Trabectedin Monotherapy Research Articles

Four Cases with FUS/CHOP Fusion Gene Products Positive Myxoid Liposarcoma Responding Effectively to Trabectedin Monotherapy

Four Cases with FUS/CHOP Fusion Gene Products Positive Myxoid Liposarcoma Responding Effectively to Trabectedin Monotherapy

Single-Agent Trabectedin Versus Physician's Choice Chemotherapy in Patients With Recurrent Ovarian Cancer With BRCA-Mutated and/or BRCAness Phenotype: A Randomized Phase III Trial.

Literature evidence suggests that trabectedin monotherapy is effective in patients with recurrent ovarian cancer (OC) presenting BRCA mutation and/or BRCAness phenotype. A prospective, open-label, randomized phase III MITO-23 trial evaluated the activity and safety of trabectedin 1.3 mg/m2 given once every 3 weeks (arm A) in BRCA 1/2 mutation carriers or patients with BRCAness phenotype (ie, patients who responded to ≥two previous platinum-based treatments) with recurrent OC, primary peritoneal carcinoma, or fallopian tube cancer in comparison with physician's choice chemotherapy in the control arm (arm B; pegylated liposomal doxorubicin, topotecan, gemcitabine, once-weekly paclitaxel, or carboplatin). The primary end point was overall survival (OS) evaluated in the intention-to-treat population. Overall, 244 patients from 21 MITO centers were randomly assigned (arm A = 122/arm B = 122). More than 70% of patients received ≥three previous chemotherapy lines and 35.7% had received a poly (ADP-ribose) polymerase inhibitor (PARPi) before enrollment. Median OS was not significantly different between the arms: arm A: 15.8 versus arm B: 17.9 months (P = .304). Median progression-free survival was 4.9 months in arm A versus 4.4 months in arm B (P = .897). Among 208 patients evaluable for efficacy, the objective response rate was 17.1% in arm A and 21.4% in arm B, with comparable median duration of response (5.62 v 5.66 months, respectively). No superior effect was observed for trabectedin in the prespecified subgroup analyses according to BRCA mutational status, chemotherapy type, and pretreatment with a PARPi and/or platinum-free interval. Trabectedin showed a higher frequency of grade ≥3 adverse events (AEs), serious AEs, and serious adverse drug reactions compared with control chemotherapy. Trabectedin did not improve median OS and showed a worse safety profile in comparison with physician's choice control chemotherapy.

Trabectedin in Cancers: Mechanisms and Clinical Applications.

Trabectedin, a tetrahydroisoquinoline alkaloid, is the first marine antineoplastic agent approved with special anticancer mechanisms involving DNA binding, DNA repair pathways, transcription regulation and regulation of the tumor microenvironment. It has favorable clinical applications, especially for the treatment of patients with advanced soft tissue sarcoma, who failed in anthracyclines and ifosfamide therapy or could not receive these agents. Currently, trabectedin monotherapy regimen and regimens of combined therapy with other agents are both widely used for the treatment of malignancies, including soft tissue sarcomas, ovarian cancer, breast cancer, and non-small-cell lung cancer. In this review, we have summarized the basic information and some updated knowledge on trabectedin, including its molecular structure, metabolism in various cancers, pharmaceutical mechanisms, clinical applications, drug combination, and adverse reactions, along with prospects of its possibly more optimal use in cancer treatment.

Cardiac safety of trabectedin monotherapy or in combination with pegylated liposomal doxorubicin in patients with sarcomas and ovarian cancer.

BackgroundAs with other alkylating agents, cardiac dysfunction can occur with trabectedin therapy for advanced soft tissue sarcomas (STS) or recurrent ovarian cancer (ROC) where treatment options for advanced disease are still limited. Cardiac safety for trabectedin monotherapy (T) for STS or in combination with pegylated liposomal doxorubicin (T+PLD) for ROC was evaluated in this retrospective postmarketing regulatory commitment.MethodsPatient data for multiple cardiac‐related treatment‐emergent adverse events (cTEAEs) were evaluated in pooled analyses of ten phase 2 trials, one phase 3 trial in STS (n = 982), and two phase 3 trials in ROC (n = 1231).ResultsMultivariate analyses on pooled trabectedin data revealed that cardiovascular medical history (risk ratio [RR (95% CI)]: 1.90 [1.24‐2.91]; p = 0.003) and age ≥65 years (RR [95% CI]: 1.78 [1.12‐2.83]; p = 0.014) were associated with increased risk for cTEAEs. Multivariate analyses showed increased risk of experiencing cTEAEs with T+PLD compared to PLD monotherapy (RR [95% CI]: 2.70 [1.75‐4.17]; p < 0.0001) and with history of prior cardiac medication (RR [95% CI]: 1.88 [1.16‐3.05]; p = 0.010).ConclusionsFor patients with STS or ROC who still have limited treatment options, trabectedin may be initiated after carefully considering benefit versus risk. Trial Registration (ClinicalTrials.gov): NCT01343277; NCT00113607; NCT01846611.

