Date: 2016-06-06
Type of information: Presentation of results at a congress
phase: 1-2a
Announcement: presentation of results at the American Society of Clinical Oncology (ASCO) annual meeting, in Chicago
Company: Galena Biopharma (USA - OR)
Product: GALE-301 GALE-302 (Folate Binding Protein (FBP))
Action
mechanism: peptide/immunotherapy product. GALE-301 and GALE-302 are cancer immunotherapies that consist of a peptide derived from Folate Binding Protein (FBP) combined with the immune adjuvant, granulocyte macrophage-colony stimulating factor (GM-CSF) for the prevention of cancer recurrence in the adjuvant setting. GALE-301 is the E39 peptide, while GALE-302 is an attenuated version of this peptide, known as E39’. FBP is a well-validated therapeutic target that is highly over-expressed in ovarian, endometrial and breast cancers, and is the source of immunogenic peptides that can stimulate cytotoxic T lymphocytes (CTLs) to recognize and destroy FBP-expressing cancer cells.
Disease: ovarian cancer, endometrial cancer
Therapeutic area: Cancer - Oncology
Country: USA
Trial
details: Folate binding protein (FBP) is highly over-expressed in breast, ovarian and endometrial cancers and is the source of immunogenic peptides (E39) that can stimulate cytotoxic T lymphocytes (CTL) to recognize and destroy FBP-expressing cancer cells in the laboratory. The purpose of this study is to test whether a peptide-based vaccine consisting of the E39 peptide mixed with immunoadjuvant granulocyte macrophage colony-stimulating factor (GM-CSF) is safe and effective at inducing an in vivo peptide-specific immune response. Furthermore, the investigators intend to determine the best dose of the vaccine to utilize to produce this immunity most efficiently. The investigators will determine whether immunity to FBP will prevent clinical recurrence. Additionally, the investigators will compare these results with results from a trial utilizing the E75 peptide (from the HER2/neu protein) in ovarian and endometrial cancer patients in preparation for studying a combination vaccine. (NCT01580696)
Latest
news: * On June 6, 2016, Galena Biopharma announced the primary analysis from the Company’s GALE-301 Phase 1/2a clinical trial at the American Society of Clinical Oncology Annual Meeting 2016. GALE-301 is a cancer immunotherapy consisting of a peptide derived from Folate Binding Protein (FBP) combined with the immune adjuvant, granulocyte macrophage-colony stimulating factor (GM-CSF) for the prevention of cancer recurrence in ovarian and endometrial cancer patients in the adjuvant setting. * On April 19, 2016, Galena Biopharma announced that data from the booster phase of GALE-301/GALE-302 Phase 1/2a clinical trial was presented at the American Association for Cancer Research (AACR) Annual Meeting. The poster, entitled, “Comparing an attenuated booster (E39’) vs. E39 booster to potentiate the clinical benefit of the folate binding protein (FBP)-derived vaccine (E39 + GM-CSF) in a phase I/IIa trial to prevent recurrence in endometrial (EC) and ovarian cancer (OC) patients,” was presented by Dr. Doreen Jackson from the San Antonio Military Medical Center . In the Phase 2a portion of the trial, patients were randomized to two different boosters: E39 (GALE-301), versus E39’ (GALE-302). The purpose of the study was to evaluate the immune responses and determine which booster, if either, would provide a sustained immune response and potentially longer disease free survival (DFS) rates. * On September 28, 2015, Galena Biopharma announced that data from the GALE-301 Phase 2a portion of the Phase 1/2a clinical trial was presented at the European Cancer Congress 2015 in Vienna, Austria. GALE-301 is Galena's cancer immunotherapy that consists of a peptide (E39) derived from Folate Binding Protein (FBP). GALE-301 is combined with the immune adjuvant, granulocyte macrophage-colony stimulating factor (GM-CSF) and administered via intradermal injection for the prevention of recurrence in ovarian and endometrial cancers. * On May 27, 2015, Galena Biopharma announced abstract publication on the preliminary results of the phase 1-2a dose finding study of GALE-301 at the American Society of Clinical Oncology (ASCO) 2015 Annual Meeting. GALE-301 (E39) is a cancer immunotherapy targeting folate binding protein receptor-alpha to prevent ovarian and endometrial cancer recurrence in the adjuvant setting. In abstract #e14031, entitled, "Preliminary Results of the Phase I/IIa Dose Finding Trial of a Folate Binding Protein Vaccine (E39+GM-CSF) in Ovarian and Endometrial Cancer Patients to Prevent Recurrence," data show that GALE-301 is well tolerated and elicits a strong and dose-dependent in vivo immune response. The trial is designed as a safety and dose optimization trial and is not powered for a disease free survival efficacy endpoint. However, early efficacy results from the trial are promising in the 1000 mcg dose cohort. Of the 51 patients enrolled in the trial, 29 were in the vaccinated group (15 patients at 1000 mcg vs. 14 patients at < 1000 mcg) and 22 were in the control group. With 9.8 months median follow-up, the 1000 mcg dose group had only one clinical recurrence vs 11 in the vaccine group (6.7% vs. 50% CG, p = 0.01). Combining all dose groups, the complete response (CR) rate was 38% in the vaccine group vs. 50% in the control group (p = 0.41). Currently, the estimate for disease free survival at two years is 85.7% (1000 mcg dose group) vs. 19.2% for the control group (p = 0.09), for a 78% reduction in relative risk of recurrence. The full abstract can be found here. Galena has completed enrollment in this Phase 2a trial with GALE-301 in two gynecological cancers: ovarian cancer and endometrial adenocarcinomas.
