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
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
Interventions
| Drug | Synonyms | Arms |
|---|
| W_ova1 Vaccine | | Treatment 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
| Name | Type | Description | Interventions |
|---|
| Treatment arm | Experimental | Patients will receive 8 W_ova1 vaccinations before and during neoadjuvant chemotherapy and adjuvant chemotherapy. | |
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
May 14, 2021