Long lasting response with trabectedin monotherapy in relapsed metastatic mesenchymal chondrosarcoma

BackgroundMesenchymal chondrosarcoma is an exceedingly rare malignancy, accounting for around 5% of all patients with chondrosarcoma. It is a translocation-related sarcoma that tends to have both local and distant recurrences. Surgery is the mainstay of treatment in localised cases however treatment of advanced cases remains a challenge. The rarity of the disease precludes dedicated clinical trials and hence guidelines for its management are not well defined. The dearth in literature makes it pertinent that the cases treated with newer therapies must be reported to contribute to existing knowledge.Case presentationWe hereby report a case of a 39-year old male without any comorbidity presenting with pelvic pain and was diagnosed as mesenchymal chondrosarcoma of the pelvis. He underwent an initial curative resection followed by a disease-free interval of 7 months. Subsequently, he was treated with pulmonary metastatectomy and local debulking surgery at time of initial relapse. He was then exposed to multiple lines of palliative chemotherapy, which limited our treatment options upon subsequent disease progression. Based on recent data, the patient was given trabectedin monotherapy as fourth line chemotherapy. He tolerated the therapy well and attained a progression-free survival of 12 months, which is an impactful figure in relapsed setting in this patient population.ConclusionThis report aims to present a comprehensive review into available and newer treatment choices for mesenchymal chondrosarcoma, and to highlight trabectedin monotherapy as a possible therapeutic option for mesenchymal chondrosarcoma in the relapsed setting.

Cardiac safety of trabectedin monotherapy and in combination with pegylated liposomal doxorubicin in patients with sarcomas and ovarian cancer.

11547 Background: Trabectedin (T) is an established option as monotherapy for advanced soft tissue sarcomas (STS; Leiomyosarcomas and Liposarcomas in the USA) and in combination with pegylated liposomal doxorubicin (PLD) for recurrent ovarian cancer (ROC). This retrospective analysis evaluated the cardiac safety profile in over 1500 patients (pts) from clinical trials administering T monotherapy for STS or in combination with PLD (T+PLD) for ROC. Methods: Integrated cardiac safety data was analyzed from ten Phase 2 trials and one Phase 3 trial in STS (T) and two Phase 3 ROC trials (T+PLD). Cardiac-related treatment-emergent adverse events (TEAEs) were summarized using MedDRA terminology and by Kaplan-Meier analysis for time-to-event variables. Subgroup analyses were performed for cardiac-related TEAEs, including any significant decrease in LVEF. Results: Integrated data on T monotherapy included 982 pts (Table). Of these, 110 (11.2%) pts who received ≥1 dose of T experienced a cardiac-related TEAE, including tachycardia (3.1%), palpitations (1.5%), LVEF decrease (1.3%), sinus tachycardia (1.0%), and/or congestive cardiac failure (1.0%). A multivariate analysis revealed factors associated with increased risk to be cardiovascular medical history (risk ratio [RR]: 1.90; 95% CI: 1.24-2.91; p = 0.003) and age &gt; 65 years (RR: 1.78; 95% CI: 1.12,2.83; p = 0.014). Cardiac-related TEAEs were reported in 78 (12.6%) of 619 pts receiving T+PLD (Table). Incidence of cardiac-related TEAEs was greater with T+PLD compared with PLD monotherapy (12.6% vs 5.6%). A multivariate analysis showed that pts were at increased risk for experiencing cardiac-related TEAEs when treated with T+PLD compared to PLD monotherapy (RR: 2.70; 95% CI: 1.75,4.17; p &lt; 0.0001) and when there was a history of prior cardiac medication (RR: 1.88; 95% CI: 1.16,3.05; p = 0.010). Conclusions: Although infrequent, patients receiving T after prior anthracyclines or in combination with PLD are at risk for cardiac dysfunction, and appropriate clinical awareness and monitoring is encouraged to optimize patient outcomes. [Table: see text]

Practical use and utility of fluorescence in situ hybridization in the pathological diagnosis of soft tissue and bone tumors.

