BXCL701 Split Dosing Improves Tolerability in Metastatic Castration-Resistant Prostate Cancer

Split-dosing of BXCL701 at 0.6 mg per day is a supported dosing strategy for the agent in combination with pembrolizumab (Keytruda) as treatment of patients with metastatic castration-resistant prostate cancer, according to phase 1b/2 study results.

The findings were presented in a poster during the virtual 27th Annual Prostate Cancer Foundation Scientific Retreat and showed the tolerability of the combination, which was defined by dose-limiting toxicities (DLTs). No DLTs were reported with the split-dose regimen, and lower rates of other toxicities were observed as well in this group. A preliminary evaluation of anti-tumor activity also demonstrated 1 patient had a prostate-specific antigen (PSA) response, while 4 patients had stable disease, which included 1 patient who remained on treatment with a minor response.

BXCL701, the first-in-class oral small molecular inhibitor of dipeptidyl peptides (DPP) DPP8 and DPP9, was designed to trigger inflammasome-mediated pyroptosis to alert and prime adoptive immune cells, which causes induction of IL-18 and IL-1 β and bridges innate and adaptive immunity. This activation of the innate immunity is known to compliment T cells targeting immunotherapy in synergic animal models, and significant responses were observed in the tumor with this agent in combination with checkpoint inhibition.

Although immunotherapy has demonstrated benefit targeting PD-1, such as with the immune checkpoint inhibitor pembrolizumab, many patients with metastatic castration-resistant prostate cancer are resistant to these therapies, whereas single agent response rates have been around 6%. The addition of BXCL701 is expected to manipulate the tumor microenvironment in such a way as to turn a “cold” tumor environment into an inflamed “hot” environment, which should help in overcoming resistance to immunotherapy.

The phase 1B safety lead-in used a standard 3+3 dose-escalation design with an expansion dependent on DLTs. Patients in the phase 1B/2 study were treated in 21-day cycles, in which BXCL701 on twice daily (BID) days 1 -14, and pembrolizumab was administered at 200 mg intravenously on day 1. Overall, 3 patients completed treatment with BXCL701 at 0.4 mg once daily (QD), 3 completed a dose of 0.6 mg QD, and 7 completed 0.6 mg of BXCL701 as a split dose.

The recommended phase 2 dose (RP2D) of BXCL701 was determined to be 0.6 mg in a split dose with 0.3 mg BID. The phase 2 efficacy stage of this study is a Simon 2-stage study and is currently enrolling patients.

The safety results looked at patients in the phase 1B portion treated with the 0.4 mg QD, 0.6 mg QD, and 0.6 mg split dose BXCL701. Serious AEs (SAEs) occurred in 2, 1, and 4 patients, respectively, and treatment-related SAEs occurred in 0, 1, and 1 patients. Treatment-related AEs (TRAEs) that led to treatment discontinuation occurred in 1 patient in the 0.6 mg QD and 0.6 mg split-dose groups each. BXCL701 TRAEs occurred in 3, 3, and 5 patients, and pembrolizumab TRAEs occurred in 2, 2, and 5 patients, respectively.

In terms of both BXCL701 or pembrolizumab TRAEs of grade 3 or higher in severity, non-hematologic events occurred in 2 patients from the 0.6 mg QD group (grade 3 syncope and grade 5 acidosis), and 3 patients from the split dose group (grade 3 fatigue, grade 3 pneumonitis, and grade 3 lactic acid increase). Hematologic events were observed in 3 patients in the 0.4 mg group (grade 3 anemia and grade 4 thrombocytopenia), 1 patient in 0.6 mg QD group (grade 3 Hgb and white blood count increase), and 1 patient in the split-dose group (grade 3 anemia). Only 1 patient in the 0.6 mg QD group had a DLT.

BXCL701 on-target AEs consistent with cytokine activation were observed primarily in the highest doses, whereas none of these events occurred in the 0.4 mg QD level. In the 0.6mg QD group, any grade events included hypertension (n = 3), dizziness (n =2), edema (n = 2), and headache, syncope, dyspnea, fatigue, and chills (n = 1 each), while in the split-dose group, these included fatigue (n = 3), hypertension, dyspnea, chills, and myalgia (n = 1 each). The only grade 3 events included syncope in 1 patient in the QD arm and fatigue in 1 in the split-dose arm.

The levels of Il-18 were generally increased post dose in all cohorts in combination with pembrolizumab, and the 0.6 mg QD combination showed maximum IL-18 levels (45 fold), which clinical findings of URI may have contributed to. The split-dose combination led to consistent increases in IL-18 on day 14 post dose (8-24 fold), and consistent dose and time-dependent increases in IL-18 levels were observed in the split-dose cohort, whereas maximal changes were noted on day 14.

The interim efficacy results demonstrated stable disease in 2 patients in the 0.4 mg QD arm, 1 in the 0.6 mg QD arm, and 1 in the split-dose cohort as the best response. Additionally, 1 patient in the 0.6 mg QD and 2 in the split-dose arms had progressive disease, and 1 and 3 were not evaluable, respectively. The remaining 1 patient in the 0.4 mg QD cohort had a non-complete response/non-partial response.

Patients were required to have received at least 1 prior line of systemic therapy for locally advanced or metastatic prostate cancer, serum testosterone <50 ng/dL during screening (except for patients with de novo small cell prostate cancer), and an ECOG performance status of 0 to 2. In the phase 2 efficacy stage, cohort A included patients who had at least 1 prior line of chemotherapy, and cohort B included patients with at least 1 but no more than 2 androgen-signaling inhibitors (ASIs) and at least 1 prior taxane-containing chemotherapy.

In the phase 1B study, the mean age of patients was 72 years (range, 61-86) in the overall population (n = 13), and the ECOG performance status of 1 in 8 patients and 2 in 5 patients. Prior systemic therapies included any androgen-deprivation therapy (ADT) in 10 patients, first-generation ADT in 6, second-generation ASIs in 9, and chemotherapy and radiotherapy in 11 patients each.

The phase 2 efficacy portion continues to enroll patients to assess the anti-tumor activity of the combination in patients where clinical benefit was limited with checkpoint inhibitor monotherapy.

_Reference

_{O’Neill V, Costin D, Zhang J, et al. Phase 1b results of BXCL701, an IL-18 inducing Innate Immune Activator in combination with pembrolizumab (Keytruda), in patients with metastatic Castration-Resistant Prostate Cancer (mCRPC) including Small Cell/Neuroendocrine Cancer. Presented at 27th Annual PCF Scientific Retreat Virtual Poster Session; Oct 20-23, 2020.}