A Single-Arm, Open-Label Phase II Study of ONC201 in Recurrent/Refractory Metastatic Breast Cancer and Advanced Endometrial Carcinoma

Abstract

Background: ONC201 is a small molecule that can cause nonapoptotic cell death through loss of mitochondrial function. Results from the phase I/II trials of ONC201 in patients with refractory solid tumors demonstrated tumor responses and prolonged stable disease in some patients.

Methods: This single-arm, open-label, phase II clinical trial evaluated the efficacy of ONC201 at the recommended phase II dose (RP2D) in patients with recurrent or refractory metastatic breast or endometrial cancer. Fresh tissue biopsies and blood were collected at baseline and at cycle 2 day 2 for correlative studies.

Results: Twenty-two patients were enrolled; 10 patients with endometrial cancer, 7 patients with hormone receptor-positive breast cancer, and 5 patients with triple-negative breast cancer. The overall response rate was 0%, and the clinical benefit rate, defined by complete response (CR) + partial response (PR) + stable disease (SD), was 27% (n = 3/11). All patients experienced an adverse event (AE), which was primarily low grade. Grade 3 AEs occurred in 4 patients; no grade 4 AEs occurred. Tumor biopsies did not show that ONC201 consistently induced mitochondrial damage or alterations in tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or the TRAIL death receptors. ONC201 treatment caused alterations in peripheral immune cell subsets.

Conclusion: ONC201 monotherapy did not induce objective responses in recurrent or refractory metastatic breast or endometrial cancer at the RP2D dose of 625 mg weekly but had an acceptable safety profile (ClinicalTrials.gov Identifier: NCT03394027).

Keywords: ONC201; breast cancer; clinical trial; endometrial cancer; phase II.

Figure 1

(A) Progression-free survival. (B) Response by RECIST v1.1. (C) Duration of ONC201 treatment. (D) Patients whose biopsy samples compared between cycle 1 day1 and Cycle 2 Day 28. (E) Representative images showing intact, partially damaged, and severely damaged mitochondria. Intact mitochondria was from Pt #1 (cycle 1 day 1, 10000×), partially damaged mitochondria Pt #1(cycle 2 day 28, 10000×), severely damaged mitochondria Pt #3 (Cycle 1 Day 1, 5000×). (F) Mitochondrial structural analysis by electron microscopy images. (G) mtDNA copy number qPCR. (H) Immunobloting analysis of Tfam and Tufm normalized with actin as an internal control. (I) qPCR analysis of TRAIL,DR4, DR5 and ATF4, and DDIT3, normalized with GAPDH. ATF4, activating transcription factor 4; DR, death receptor; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; mtDNA, mitochondrial DNA; N.D., not determined due to no detectable amplification;qPCR, quantitative polymerase chain reaction; RECIST, Response Evaluation Criteria in Solid Tumors; TRAIL, tumor necrosis factor-related apoptosis-inducing ligand.

Figure 2.

(A) Natural killer cells did not change significantly at C2D1 and C3D1. (B) Naïve cells were increased and effector memory (EM)1 and EM4 cells were decreased among total peripheral CD4+ T cells (*P < .05; **P < .005). (C) Activated (HLA-DR+ or PD-1+ or ICOS+) and proliferating (Ki67+) cells were decreased among total peripheral CD4+ T cells. (D) CTLA4 expression on peripheral CD4+ T cells was increased.