During routine pathological examination, fluorescence in situ hybridization (FISH) plays a significant role in the genetic analysis of samples. FISH can detect genetic abnormalities such as chromosomal translocations, gene amplifications, and deletions in formalin-fixed, paraffin-embedded (FFPE) specimens. Due to its practical advantages, FISH is already used in many pathology laboratories. It is especially useful for the diagnosis of translocation-related sarcomas (TRSs), which comprise about 25% of soft tissue sarcomas. Because TRSs have specific chimeric genes derived from characteristic chromosomal translocations, their diagnosis would not be possible without FISH. FISH significantly contributes to the genetic confirmation of TRS. Analysis using next-generation sequencing (NGS), the latest powerful method for comprehensive genomic analysis, has recently revealed many kinds of chromosomal translocations in various TRSs. We often use experimental results to create custom probes for FISH and have applied NOCA2 split probes and CIC split, CIC-FOXO4 fusion probes to the pathological diagnosis of soft tissue angiofibroma and CIC-rearranged sarcoma, respectively. Some chimeric fusions detected by NGS induce the expression of related proteins and their detection using immunohistochemistry is beneficial for pathological diagnosis. We previously identified characteristic FOSB expression in pseudomyogenic hemangioendothelioma (PHE) with a specific SERPINE1-FOSB fusion, revealing the usefulness of FOSB immunohistochemistry in the differential diagnosis of PHE and its mimics. Finally, we participated in a central review of a clinical trial of trabectedin monotherapy. We guaranteed an accurate diagnosis by using FISH and genetic confirmation to select appropriate TRS patients and thereby confirm the accuracy of the patient enrollment of the clinical trial. FISH is an essential tool for the pathological diagnosis of soft tissue and bone tumors. It can detect various genetic abnormalities in an "in situ" fashion using FFPE specimens on glass slides during routine examination. It is also an excellent tool for translating the latest experimental findings to practical use in routine pathological diagnosis. Further instrumental improvements in FISH will help it to become the universal method for the genetic analysis of pathological diagnoses.

Central venous access related adverse events after trabectedin infusions in soft tissue sarcoma patients; experience and management in a nationwide multi-center study

BackgroundTrabectedin has shown efficacy against soft tissue sarcomas (STS) and has manageable toxicity. Trabectedin is administered through central venous access devices (VAD), such as subcutaneous ports with tunneled catheters, Hickman catheters and PICC lines. Venous access related adverse events are common, but have not yet been reported in detail.MethodsA retrospective analysis of patient files of STS patients receiving trabectedin monotherapy between 1999 and 2014 was performed in all five STS referral centers in the Netherlands. This survey focused on adverse events related to the VAD and the actions taken in response to these events.ResultsIn the 127 patients included in this analysis, 102 venous access ports (VAP), 15 Hickman catheters and 10 PICC lines were used as primary means of central venous access. The most frequently reported adverse events at the VAD site were erythema (30.7%), pain (28.3%), inflammation (11.8%) and thrombosis (11.0%). Actions taken towards these adverse events include oral antibiotics (17.3%), VAD replacement (15.0%) or a wait-and-see policy (13.4%). In total, 45 patients (35.4%) with a subcutaneous port developed a varying degree of inflammation along the trajectory of the tunneled catheter. In all but three patients, this was a sterile inflammation, which was considered a unique phenomenon for trabectedin. Microscopic leakage of trabectedin along the venous access device and catheter was considered the most plausible cause for this adverse event. Placing the catheter deeper under the skin resolved the issue almost completely.ConclusionTrabectedin infusion commonly leads to central venous access related adverse events. Sterile inflammation along the catheter trajectory is one of the most common adverse events and can be prevented by placing the catheter deeper under the skin.

Emesis and nausea related to single agent trabectedin in ovarian cancer patients: a sub-study of the MITO15 project.

