Dataset Information

Efficacy and safety of chiauranib in a combination therapy in platinum-resistant or refractory ovarian cancer: a multicenter, open-label, phase Ib and II study.

ABSTRACT:

Background

Platinum-resistant or refractory ovarian cancer is a highly lethal gynecologic disease with limited treatment options. Chiauranib is a novel small-molecule selective inhibitor, which could effectively target multiple pathways including Aurora B and CSF-1R to inhibit cell cycle process and improve anti-tumor immune function, as long as VEGF pathway for tumor extinction.

Methods

A phase II study was sequentially conducted after a phase Ib monotherapy study to evaluate the efficacy of chiauranib combined with chemotherapy. Chinese patients with recurrent ovarian cancer were enrolled. Eligible patients received chiauranib combined with a maximum of six cycles of chemotherapy: etoposide (CE group) or weekly-paclitaxel (CP group). Patients, who exhibited a complete or partial response, or stable disease following combo treatment, progressed to maintenance phase to receive chiauranib monotherapy. Primary endpoint was progression-free survival (PFS) according to RECIST v1.1.

Results

From November 2017 to March 2019, 25 patients were enrolled in a phase 1b study and a median PFS of 3.7 months (95% CI 1.8-NE) was achieved by chiauranib monotherapy. From July 2019 to December 2020, a total of 47 patients were enrolled in the phase II study. One CP patient did not receive the study drugs, and three patients withdrew before the first tumor assessment. Thus, 43 patients (CE group: 22 patients; CP group: 21 patients) were included in the evaluation. The median PFS was 5·4 months (95% CI 2·8-5·6) and 5·6 months (95% CI 3·4-7·0), respectively.

Conclusions

This was the first study to evaluate chiauranib, a novel multi-targeted kinase inhibitor in patients with ovarian cancer. The administration of chiauranib along with etoposide or weekly-paclitaxel significantly enhanced the efficacy with manageable adverse events. This warrants further clinical studies on this novel treatment. A phase III study is promising and ongoing.

Trial registration

ClinicaTrials.gov identifier: NCT03901118 (phase II) and NCT03166891 (phase Ib).

SUBMITTER: Li J

PROVIDER: S-EPMC11312147 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Efficacy and safety of chiauranib in a combination therapy in platinum-resistant or refractory ovarian cancer: a multicenter, open-label, phase Ib and II study.

Li Jin J Liu Jihong J Yin Rutie R Zou Dongling D Zheng Hong H Cao Junning J Chen Zhendong Z Sun Wei W Gao Yunong Y Zhang Songling S Zeng Linjuan L An Ruifang R Lu Xianping X Ye Shuang S Wu Xiaohua X

Molecular cancer 20240809 1

<h4>Background</h4>Platinum-resistant or refractory ovarian cancer is a highly lethal gynecologic disease with limited treatment options. Chiauranib is a novel small-molecule selective inhibitor, which could effectively target multiple pathways including Aurora B and CSF-1R to inhibit cell cycle process and improve anti-tumor immune function, as long as VEGF pathway for tumor extinction.<h4>Methods</h4>A phase II study was sequentially conducted after a phase Ib monotherapy study to evaluate the ...[more]

