Interim analysis of a phase I/IIa trial assessing E39+GM-CSF, a folate binding protein vaccine, to prevent recurrence in ovarian and endometrial cancer patients

Abstract

BACKGROUNDFolate binding protein(FBP) is an immunogenic protein over-expressed in endometrial(EC) and ovarian cancer(OC). We are conducting a phase I/IIa trial of E39 (GALE 301)+GM-CSF, an HLA-A2-restricted, FBP-derived peptide vaccine to prevent recurrences in disease-free EC and OC patients. This interim analysis summarizes toxicity, immunologic responses, and clinical outcomes to date.METHODSHLA-A2+ patients were vaccinated(VG), and HLA-A2- or -A2+ patients were followed as controls(CG). Six monthly intradermal inoculations of E39+250mcg GM-CSF were administered to VG. Demographic, safety, immunologic, and recurrence rate(RR) data were collected and evaluated.RESULTSThis trial enrolled 51 patients; 29 in the VG and 22 in the CG. Fifteen patients received 1000mcg E39, and 14 received <1000mcg. There were no clinicopathologic differences between groups(all p = 0.1). E39 was well-tolerated regardless of dose. DTH increased pre- to post-vaccination (5.71.5 mm vs 10.33.0 mm, p = 0.06) in the VG, and increased more in the 1000mcg group (3.82.0 mm vs 9.53.5 mm, p = 0.03). With 12 months median follow-up, the RR was 41% (VG) vs 55% (CG), p = 0.41. Among the 1000mcg patients, the RR was 13.3% vs 55% CG, p = 0.01. Estimated 2-year DFS was 85.7% in the 1000mcg group vs 33.6% in the CG (p = 0.021).CONCLUSIONSThis phase I/IIa trial reveals that E39+GM-CSF is well-tolerated and elicits a strong, dose-dependent in vivo immune response. Early efficacy results are promising in the 1000 mcg dose cohort. This study proves the safety and establishes the dose of E39 for a larger prospective, randomized, controlled trial in HLA-A2+ EC and OC patients to prevent recurrence.

Phase Ib trial of folate binding protein (FBP)-derived peptide vaccines, E39 and an attenuated version, E39’: An analysis of safety and immune response

“…While the E39 peptide was previously shown to be safe and well-tolerated in a trial enrolling patients with ovarian and endometrial cancer, the safety of E39′ inoculations in humans has not been previously demonstrated [10]. In this study, patients receiving E39′ as a component of their PVS experienced only grade 1 and 2 toxicities confirming the safety of this attenuated peptide.…”

“…Interestingly, the indication from these DTH results, that a lower dose of peptide induces a more meaningful immune response, is in contrast with our recently published results from the phase I/IIb trial of the E39 peptide vaccine in patients with endometrial and ovarian cancer where patients receiving a higher vaccine dose demonstrated better clinical outcome [10]. This difference may be related to the differences in patient populations.…”

“…In this study, patients receiving E39′ as a component of their PVS experienced only grade 1 and 2 toxicities confirming the safety of this attenuated peptide. As seen in our previous study evaluating the E39 peptide vaccine, as well as our studies evaluating HER2-derived peptide vaccines, most of the toxicity experienced was skin reactions, to include erythema and pruritus, and mild flu-like symptoms [4–6, 10]. In several of our previous randomized, controlled trials, control patients have received GM-CSF alone, and we have seen similar rates of systemic toxicity between vaccine and control arms, implying that the toxicity from the peptide vaccines is related to the GM-CSF, not the peptide itself [4, 5].…”

“…The E39 (FBP 191–199: EIWTHSYKV) peptide is an immunogenic epitope derived from the FBP protein, which can be administered with an immunoadjuvant (granulocyte macrophage colony stimulating factor [GM-CSF]) as a peptide vaccine (GALE-301). A phase I/IIa trial vaccinating patients with ovarian and endometrial cancer in the adjuvant setting has shown that it is safe, elicits a strong in vivo immune response and has promising clinical efficacy [10]. …”

“…This is, at least in part, due to specific challenges of treating metastatic disease, such as large disease burden and the immunosuppressive tumor microenvironment [12, 13]. Consequently, our group has focused on administering peptide vaccines in the adjuvant, minimal disease setting [4–6, 10]. Even patients rendered disease-free after completion of standard therapies, however, will have some immune tolerance to their tumor and the associated antigens.…”