The MITO 15 was a prospective, single-arm trial, evaluating trabectedin monotherapy in patients with recurrent ovarian cancer (OC) who were BRCA mutation-carriers or had a BRCAness phenotype. It is largely reported that trabectedin may induce nausea and vomiting but the real emetogenic potential of the drug, in the different schedules, has never been fully described; furthermore, OC patients are known to have an enhanced risk of developing nausea and vomiting due to female gender, abdominal spreading of the disease, and major surgery experienced by most of them. We thought to carry on a sub-study in the MITO 15 context focused on chemotherapy-induced nausea and vomiting (CINV) associated with trabectedin single agent. For all patients enrolled in the trial, we evaluated the antiemetic regimen at the first cycle, acute and delayed CINV, any rescue therapy, any change in the prophylactic antiemetic regimen, and the potential relationship between dexamethasone dosage and incidence of CINV. Overall, our findings were consistent with literature and confirmed that trabectedin can be classified as moderately emetogenic. We observed slightly higher rates of both nausea and vomiting compared to previous experiences with trabectedin monotherapy, probably due to intrinsic features of our population: all females and suffering from ovarian cancer. It seems that in preventing acute CINV, the combination of three drugs was more effective than the doublet; however, the difference did not reach statistical significance; further studies are required to verify such hypothesis. Given the extreme heterogeneity of the antiemetic regimens used, it appears that a standard antiemetic protocol does not exist and more specific guidelines for clinicians are needed.

Trabectedin monotherapy after standard chemotherapy versus best supportive care in patients with advanced, translocation-related sarcoma: a randomised, open-label, phase 2 study

Trabectedin binds to the minor groove of DNA and blocks DNA repair machinery. Preclinical data have shown that trabectedin also modulates the transcription of the oncogenic fusion proteins of translocation-related sarcomas. We aimed to assess the efficacy and safety of trabectedin as second-line therapy or later for patients with advanced translocation-related sarcoma. We did a multicentre randomised open-label study in Japan. Eligible patients had pathological diagnosis of translocation-related sarcoma, were aged 19 years or older, were unresponsive or intolerant to standard chemotherapy regimens, no more than four previous chemotherapy regimens, Eastern Cooperative Oncology Group performance status 0 or 1, adequate bone marrow reserve, renal and liver functions, and had measurable lesions. Patients were randomly assigned (1:1) by the minimisation method to receive either trabectedin (1·2 mg/m(2) given via a central venous line over 24 h on day 1 of a 21 day treatment cycle) or best supportive care, which was adjusted centrally by pathological subtype. Investigators, patients, and the sponsor were unmasked to the treatment assignment. Progression-free survival and objective responses were assessed by a masked central radiology imaging review. Efficacy was assessed by masked central radiology imaging review. The primary endpoint was progression-free survival for the full analysis set population. Follow-up is ongoing for the patients under study treatment. The study is registered with Japan Pharmaceutical Information Center, number JapicCTI-121850. Between July 11, 2012, and Jan 20, 2014, 76 patients were enrolled and allocated to receive either trabectedin (n=39) or best supportive care (n=37). After central review to confirm pathological subtypes, 73 patients (37 in the trabectedin group and 36 in the best supportive care group) were included in the primary efficacy analysis. Median progression-free survival of the trabectedin group was 5·6 months (95% CI 4·1-7·5) and the best supportive care group was 0·9 months (0·7-1·0). The hazard ratio (HR) for progression-free survival of trabectedin versus best supportive care was 0·07 (90% CI 0·03-0·14 and 95% CI 0·03-0·16) by a Cox proportional hazards model (p<0·0001). The most common drug-related adverse events for patients treated with trabectedin were nausea (32 [89%] of 36), decreased appetite (21 [58%]), decreased neutrophil count (30 [83%]), increased alanine aminotransferase (24 [67%]), and decreased white blood cell count (20 [56%]). Trabectedin significantly reduced the risk of disease progression and death in patients with advanced translocation-related sarcoma after standard chemotherapy such as doxorubicin, and should be considered as a new therapeutic treatment option for this patient population. Taiho Pharmaceutical Co., Ltd.