PMID: 39123210

Similar Datasets

Project description:BackgroundAdavosertib is a first-in-class, selective small-molecule inhibitor of Wee1. Olaparib is an inhibitor of poly(ADP-ribose) polymerase (PARP). Preclinical data suggest that adavosertib enhances the antitumor effect of PARP inhibitors.ObjectiveThe safety, tolerability, and efficacy of adavosertib plus olaparib were evaluated in patients with refractory solid tumors to define the maximum tolerated dose (MTD) and recommended phase II dose (RP2D).Patients and methodsEligible patients in part A (dose finding) had a refractory solid tumor for which there is no established treatment and had received ≥ 1 prior course of systemic therapy; in part B (dose expansion), patients had platinum-sensitive extensive-stage or relapsed small-cell lung cancer (SCLC). Patients received adavosertib [once (qd) or twice daily (bid)] for 3 consecutive days with 4 days off treatment (3/4), or 5 consecutive days with 2 days off (5/2), plus olaparib (bid) for 14 or 21 days of a 21-day cycle.ResultsA total of 130 patients were enrolled in the study, 120 in part A and 10 in part B. The MTD for adavosertib bid was 175 mg (days 1-3, 8-10/21-day cycle) plus continuous olaparib 200 mg bid; the once-daily MTD (and RP2D) was adavosertib 200 mg (days 1-3, 8-10/21-day cycle) plus continuous olaparib 200 mg bid. In the MTD/RP2D cohort, one patient (7%) experienced a dose-limiting toxicity (DLT) of thrombocytopenia. The most common treatment-related adverse events (TRAEs) in the cohorts in which MTD/RP2D for bid dosing and RP2D for qd dosing were determined were fatigue (64.3% and 15.4%, respectively), diarrhea (42.9% and 30.8%), decreased appetite (35.7% and 23.1%), nausea (35.7% and 15.4%), and anemia (35.7% and 38.5%). In the SCLC dose-expansion cohort, TRAEs occurred in eight patients (88.9%), including thrombocytopenia (66.7%) and anemia (55.6%). In part A, objective response rate (ORR) was 14.8% [95% confidence interval (CI) 8.7-22.9] overall; for the cohorts in which MTD/RP2D for bid dosing and RP2D for qd dosing were determined, ORR was 30.8% (9.1-61.4) and 9.1% (0.2-41.3), respectively. ORR was 11.1% [95% CI 0.3-48.2; one partial response (PR)], disease control rate was 22.2% (2.8-60.0; one PR, one stable disease), and median progression-free survival was 1.5 months (1.3-4.2) in the SCLC dose-expansion cohort.ConclusionsAdverse events and DLTs observed in the bid MTD and once-daily MTD/RP2D dosing schedules were manageable and consistent with known adavosertib and olaparib safety profiles. Limited antitumor activity was observed with adavosertib plus olaparib combination therapy.Trial registrationClinicalTrials.gov, NCT02511795 (registration: 28 July 2015).

Project description:Purpose Seribantumab is a fully human immunoglobulin G2 monoclonal antibody that binds to human epidermal growth factor receptor (HER) 3 (ErbB3), blocking heregulin (HRG) -mediated ErbB3 signaling and inducing ErbB3 receptor downregulation. This open-label randomized phase II study evaluated progression-free survival (PFS) with seribantumab in combination with once-per-week paclitaxel compared with paclitaxel alone in patients with platinum-resistant or -refractory ovarian cancer. A key secondary objective was to determine if any of five prespecified biomarkers predicted benefit from seribantumab. Patients and Methods Patients with platinum-resistant or -refractory epithelial ovarian, fallopian tube, or primary peritoneal cancer were randomly assigned at a ratio of two to one to receive seribantumab plus paclitaxel or paclitaxel alone. Patients underwent pretreatment core needle biopsy; archival tumor samples were also obtained to support biomarker analyses. Results A total of 223 patients were randomly assigned (seribantumab plus paclitaxel, n = 140; paclitaxel alone, n = 83). Median PFS in the unselected intent-to-treat population was 3.75 months with seribantumab plus paclitaxel compared with 3.68 months with paclitaxel alone (hazard ratio [HR], 1.027; 95% CI, 0.741 to 1.425; P = .864). Among patients whose tumors had detectable HRG mRNA and low HER2 (n = 57 [38%] of 151 with available biomarker data), increased treatment benefit was observed in those receiving seribantumab plus paclitaxel compared with paclitaxel alone (PFS HR, 0.37; 95% CI, 0.18 to 0.76; P = .007). The HR in patients not meeting these criteria was 1.80 (95% CI, 1.08 to 2.98; P = .023). Conclusion The addition of seribantumab to paclitaxel did not result in improved PFS in unselected patients. Exploratory analyses suggest that detectable HRG and low HER2, biomarkers that link directly to the mechanism of action of seribantumab, identified patients who might benefit from this combination. Future clinical trials are needed to validate this finding and should preselect for HRG expression and focus on cancers with low HER2 levels.

