Epithelial ovarian cancer is the most lethal gynecologic malignancy, and most patients eventually relapse and develop resistance to available therapies. Immune checkpoint inhibitors have shown limited overall efficacy in recurrent ovarian cancer, partly because of its immunosuppressive tumor microenvironment. Manganese (Mn2+) can activate the cGAS-STING pathway and may enhance antitumor immunity and the therapeutic effects of PD-1 blockade combined with chemotherapy. Following encouraging findings from an early-phase study, a randomized, single-blind, placebo-controlled phase II trial showed that the addition of manganese chloride to anti-PD-1 antibody, nab-paclitaxel, and cisplatin improved clinical outcomes compared with placebo, with an overall manageable safety profile. Based on these findings, this phase III trial is designed to confirm the efficacy and further evaluate the safety of Mn2+-primed immunochemotherapy in patients with advanced ovarian cancer.
Patients with histologically or cytologically confirmed epithelial ovarian cancer, primary fallopian tube cancer, or peritoneal cancer.
Patients who have received at least two prior lines of systemic therapy, including at least one platinum-based regimen.
Patients who experienced disease progression during or within 6 months after completion of the most recent line of systemic therapy.
Patients with at least one measurable lesion.
Absolute neutrophil count (ANC) < 1×10 /L or platelets < 80×10 /L or hemoglobin < 80 g/dL (according to the normal values of the clinical trial center）.
Serum total bilirubin levels higher than 3 times the upper limit of the reference range.
ALT, AST, or ALP levels higher than 3 times the upper limit of the reference range when there are no liver metastases; ALT, AST, or ALP levels higher than 5 times the upper limit of the reference range when there are liver metastases.
Patients receiving known strong inhibitors (e.g., ketoconazole) or inducers (e.g., rifampicin or St. John's Wort) of CYP3A4, or strong inhibitors (e.g., gemfibrozil) or inducers of CYP2C8; patients receiving treatment with potent P-gp inhibitors or inducers, or patients who cannot stop treatment with these agents for 2 weeks before the start of the study.
Parallel
Manganese Chloride
DrugAdministered by inhalation at 0.4mg/kg twice per week in the first 3-week cycle, and then inhaled 0.4mg/kg twice in the first week of each 3-week cycle thereafter
Nab-paclitaxel
DrugAdministered intravenously, 180-220mg/m2 on day 2 in a 3-week cycle (day 1 without Manganese priming)
Platinum chemotherapy
DrugAdministered intravenously, Cisplatin (60-80mg/m2) or Carboplatin (area under the curve \[AUC\] 4-6 mg/ mL per min) on day 2 in a 3-week cycle (day 1 without Manganese priming)
Anti-PD-1 antibody
DrugAdministered intravenously, 200mg on day 3 in a 3-week cycle (day 2 without Manganese priming)
Placebo
DrugAdministered by inhalation twice per week in the first 3-week cycle, and then inhaled twice in the first week of each 3-week cycle thereafter
Progression-free survival (PFS)
PFS time was measured from study entry to the first documentation of disease progression or death. Disease progression was determined per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
Overall survival (OS)
OS time was measured from the study entry to the date of death.
Object response rate (ORR)
ORR is defined as the proportion of subjects who achieved a partial response (PR) or complete response (CR) according to the RECIST V1.1.
Number of Subjects with treatment-related adverse events (AEs)
Incidence, nature, and severity of adverse events graded according to the NCI CTCAE v5.0. AEs were considered to be treatment-related if they had started or worsened within the interval from first study drug administration until the follow-up visit.
Number of participants with laboratory test abnormalities
The laboratory tests of serum cytokines and chemokines will be performed on day 1 and 3 of each cycle, and the abnormality will be determined by the investigator.
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