The poster, entitled, “The primary analysis of a phase I/IIa dose finding trial of a folate binding protein vaccine, E39 + GM-CSF in ovarian and endometrial cancer patients to prevent recurrence,” demonstrated that the vaccine is well tolerated and immunogenic. In the optimal dose group, the results demonstrate potential clinical benefit for GALE-301 to prevent recurrence in these patients, and that boosters may sustain this effect.
The Phase 1/2a trial began as a dose-escalation Phase 1 trial, transitioning to a Phase 2a comparing expanded dose cohorts with a total of 51 patients enrolled, n=29 in the vaccine group (VG) and n=22 in the control group (CG). After a median follow-up of 16 months, the overall recurrence rate was 44.8% in the VG versus 54.5% in the CG (p=0.58), with a recurrence rate of only 23.5% in those patients who received booster inoculations. The estimated two-year disease free survival (DFS) is 46.3% in the VG versus 38.1% in the CG (p=0.36). Importantly, in the optimally dosed group (OPT) that received the primary vaccine series (PVS) with 1000 mcg of peptide, there was a significant survival benefit with the estimated 2-year DFS at 73.5% in the VG (n=15), versus 38.1% in the CG (n=22) (p=0.03).
Of the 51 patients, all entered the trial with no evidence of disease with 40 enrolled after completion of standard of care treatment for their primary diagnosis and 11 after completion of standard of care treatment for the recurrence of their disease. A further subset analysis was completed comparing the DFS of patients with primary or recurrent disease at enrollment. The survival benefit observed in the optimally dosed group persisted in the primary disease patients (DFS: OPT 66.7% versus CG 36.7%, p=0.02) but not in the recurrent patients (DFS: OPT 33.3% versus CG 22.2%, p=0.96).
In the Phase 1/2a trial, HLA-A2 positive patients were vaccinated and HLA-A2 negative patients were prospectively followed as a control group. The VG received six monthly inoculations of E39 + 250 mcg GM-CSF as the PVS, followed by two boosters every six months. Of the 29 vaccinated patients, 24 completed the PVS, 17 received one booster, and 14 received two boosters. There were no clinicopathologic differences between groups with primarily grade 1 and grade 2 toxicities. The three most common toxicities were injection site erythema, skin induration and pruritus, which occurred in all vaccinated patients. Immunologic evaluation was performed as a delayed type hypersensitivity (DTH) reaction pre- and post- PVS. Overall, DTH increased pre- to post-PVS in vaccinated patients (5.9+1.5 mm vs 11.7+3.2 mm, p=0.07), with a larger increase seen in the optimally dosed patients (3.8+2.0 mm vs 9.5+3.5 mm, p=0.07) versus those not optimally dosed (7.8+2.1 mm v 11+5.0 mm, p=0.24). Demographic, safety, immunologic, and recurrence data were collected and analyzed using the appropriate statistical tests.
The use of the wildtype peptide (GALE-301/E39) demonstrated the same tolerable safety profile as the attenuated peptide (GALE-302/E39’) with only Grade 1 local reactions and minimal Grade 2 toxicities. Importantly, the percentage of patients who received two booster inoculations and remained disease free was significantly better in the drug treatment arm, versus the control arm (p=0.02), regardless of which booster was used. At median follow up of 16 months, the boosters demonstrated equivalent efficacy after two booster inoculations with an estimated, two-year DFS rate of 66.7% (GALE-301 n=7, GALE-302 n=7) in each booster arm versus 36% (n=22) in the control arm.
A total of 51 patients were enrolled in the Phase 1/2a trial with 29 HLA-A2-positive patients in the vaccine group (VG) and 22 HLA-A2-negative patients in the control group (CG). Six monthly intradermal inoculations of GALE-301 plus 250mcg GM-CSF were administered to the VG to complete the primary vaccine series (PVS). Patients were then randomized to receive two booster inoculations of 500mcg of GALE-301 or GALE-302 plus 250mcg GM-CSF at six and twelve months post-PVS. Seventeen patients continued onto the booster series and were randomized with 14 receiving two boosters. There were no significant demographic or baseline differences between groups, no difference in toxicities were observed, and there were no Grade 3 or 4 toxicities in either group.
Poster #P427 (abstract #2764), entitled "Preliminary results of the phase I/IIa dose finding trial of a folate binding protein vaccine GALE-301 (E39) + GM-CSF in ovarian and endometrial cancer patients to prevent recurrence," provided updated data for all patients who have received at least twelve months of treatment. As presented, the clinical recurrence rate based on all treatment cohorts was 41% in the Vaccine Group (VG) (n=29) versus 55% in the Control Group (CG) (n=22), p=0.41. However, in the 1000 mcg VG cohort (n=15), there have only been two clinical recurrences (13.3% versus 55% CG, p=0.02), and the two-year Disease Free Survival (DFS) estimate is 85.7% (1000 mcg patients) versus 33.6% (CG), p < 0.02, as compared by Kaplan-Meir and Log rank tests.
Based on these data, BergenBio intends to meet with the FDA to discuss a potential path forward to move GALE-301 into a prospective, randomized trial in ovarian and endometrial cancer patients to prevent recurrence.
The clinical trial program for GALE-301 began as a Phase 1 3x3, safety and dose-escalation (100, 500, 1000 mcg of E39) trial and transitioned to a Phase 2a, expanding the optimal dose cohort. Disease-free endometrial and ovarian cancer patients were enrolled after receiving their standard of care therapy. HLA-A2+ patients were vaccinated (VG), and HLA-A2- patients followed prospectively as a CG. Six monthly intradermal inoculations of GALE-301 (E39) + 250 mcg GM-CSF were administered followed by two boosters, one every six months. A total of 51 patients were enrolled: 29 VG and 22 CG. Of the 29 VG patients, 15 received the optimal dose of 1000 mcg, and 14 patients received a suboptimal dose of less than 1000 mcg.
