Study Design for the Phase III GLORIA Trial of OBI-822/OBI-821 Vaccine Combination

The study design for the ongoing phase III GLORIA trial of patients with early-stage triple negative breast cancer evaluating adagloxad simolenin (OBI-822) administered with the saponin adjuvant OBI-821 as a therapeutic vaccine targeting the antigen Globo H ceramide was detailed at the 37th Annual Miami Breast Cancer Conference, held from March 3-9, in Miami, Florida. 

The goal of the study is to determine the effect of the combination vaccine treatment on improving invasive disease-free survival (IDFS) in the study population and determining the impact of OBI-822/OBI-821 in triple negative breast cancer patients at high risk for relapse on overall survival (OS) and quality of life (QoL). 

“This is quite a long-term study, so it could take 4 or 5 years for us to really understand what’s going on here,” said Neil Matheson of OBI Pharma, Inc. “But I think that the idea of using the body’s own immune system to fight the cancer is not a new concept, but the problem is a lot of therapeutic vaccines that have been developed have not really delivered the promise.”

The rationale for the design was based on results from phase I and II trials which informed the selection of patient population that would likely respond to vaccine therapy with the combination of OBI-822 and OBI-821. In the randomized phase II study, which helped inform the design, patients had metastatic disease and a broad range of breast tumor subtypes (HR-positive/HER2-negative, triple negative, and HER2-positive). Additionally, the patients had received up to 2 prior therapies and there was no requirement for Globo H expression. 

No differences were observed in the primary endpoint of progression-free survival. Immunoglobin M (IgM) and immunoglobin G (IgG) responses were observed with mean IgM titer peak at about 4 weeks and mean IgG titer peak at around 40 weeks. A post hoc analysis showed that patients were more likely to develop an effective anti-Globo H IgG ≥ 1:160 if they had no progression after a diagnosis of metastatic disease, complete response status at randomization, and ER+ disease. 

Patients treated with the combination with an IgG titer 1:160 at any time during the study treatment (n = 112) saw an improved median PFS (P = 0.02). Post hoc analysis also indicated that 104 patients who received all 9 planned injections of OBI-822/OBI-821 had a trend for superior PFS compared with 64 placebo patients who received all 9 planned doses (P = 0.06).

Notably, not unlike the findings observed with checkpoint inhibitors in triple negative breast cancer, low disease burden and longer duration of therapy appeared to correlate with response to therapy.

“I think the thing that physician’s will be interested in is that this is likely to be used in combination with other treatments,” said Matheson. “So, by stimulating the immune system you then allow other treatments to work better as well.” 

Beyond the safety, efficacy, and QoL in the ongoing phase III GLORIA study, exploratory endpoints will assess the relationship between aberrant Globo H expression and baseline characteristics, including tumor pathology and immune factors. 

The authors indicated that, assuming they will observe a treatment effect with a hazard ratio of 0.66 in the final analysis, a total of 187 endpoint events (invasive disease recurrence or death) will be required to detect a treatment difference with 80% power. Moreover, to reach the 187 endpoint errors, it was estimated that 668 subjects will be randomized at a ratio of 1:1 to OBI-822/OBI-821 (n = 334) and placebo (n =334) treatment groups, assuming an improvement of IDFS is shown at 3 years with 65% in the placebo group to 75% in the combination vaccine group (i.e. HR = 0.66), 2 years of enrollment, and at least 3 years of IDFS follow-up (i.e. a maximum of 5 years of IFS follow-up). A drop-out rate of 15% was accounted for in this estimation.

The global study is currently enrolling, with 35 patients enrolled thus far.

Reference:

Rugo HS, Chow L, Cortes J, et al. Phase 3, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of adagloxad simolenin (OBI-822) and OBI-821 treatment in patients with early-stage triple-negative breast cancer (TNBC) at high risk for recurrence. Presented at the 37th Annual Miami Breast Cancer Conference, held March 5-8, 2020 in Miami, Florida. Poster 10.