Activity of trabectedin in germline BRCA1/2-mutated metastatic breast cancer: results of an international first-in-class phase II study

Breast cancer is a heterogeneous disease defined by both germline and somatic abnormalities. In preclinical models, tumors carrying homologous recombination defects are highly sensitive to trabectedin. This phase II trial evaluated the efficacy and safety of trabectedin in BRCA1/2 germline mutation carriers with pretreated metastatic breast cancer (MBC). Trabectedin 1.3 mg/m(2) as a 3-h i.v. infusion was administered every 3 weeks until progression or intolerance. The primary efficacy end point was the objective response rate (ORR) as per RECIST. Secondary efficacy end points comprised time-to-event end points, and changes in tumor volume and expression of tumor marker CA15.3. Safety was evaluated using the NCI-CTCAE. Forty BRCA1/2 germline mutation carriers with MBC were included. Confirmed partial response (PR) occurred in 6 of 35 assessable patients [ORR = 17%; 95% confidence interval (CI) 7% to 34%] and lasted 1.4-6.8 months. Median PFS was 3.9 months (95% CI 1.6-5.5 months). Eight patients (21%) showed changes in tumor volume, and 14 (40%) a clinical benefit. Trabectedin-related adverse events were generally mild/moderate, the most common being fatigue, nausea, constipation and anorexia. Severe laboratory abnormalities (neutropenia, transaminase increases) were mostly transient and noncumulative, and were managed by dose adjustments. With the caveat of the limited patient number, trabectedin monotherapy showed activity and was well tolerated in heavily pretreated MBC patients selected for germline BRCA mutation. These results prompt further evaluation of trabectedin alone or combined with other specific drugs in this indication. NCT00580112.

Prolonged response to trabectedin in a patient with carcinosarcoma of the ovary refractory to adjuvant platinum-taxane

Background: Carcinosarcoma of the ovary carries an unfavorable prognosis and the optimal chemotherapeutic regimen for this disease is yet to be determined. To the authors´ knowledge, this is the first report of a metastatic ovarian carcinosarcoma successfully treated with trabectedin monotherapy after failure of platinum/taxane-based therapy. Case report: The case of a platinum-refractory advanced ovarian carcinosarcoma in a 73-year-old female is presented. After initial tumor debulking, the patient received adjuvant carboplatin and paclitaxel. After 2 cycles, tumor progression occurred. The authors speculated that rapid tumor progression occurred as a consequence of regrowth of sarcomatous elements within the carcinosarcoma. This platinum-refractory disease was treated with single-agent trabectedin 1.5 mg/m 2 every three weeks. A prolonged partial response for 13 months along with an acceptable safety profile was achieved. During this time, the patient was able to perform her daily activities without restrictions. Conclusion: Our case suggests that trabectedin monotherapy may represent a viable therapeutic option for patients with platinum-refractory advanced ovarian carcinosarcoma.

Trabectedin as single agent in relapsed advanced ovarian cancer: results from a retrospective pooled analysis of three phase II trials

Three phase II studies evaluated trabectedin monotherapy as second-/third-line therapy in patients with refractory/recurrent ovarian cancer (ROC). Three different schedules were investigated: 3-h infusion every 3 weeks (3-h_q3w), 24-h infusion q3w (24-h_q3w), and 3-h weekly infusion for 3 weeks of a 4-week cycle. This retrospective pooled analysis evaluated the efficacy and the safety profile of trabectedin according to each administered regimen. Data from 295 patients were used to compare weekly versus q3w schedules, and 3-h versus 24-h infusion given q3w. Both q3w regimens showed higher overall response rate (36 vs. 16 %; p = 0.0001), disease control rate (66 vs. 46 %; p = 0.0007), and longer median progression-free survival (5.6 vs. 2.8 months; p < 0.0001) than the weekly schedule. Comparable activity was observed for the 3- and 24-h infusions q3w. Common adverse events were nausea, fatigue, vomiting, transient neutropenia, and transaminase increases. A better safety profile regarding neutropenia, fatigue, and vomiting was seen for the 3-h_q3w regimen as compared to the 24-h_q3w one. Trabectedin given as a single agent q3w as 3-h infusion is the schedule of choice for the treatment of ROC, and its efficacy and safety profile favorably compares with other active salvage treatments.

