Eight doses of the W_ova1 vaccine will be administered prior and in combination with the (neo-)adjuvant chemotherapy to induce an anti-tumor immune response. Systemic immune responses are determined using peripheral blood mononuclear cells collected before, during and after vaccinations. Intratumoral accumulation of T-cells recognizing vaccine-encoded TAAs will be determined before vaccination in a tumor biopsy and after the 3 cycles of chemotherapy and the 5th vaccination using tumor tissue derived from interval surgery. [18F]FB-IL2 PET-CT will be used for the non-invasive assessment of T-cell activation and correlated to immunohistochemistry tumor tissue data from pre-treatment biopsy and interval debulking surgery

Detailed Description

      This is a first-in-human, open label phase I intra-patient dose escalation study (vaccination
      1 and 2) in OC patients with primary disease eligible for SoC treatment with neo-adjuvant
      chemotherapy, i.e. 3 cycles carboplatin/paclitaxel, interval surgery and 3 additional cycles
      carboplatin/paclitaxel.

      OC patients will be vaccinated prior and during (neo)-adjuvant chemotherapy with the W_ova1
      vaccine, which includes 3 OC TAA RNAs. Vaccines will be administered by means of intravenous
      injection. A total of eight vaccinations will be administered with intra-patient dose
      escalation planned for the first two doses, i.e. the first vaccine will contain 50 µg total
      RNA and the subsequent seven vaccines will contain the target dose of 100 µg total RNA. Dose
      reductions/modifications to 50, 25 and 14.4 µg are allowed per protocol.

      The first two vaccinations will be administered before the start of neo-adjuvant chemotherapy
      with 7 day time lag (+/- 2 days) between each vaccination. The subsequent 6 vaccinations are
      scheduled 15 days (+/- 3 days) after the start of each cycle of chemotherapy to avoid overlap
      with immune-suppressive corticosteroid premedication as well as with the direct effects of
      the chemotherapy. Patient evaluation will be performed before, during and after vaccination,
      including history, physical examination, ECOG performance status and toxicity scoring using
      NCI CTCAE 5.0 toxicity grades. Blood sample collection for bio monitoring by means of a vena
      puncture will occur before each vaccination. During the two-step dose escalation blood
      samples will also be collected 6 hours and 24 hours after vaccination. Blood samples will be
      analyzed for biochemistry, hematology and tumor marker CA-125.

      To determine the systemic immune response (primary objective), PBMCs are obtained by venous
      blood collection at baseline (100 mL) and twice during study related treatment period (60
      mL). In addition, three leukaphereses (or 100 mL blood draw alternatively) and four blood
      draws for ctDNA analysis are scheduled during the trial for each patient.

      To determine the intratumoral immune response (secondary objective), tumor material will be
      collected before vaccination by an image-guided biopsy and during surgery (standard
      treatment).

      The first [18F]FB-IL2 PET-CT (exploratory objective) will occur at baseline and the second
      [18F]FB-IL2 PET-CT as close to the surgery as possible. These study procedures are optional
      and patients can still participate in the trial without the [18F]FB-IL2 PET-CT.

      In case of premature drop-out, patients will be asked to undergo the leukapheresis (or 100 mL
      blood draw alternatively) and if possible / feasible, additional tumor material sampling at
      time of the planned interval surgery.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment armExperimentalPatients will receive 8 W_ova1 vaccinations before and during neoadjuvant chemotherapy and adjuvant chemotherapy.
  • W_ova1 Vaccine

Eligibility Criteria

        Inclusion Criteria:

          -  Primary epithelial OC patients with measurable tumor lesions (determined by CT or
             MRI), who are intended to be treated with neo-adjuvant chemotherapy
             (carboplatin/paclitaxel), subsequent surgery and adjuvant chemotherapy

          -  Age ≥ 18 years

          -  Signed informed consent in accordance with institutional and regulatory guidelines

          -  Adequate access of the tumor for image-guided biopsy

          -  Adequate (according to the institutional standards) hematology, liver and kidney
             function to undergo chemotherapy with carboplatin and paclitaxel

          -  ECOG-performance status of 0 or 1 at screening

          -  Current BMI > 18.5 and no weight loss of >5% over the past month. Notably, weight loss
             due to drainage of ascites is not applicable.

        Exclusion Criteria:

          -  History of a second malignancy except for curatively treated low-stage tumors with a
             histology that can be differentiated from the epithelial OC type

          -  History of an autoimmune disease, specifically HAV, HBV, HCV and HIV, or any other
             systemic intercurrent disease or condition that might affect the immunocompetence of
             the patient, or treatment with systemic highly immunosuppressive therapy (e.g.
             transplant recipients or patients who underwent a splenectomy)

          -  Use of systemic continuous corticosteroid therapy (e.g. prednisone i.v. or p.o. >7.5
             mg / day).

          -  Pregnancy or breast feeding

          -  Participation in a trial with another investigational drug within 30 days prior to the
             enrolment in this trial

          -  Any condition that in the opinion of the investigator could interfere with the conduct
             of the trial.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:N/A
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Change from baseline W_ova1 vaccine antigen-specific T cells in the peripheral blood (systemic induction / expansion of W_ova1 vaccine antigen-specific T cells).
Time Frame:A PBMC collection is planned at baseline, before start treatment. A further PBMC collection is scheduled after 5 vaccinations before surgery. The post-vaccination PBMC collections are scheduled at approx. 14 days and 2.5 months after final vaccination.
Safety Issue:
Description:Number of patients with de novo or increased systemic immune responses (based on the ELISpot Data Analysis Tool 1.0) in the post-vaccination PBMC sample compared to baseline PBMC sample to at least one of the three vaccine antigens

Secondary Outcome Measures

Measure:Change from baseline W_ova1 vaccine antigen-specific T cells in the tumor (Intratumoral induction / expansion of W_ova1 vaccine antigen-specific T cells)
Time Frame:Tumor material is collected at baseline by biopsy and compared to tumor material collected during standard-of-care cytoreductive surgery (mid-vaccination, week 12)
Safety Issue:
Description:Number of patients with a significant increase (p<0.05) in CD8-cell density (CD8-cells / mm2 cancer epithelium [cytokeratin-positive area]) in tumor (pre- and post-treatment biopsy)
Measure:Progression free survival
Time Frame:Up to 2 years from disease diagnosis
Safety Issue:
Description:PFS defined as the number of patients alive without any progress or recurrence (local or regional, or distant) and death due to any cause
Measure:Safety and tolerability of repetitive doses of the W_ova1 vaccine in combination with carboplatin/paclitaxel
Time Frame:Up to 28 days after last vaccination
Safety Issue:
Description:Number of patients with AEs, and SAEs

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University Medical Center Groningen

Last Updated

December 3, 2019