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Clinical Trial
. 2019 Aug;8(10):4678-4687.
doi: 10.1002/cam4.2378. Epub 2019 Jul 5.

Final analysis of a phase I/IIa trial of the folate-binding protein-derived E39 peptide vaccine to prevent recurrence in ovarian and endometrial cancer patients

Tommy A Brown  1 , Kevin Byrd  2 , Timothy J Vreeland  3 , Guy T Clifton  1 , Doreen O Jackson  1 , Diane F Hale  1 , Garth S Herbert  1 , John W Myers  1 , Julia M Greene  1 , John S Berry  4 , Jonathan Martin  5 , John C Elkas  6   7 , Thomas P Conrads  2   6   8 , Kathleen M Darcy  2 , Chad A Hamilton  2 , George L Maxwel  2   6   8 , George E Peoples  6
Affiliations
Clinical Trial

Final analysis of a phase I/IIa trial of the folate-binding protein-derived E39 peptide vaccine to prevent recurrence in ovarian and endometrial cancer patients

Tommy A Brown et al. Cancer Med. 2019 Aug.

Abstract

Background: E39, an HLA-A2-restricted, immunogenic peptide derived from the folate-binding protein (FBP), is overexpressed in multiple malignancies. We conducted a phase I/IIa trial of the E39 + GM-CSF vaccine with booster inoculations of either E39 or E39' (an attenuated version of E39) to prevent recurrences in disease-free endometrial and ovarian cancer patients(pts). Here, we present the final 24-month landmark analysis.

Patients and methods: HLA-A2 + patients receiving E39 + GM-CSF were included in the vaccine group (VG), and HLA-A2- pts (or HLA-A2 + patients refusing vaccine) were followed as the control group (CG). VG group received 6 monthly inoculations as the primary vaccine series (PVS) and were randomized to receive either E39 or E39' booster inoculations. Demographic, safety, immunologic, and disease-free survival (DFS) data were collected and evaluated.

Results: Fifty-one patients were enrolled; 29 in the VG and 22 in the CG. Fourteen patients received <1000 μg and 15 received 1000 μg of E39. There were no clinicopathologic differences between VG and CG or between dose groups. E39 was well tolerated. At the 24 months landmark, DFS was 55.5% (VG) vs 40.0% (CG), P = 0.339. Patients receiving 1000 μg and boosted patients also showed improved DFS (P < 0.03). DFS was improved in the 1000 μg group after treatment of primary disease (90.0% vs CG:42.9%, P = 0.007), but not in recurrent patients. In low-FBP expressing patients, DFS was 100.0% (1000 μg), 50.0% (<1000 μg), and 25.0% (CG), P = 0.029.

Conclusions: This phase I/IIa trial reveals that E39 + GM-CSF is safe and may be effective in preventing recurrence in high-risk ovarian and endometrial cancer when optimally dosed (1000 μg) to FBP low patients being treated for primary disease.

Keywords: E39; FBP; endometrial cancer; immunotherapy; ovarian cancer; vaccine.

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Conflict of interest statement

Dr George Peoples has partial inventor rights for the E39 and E39′ vaccines. The view(s) expressed herein are those of the author(s) and do not reflect the official policy or position of San Antonio Military Medical Center, the US Army Medical Department, US Air Force Medical Department, the Department of the Army, the Department of Air Force, Department of Defense or the US Government.

Figures

Figure 1
Figure 1
Trial Profile. The final analysis was done on the population as depicted in the consort diagram. HLA‐A2 positive patients were vaccinated while HLA‐A2 negative patients were followed prospectively as controls. The trial initially began as a dose escalation trial with three dosing cohorts. Dosing groups 2 and 3 were expanded. Patients who received <1000 μg per dose (all patients in dosing groups 1 and 2) were compared to those who received 1000 μg per dose (all patients in dosing group 3). All early recurrences occurred in dosing group 2
Figure 2
Figure 2
Maximum local and systemic toxicity experienced during the trial per patient divided by dose. The vaccine well tolerated with a single grade 3 systemic toxicity event
Figure 3
Figure 3
Disease‐fee survival in the (A) overall population, (B) by E39 dosing groups, and by (C) patients who received booster inoculations. Patients had to be disease‐free for 6 months after completion of the primary vaccine series to receive booster inoculations
Figure 4
Figure 4
Disease‐free survival in patients rendered disease‐free from (A) recurrent and (B) primary endometrial or ovarian cancer divided by dosing groups
Figure 5
Figure 5
Disease‐free survival in patients by FBP expression levels. Patients with FBP high cancer did not benefit from vaccination in the (A) overall group or by (B) dosing groups. Vaccinated patients with FBP low cancer demonstrated a significant improvement in 24‐month disease‐free survival in the (C) overall population and by (D) the two dosing groups
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