Cost Effectiveness of First-Line Treatment with Doxorubicin/Ifosfamide Compared to Trabectedin Monotherapy in the Management of Advanced Soft Tissue Sarcoma in Italy, Spain, and Sweden

Background. Doxorubicin/ifosfamide is a first-line systemic chemotherapy for the majority of advanced soft tissue sarcoma (ASTS) subtypes. Trabectedin is indicated for the treatment of ASTS after failure of anthracyclines and/or ifosfamide; however it is being increasingly used off-label as a first-line treatment. This study estimated the cost effectiveness of these two treatments in the first-line management of ASTS in Italy, Spain, and Sweden. Methods. A Markov model was constructed to estimate the cost effectiveness of doxorubicin/ifosfamide compared to trabectedin monotherapy, defined as the cost per QALY gained, in each country. Results. First-line treatment with doxorubicin/ifosfamide resulted in lower two-year healthcare costs and more QALYs than first-line treatment with trabectedin monotherapy in all three countries. Probabilistic sensitivity analysis showed that at a cost per QALY threshold of €35,000, >90% of a cohort would be cost effectively treated with doxorubicin/ifosfamide compared to trabectedin monotherapy in all three countries. Conclusion. Within the model's limitations, first-line treatment of patients with ASTS with doxorubicin/ifosfamide instead of trabectedin monotherapy affords a cost-effective use of publicly funded healthcare resources in Italy, Spain, and Sweden and is therefore the preferred treatment in all three countries. These findings support the recommendation that trabectedin should remain a second-line treatment.

Efficacy and tolerability of trabectedin in heavily pretreated soft tissue sarcomas (STS).

e20513 Background: Advanced STS have a dismal prognosis with a median overall survival of 1 year, reported in most phase III clinical trials. Although newer targeted therapies are currently being evaluated, chemotherapy continues to be the mainstay of treatment. However, due to the limited activity of current treatments, new therapies are needed. Trabectedin, an alkylating agent to the minor groove of DNA, has demonstrated significant activity after failure of anthracyclines and ifosfamide. Methods: This is a retrospective analysis of 22 patients diagnosed with advanced, heavily pretreated STS, treated with trabectedin in a single institution. From 06/ 2000 to 06/ 2011, trabectedin was administered as a 3-hour infusion every 21 days at a dose of 1.1-1.5mg/m2 with steroid premedication. No patients were excluded from this analysis. Results: Median age was 53 years (range 21-82). The most frequent histologic subtypes were: 27% liposarcomas, 18% leiomyosarcomas, 13% malignant fibrous histiocytomas and 9% synovial sarcomas. One third of patients had received 3 or more prior therapy lines. Overall response rate was 8.33% and stable disease (more than 16 weeks) was achieved in 36.3% of patients (75% of liposarcomas and 50% of leiomiosarcomas). The median duration of response was 11 weeks (range 4-22). Dose reduction was required in two patients, but no patient discontinued treatment due to drug-related toxicity. There were no treatment-related deaths. The most relevant toxicity was grade 3/4 neutropenia in 25% of patients (one case of febrile neutropenia). Grade 3/4 transaminitis was observed in the only patient who received trabectedin with doxorubicin for one cycle, and continued with trabectedin monotherapy without further liver function test disturbances. A case of transient rhabdomyolysis was observed; the patient had mild renal dysfunction and liver metastases, but recovered completely. Grade 1/2 nausea, vomiting and asthenia were reported in 8.33%, 4.17% and 45.83% of patients, respectively. Conclusions: Trabectedin achieves significant clinical benefit in heavily pretreated advanced STS patients. Trabectedin was well tolerated with reversible and manageable toxicity, demonstrating an acceptable safety profile.

Trabectedin combined with liposomal doxorubicin in women with relapsed ovarian cancer

In the absence of a curative treatment for patients with recurrent ovarian cancer, many agents have shown different levels of activity in the control of this disease. Trabectedin is an antineoplastic agent originally derived from the Caribbean marine tunicate Ecteinascidia turbinate. This drug has a new mechanism of action based on DNA minor-groove binding. Following the encouraging results from Phase I and II studies of trabectedin monotherapy or in combination in patients with relapsed ovarian cancer, a Phase III trial investigating the use of trabectedin plus liposomal doxorubicin versus liposomal doxorubicin was launched. This study demonstrated a benefit for the combination in terms of progression-free survival that was consistent with published data of platinum-based regimens. This study has opened up the possibility of effective, nonplatinum, trabectedin-based combination therapy in patients with advanced or recurrent ovarian cancer.