Dataset Information

A phase I study of combined trabectedin and pegylated liposomal doxorubicin therapy for advanced relapsed ovarian cancer.

ABSTRACT:

Background

Advanced relapsed ovarian cancer has a poor prognosis, and treatment options are limited.

Methods

This phase I trial investigated the dosage, safety, pharmacokinetics and efficacy of trabectedin plus pegylated liposomal doxorubicin (PLD) in Japanese patients with advanced relapsed ovarian, fallopian tube, or primary peritoneal cancer. Patients received trabectedin 0.9 or 1.1 mg/m² immediately after PLD 30 mg/m²; both drugs were given by intravenous infusion. Treatment was repeated every 21 days until disease progression or unacceptable toxicity. The maximum tolerated dose (MTD) was determined in an initial dose escalation phase, and this was used in a subsequent safety assessment phase. Safety and tumor response were monitored throughout the trial, and drug concentrations for pharmacokinetic analysis were measured during cycle 1.

Results

Eighteen patients were included. The MTD of trabectedin was determined as 1.1 mg/m². Gastrointestinal adverse events were experienced by all patients, but were mostly grade 1 or 2 in intensity. Most patients had grade ≥ 3 elevations in transaminase levels or grade ≥ 3 reductions in neutrophil count, but these events were generally manageable through dose reduction and/or supportive therapies, as appropriate. There were no deaths during the trial. Trabectedin exposure increased in a dose-dependent manner. The overall response rate was 27.8%.

Conclusions

Trabectedin, in combination with PLD, may have clinical benefits in Japanese patients with relapsed advanced ovarian cancer. The recommended dosage of trabectedin for further study in this population is 1.1 mg/m² once every 21 days.

Clinical trial registration number

JapicCTI-163164.

SUBMITTER: Takahashi S

PROVIDER: S-EPMC8449774 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundIn recent years, pegylated liposomal doxorubicin (PLD) has been widely used to improve the survival of patients with ovarian cancer; however, it is unclear whether the combinational use of PLD with other drugs is more effective. Therefore, this meta-analysis aimed to confirm the efficacy and safety of trabectedin, combined with PLD, in the treatment of recurrent ovarian cancer.MethodsData corresponding to all eligible clinical trials as of May 15, 2022, was retrieved using several electronic retrieval databases including PubMed, Medical Literature Analysis and Retrieval System Online (MEDLINE), ClinicalTrials.gov, Excerpta Medica Database (EMBASE) and Cochrane Library clinical controlled trials (CENTRAL). Comprehensive hazard ratios (HRs), risk ratios (RRs), and 95% confidence intervals (CIs) were calculated using the Review Manager software 5.4 (RevMan 5.4).ResultsFrom two phase III randomized controlled trials, 1248 patients with recurrent ovarian cancer were included in this meta-analysis. Results of meta-analysis revealed that trabectedin, combined with PLD chemotherapy, significantly improved overall survival (OS) in patients with BReast CAncer gene (BRCA)-associated recurrence (HR, 0.49; 95% CI, [0.33-0.73]; P = 0.0004) and platinum-sensitive recurrence whose platinum-free interval (PFI) was 6-12 months (HR, 0.66; 95% CI, [0.52-0.84]; P = 0.0005). In addition, compared with PLD alone, combination therapy significantly improved the progression-free survival (PFS) in patients with recurrent ovarian cancer (HR, 0.86; 95% CI, [0.74-0.99]; P = 0.03). Combination therapy also significantly improved PFS in patients with BRCA-associated recurrence (HR, 0.58; 95% CI, [0.40-0.58]; P = 0.004), and platinum-sensitive recurrence (HR, 0.73; 95% CI, [0.56-0.95]; P = 0.02). Trabectedin combined with PLD was more prone to grade 3-4 toxic side effects than PLD alone (P < 0.05); however, fatal adverse events related to non-toxic side effects occurred.ConclusionTrabectedin combined with PLD significantly improves OS and PFS in patients with BRCA-associated and platinum-sensitive recurrent ovarian cancers. The potential use of trabectedin combined with PLD should be selected according to the PFI and BRCA mutation status of patients.

Project description:PurposeThe noninterventional, prospective NIMES-ROC phase IV study (NCT02825420) evaluated trabectedin plus pegylated liposomal doxorubicin (PLD) in real-life clinical practice.Patients and methodsEligible participants included adults with platinum-sensitive recurrent ovarian cancer (PS-ROC) who had received one or more cycles of trabectedin/PLD before inclusion according to the marketing authorization. The primary endpoint was progression-free survival (PFS) according to investigator criteria.ResultsTwo hundred eighteen patients from five European countries were evaluated, 72.5% of whom were pretreated with at least two prior chemotherapy lines and received a median of six cycles of trabectedin/PLD (range: 1-24). Median PFS was 9.46 months (95% confidence interval [CI], 7.9-10.9), and median overall survival (OS) was 23.56 months (95% CI, 18.1-34.1). Patients not pretreated with an antiangiogenic drug obtained larger median PFS (p < .007) and OS (p < .048), largely owning to differences between the two populations. Twenty-four patients (11.0%) had a complete response, and 57 patients (26.1%) achieved a partial response for an objective response rate (ORR) of 37.2%. Fifty-nine patients (27.1%) had disease stabilization for a disease control rate of 64.2%. No statistically significant difference in PFS, OS, or ORR was observed by BRCA1/2 status and platinum sensitivity. Most common grade 3/4 adverse events (AEs) were neutropenia (30.3%), anemia (6.4%), thrombocytopenia (5.5%), and asthenia (5.0%). No deaths attributed to treatment-related AEs or unexpected AEs occurred.ConclusionThe combination of trabectedin/PLD represents a clinically meaningful and safe option for patients with PS-ROC regardless of prior treatment with an antiangiogenic drug, being comparable with previously observed outcomes in selected and less pretreated patients from clinical trials.Implications for practiceThis noninterventional, prospective study, conducted in 57 reference sites across Europe, consistently confirmed that trabectedin plus pegylated liposomal doxorubicin (PLD) in routine clinical practice represents a clinically meaningful and safe option for women with platinum-sensitive recurrent ovarian cancer. Although the study population represented a heterogeneous, older, and more pretreated population than those in prospective clinical trials, the combination of trabectedin plus PLD induced comparable clinical benefits, with a similar and manageable safety profile. Overall, these findings show that trabectedin in combination with PLD maintains antitumor activity when administered to heavily pretreated patients in real-life clinical practice.