Abstract
Simple SummarySurvival outcomes with standard cytotoxic chemotherapy are poor, and most patients with ovarian cancer will die with platinum-resistant disease. This may reflect the existence of drug-resistant ovarian cancer stem cells. Cantrixil is a novel third-generation benzopyran molecule, with potent cytotoxicity against chemoresistant ovarian cancer stem cells and chemosensitive ovarian cancer cell lines. The aims of this Phase I study were to define the maximum tolerated dose, tolerability, and antitumor activity of Cantrixil when administered via an intraperitoneal (IP) port. Cantrixil was tolerable even in patients with heavily pretreated disease. This first in-human study has demonstrated the potential for prolonged survival in advanced ovarian cancer by inducing ovarian cancer stem cells’ death and sensitizing cells to standard chemotherapy with IP-administered Cantrixil. Future studies should focus on confirming its mechanism of action alongside further assessment of cancer stem cell biomarkers, and determining optimal clinical settings to maximize survival outcomes in ovarian cancer.Survival outcomes in ovarian cancer are poor. The aims of this Phase I progressive design study (NCT02903771) were to evaluate the maximum tolerated dose (MTD), tolerability, and antitumor activity of Cantrixil—a novel third-generation benzopyran molecule—in patients (n = 25) with advanced, recurrent/persistent epithelial ovarian, primary peritoneal, or fallopian tube cancer. All had completed ≥ 2 prior regimens; 3 (12%) had platinum-refractory disease, and 17 (68%) had platinum-resistant disease. Following intraperitoneal (IP) port placement, patients received weekly IP Cantrixil in 3-week cycles as monotherapy (Cycles 1–2), and then in combination with intravenous (IV) chemotherapy (Cycles 3–8). Part A (dose escalation) enrolled 11 patients in 6 dose-level cohorts. An MTD of 5 mg/kg was established with dose-limiting toxicity of ileus. Most treatment-related adverse events were gastrointestinal. Across Parts A and B (dose expansion), 16 (64%) patients received ≥ 1 3-week Cantrixil cycle, and had ≥ 1 post-baseline efficacy measurement available. The results show promising anti-tumor activity in monotherapy (stable disease rate of 56%) and in combination with IV chemotherapy (objective response rate of 19%, disease control rate of 56%, and median progression-free survival of 13.1 weeks). The molecular target and mechanism of action of Cantrixil are yet to be confirmed. Preliminary analysis of stem cell markers suggests that IP Cantrixil might induce ovarian cancer stem cell death and sensitize cells to standard chemotherapy, warranting further evaluation.
Highlights
Each year over 300,000 people are diagnosed with ovarian cancer [1]
The confirmed overall response rate (ORR) in the efficacyevaluable population was 18.8% and, based on Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 criteria, the median progression-free survival (PFS) was 13.1 weeks
Post-hoc subgroup analysis of efficacy in patients (n = 11) confirmed to have either PFS and the corresponding 2-sided Refractory (Pt-Rf) disease or Pt-R disease showed an improved median PFS of 19.4 weeks, which was further improved to 23.8 weeks in the cohort of three patients with Pt-Rf disease
Summary
Each year over 300,000 people are diagnosed with ovarian cancer [1]. Two-thirds of patients present with advanced disease at diagnosis [2], primarily because early disease is difficult to detect, and is hampered by the non-specific nature of the presenting symptoms and the limitations of current clinical tests [3]. The standard of care for advanced ovarian cancer comprises primary debulking followed by combination chemotherapy using paclitaxel and carboplatin [4,5]. Despite an initial clinical response, approximately 80% of patients experience disease recurrence within 2 years [6]. Include the use of neoadjuvant chemotherapy prior to cytoreduction, use of a variety of different chemotherapy dosing strategies (e.g., weekly paclitaxel with or without weekly carboplatin), and the addition of antiangiogenic drugs (e.g., IV bevacizumab) into first-line treatment, followed by maintenance [7]. While efforts have shown maintenance treatment with poly (ADP-ribose) polymerase (PARP) inhibitors with or without bevacizumab plays a role in prolonging progression-free survival (PFS) in appropriately selected patients, it is not yet clear if this translates to improved overall survival; outcomes remain poor
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