Project description:PurposeDespite therapeutic advances, outcomes for patients with platinum-resistant/refractory ovarian cancer remain poor. Selective glucocorticoid receptor modulation with relacorilant may restore chemosensitivity and enhance chemotherapy efficacy.MethodsThis three-arm, randomized, controlled, open-label phase II study (ClinicalTrials.gov identifier: NCT03776812) enrolled women with recurrent, platinum-resistant/refractory, high-grade serous or endometrioid epithelial ovarian, primary peritoneal, or fallopian tube cancer, or ovarian carcinosarcoma treated with ≤4 prior chemotherapeutic regimens. Patients were randomly assigned 1:1:1 to (1) nab-paclitaxel (80 mg/m2) + intermittent relacorilant (150 mg the day before, of, and after nab-paclitaxel); (2) nab-paclitaxel (80 mg/m2) + continuous relacorilant (100 mg once daily); or (3) nab-paclitaxel monotherapy (100 mg/m2). Nab-paclitaxel was administered on days 1, 8, and 15 of each 28-day cycle. The primary end point was progression-free survival (PFS) by investigator assessment; objective response rate (ORR), duration of response (DOR), overall survival (OS), and safety were secondary end points.ResultsA total of 178 women were randomly assigned. Intermittent relacorilant + nab-paclitaxel improved PFS (hazard ratio [HR], 0.66; log-rank test P = .038; median follow-up, 11.1 months) and DOR (HR, 0.36; P = .006) versus nab-paclitaxel monotherapy, while ORR was similar across arms. At the preplanned OS analysis (median follow-up, 22.5 months), the OS HR was 0.67 (P = .066) for the intermittent arm versus nab-paclitaxel monotherapy. Continuous relacorilant + nab-paclitaxel showed numerically improved median PFS but did not result in significant improvement over nab-paclitaxel monotherapy. Adverse events were comparable across study arms, with neutropenia, anemia, peripheral neuropathy, and fatigue/asthenia being the most common grade ≥3 adverse events.ConclusionIntermittent relacorilant + nab-paclitaxel improved PFS, DOR, and OS compared with nab-paclitaxel monotherapy. On the basis of protocol-prespecified Hochberg step-up multiplicity adjustment, the primary end point did not reach statistical significance (P < .025). A phase III evaluation of this regimen is underway (ClinicalTrials.gov identifier: NCT05257408).

Project description:ObjectiveManagement of heavily pre-treated platinum-resistant ovarian cancer remains a therapeutic challenge. Outcomes are poor with non-platinum, single-agent chemotherapy (CT); however, molecularly targeted anticancer therapies provide new options.MethodsThis open-label, investigator-initiated, phase 2 umbrella trial (NCT03699449) enrolled patients with platinum-resistant ovarian cancer (at least 2 prior lines of CT and Eastern Cooperative Oncology Group 0/1) to receive combination therapy based on homologous recombination deficiency (HRD) and programmed death ligand 1 (PD-L1) status determined by archival tumour sample assessment. HRD-positive patients were randomised to either olaparib 200mg bid tablet + cediranib 30mg qd (arm 1) or olaparib 300mg bid tablet + durvalumab 1,500mg q4w (arm 2). HRD-negative patients were allocated to either durvalumab 1,500 mg q4w + pegylated liposomal doxorubicin (PLD) or topotecan or weekly paclitaxel (6 cycles; arm 3, those with PD-L1 expression) or durvalumab 1,500 mg q4w + tremelimumab 75mg q4w (4 doses) + PLD or topotecan or weekly paclitaxel (4 cycles; arm 4, those without PD-L1 expression). Arm 5 (durvalumab 1,500 mg q4w + tremelimumab 300mg [1 dose] + weekly paclitaxel [60 mg/m² D1,8,15 q4w for 4 cycles] was initiated after arm 4 completed. The primary endpoint was objective response rate (ORR; Response Evaluation Criteria in Solid Tumours 1.1).ResultsBetween Dec 2018 and Oct 2020, 70 patients (median 57 years; median 3 prior treatment lines [range 2-10]) were treated (n=16, 14, 5, 18, and 17, respectively). Overall ORR was 37.1% (26/70, 95% confidence interval=25.9, 49.5); 2 achieved complete response. ORR was 50%, 42.9%, 20%, 33.3%, and 29.4%, respectively. Grade 3/4 treatment-related adverse events (TRAEs) were reported in 37.5%, 35.7%, 20%, 66.7%, and 35.3% of patients, respectively. No TRAEs leading to treatment discontinuation and no grade 5 TRAEs were observed.ConclusionThis study, the first biomarker-driven umbrella trial in platinum-resistant recurrent ovarian cancer, suggests clinical utility with biomarker-driven targeted therapy. All treatment combinations were manageable, and without unexpected toxicities.Trial registrationClinicalTrials.gov Identifier: NCT03699449.

Dataset Information

Efficacy and safety of chiauranib in a combination therapy in platinum-resistant or refractory ovarian cancer: a multicenter, open-label, phase Ib and II study.

Background

Methods

Results

Conclusions

Trial registration

Publications

Efficacy and safety of chiauranib in a combination therapy in platinum-resistant or refractory ovarian cancer: a multicenter, open-label, phase Ib and II study.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets