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Trabectedin for Women With Ovarian Carcinoma After Treatment With Platinum and Taxanes Fails

From the Istituto Oncologico della Svizzera Italiana, Bellinzona; Centre Pluridisciplinaire d'Oncologie, Lausanne, Switzerland; Istituto Europeo di Oncologia; Istituto Nazionale dei Tumori; Southern Europe New Drugs Organization Foundation; Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy; and PharmaMar SA, Madrid, Spain

Address reprint requests to Silvia Marsoni, Southern Europe New Drugs Organization Foundation, Via Visconti di Modrone 12, 20100 Milano, Italy; e-mail: marsonis{at}sendo-org.it

	ABSTRACT

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PURPOSE: To assess the efficacy and toxicity of the marine-derived alkaloid trabectedin (ET-743) in patients with advanced ovarian cancer refractory to or experiencing disease relapse after platinum- and taxane-based chemotherapy.

PATIENTS AND METHODS: Fifty-nine patients from four institutions either resistant (n = 30) or sensitive (n = 29) to prior platinum and taxanes were treated with a 3-hour infusion of trabectedin every 3 weeks. Patients were monitored weekly for toxicity and restaged every two cycles for response. Response was assessed according to Response Evaluation Criteria in Solid Tumors Group.

RESULTS: The peer-reviewed objective response rate in platinum-sensitive patients was 43% (95% CI, 23% to 65%) with an estimated median time to progression of 7.9 months (95% CI, 7.5 to 14.1 months); in platinum-resistant patients two partial responses were observed. Responses were durable for up to 12.9 months (median, 5 months). The predominant toxicities at the recommended dose of 1,300 µg/m² were neutropenia, asthenia, and self-limited increase of aminotransferases never requiring treatment interruption.

CONCLUSION: Trabectedin administered as a 3-hour infusion at 1,300 µg/m² is a safe new drug with promising activity in relapsed ovarian cancer, showing a 43% objective response rate in patients with platinum-sensitive disease, which favorably compares with other salvage treatments and warrants additional development either alone or in combination.

	INTRODUCTION

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In women with advanced ovarian carcinoma, long-term survival is still an unsatisfactory 30%, even after the introduction of front-line platinum and taxane combinations.¹ Identifying new compounds in patients pretreated with platinum and taxanes is a priority because of the limited activity of commercially available drugs for salvage therapy (such as liposomal doxorubicin, gemcitabine, and topotecan).² The need for new therapeutic options justifies testing agents with completely new structure and mechanism of action in second-line therapy based on evidence of antitumor activity in sensitive animal models.

Trabectedin (ET-743; Yondelis, PharmaMar, SA, Spain) is a tetrahydroisoquinoline alkaloid isolated from the marine tunicate Ecteinascidia turbinate.³ It binds to the N2 position of guanine in the minor groove of DNA, thereby causing structural changes of DNA different from those induced by other DNA-interacting agents⁴ and leading to inhibition of transcription in a promoter- and gene-dependent fashion.⁵-⁷ In addition, the mechanisms of repair of trabectedin-induced DNA damage are clearly different from those previously characterized for other drugs, such as cisplatin.⁶,⁸-¹⁰

Tests in human ovarian carcinoma xenografts showed that trabectedin is among the most active molecules ever investigated in these tumors.¹¹ Interestingly, some xenografts that showed a low sensitivity to cisplatin or paclitaxel were sensitive to trabectedin.¹¹ This was the rationale for the evaluation of trabectedin in ovarian cancer patients previously treated with platinum compounds and taxanes.

Phase I studies of trabectedin investigated different infusion durations: the 1-hour infusion was associated with the highest incidence of early increase of liver enzymes¹²; the 24-hour infusion caused less hepatic toxicity and more myelosuppression¹³; and the 3-hour infusion showed acceptable tolerability and allowed outpatient administration.¹⁴

We report the results of a phase II study of trabectedin infused during 3 hours in patients with epithelial ovarian cancer who had experienced treatment failure after platinum and taxane therapy. The study was conducted by the Southern Europe New Drugs Organization (SENDO).

	PATIENTS AND METHODS

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Patients
Eligibility criteria included histologic or cytologic diagnosis of epithelial ovarian cancer (excluding borderline and mesodermal tumor); age 18 years; Eastern Cooperative Oncology Group performance status 1; adequate baseline hematologic (hemoglobin 9 mg/dL, absolute neutrophil count 1.500 x 10⁹/L, and platelets 100 x 10⁹/L), renal (serum creatinine 133 µmol/L), and hepatic function (alkaline phosphatase [AP] and total serum bilirubin the upper limit of normal [ULN], AST or ALT 1.5x ULN, and albumin 2.5 mg/dL).

At least one measurable lesion according to Response Evaluation Criteria in Solid Tumors Group (RECIST) criteria¹⁵ and treatment failure after first-line chemotherapy containing cisplatin or carboplatin with taxane, with or without other drugs, were requested. Reintroduction of a platinum-based combination and/or a taxane after a progression-free interval (PFI) longer than 6 months was allowed, provided that the last chemotherapy before starting trabectedin included a platinum drug and/or taxane.

Patients were stratified by response to the last chemotherapy in two categories: platinum resistant (no change after at least four cycles of platinum and taxane, progressive disease after two cycles while receiving chemotherapy, or relapse within an interval of less than 6 months after therapy discontinuation) or platinum sensitive (patient experienced disease relapse after a PFI of 6 months between the last chemotherapy cycle and documentation of relapse).

Criteria of exclusion were prior high-dose chemotherapy, prior extended radiotherapy, second malignancy, significant infection, cardiac disease, cirrhosis, chronic active hepatitis, and documented brain or leptomeningeal disease. The trial was approved by the ethics and scientific committees of the participating hospitals; all patients gave their written informed consent to participate in the study.

Toxicity and Response
Physical examination, pretreatment evaluations (including ECG, chest x-ray, and laboratory tests), and instrumental tumor assessment (also including CA-125 determination) were performed respectively within 2, 7, and 28 days before drug administration. Hematology and liver function tests were performed weekly; blood chemistry (including creatinine, serum electrolytes, and coagulation tests) were performed at least every 3 weeks or more often if grade 3 toxicity occurred. CA-125 and tumor response were assessed every two cycles.

Toxicity was evaluated by the National Cancer Institute Common Toxicity Criteria (Version 2.0, 1999). Response to treatment was evaluated by RECIST criteria.¹⁵

Drug Treatment
Trabectedin was supplied by PharmaMar (Colmenar Viejo, Madrid, Spain) as a lyophilized powder in 250-µg vials, to be reconstituted with 5 mL of sterile water. Trabectedin was initially given at the dose of 1,650 µg/m² and was subsequently decreased to 1,500 µg/m² and then to 1,300 µg/m² because of toxicity. The total amount of drug was diluted in 500 mL of 0.9% normal saline and administered as a 3-hour infusion using an ambulatory infusion pump through a separate line; a central venous access was recommended.

Antiemetic prophylaxis was mandatory and included intravenous 5-hydroxytryptamine-3 antagonists with dexamethasone 10 mg intravenously, 1 hour before starting chemotherapy; oral metoclopramide 10 mg tid was given during the infusion and afterward. Pre- and postmedication with corticosteroids as prophylaxis against hepatic toxicity consisted of oral dexamethasone 4 mg bid starting 24 hours before treatment and up to 48 hours after treatment.

Prophylactic use of granulocyte colony-stimulating factor was not permitted; the use of drugs known to induce or inhibit cytochrome P450 3A4 was discouraged. Treatment was repeated every 3 weeks provided that re-treatment criteria were met; treatment could be delayed for a maximum of 2 weeks, after which the patient was removed from the study.

The dose of trabectedin at subsequent cycles was decreased by one dose level (from 1,650 to 1,500 µg/m², from 1,500 to 1,300 µg/m², and from 1,300 to 1,100 µg/m²) if any of the following events occurred: grade 4 neutropenia lasting more than 5 days, febrile neutropenia, platelets 25,000 x 10⁹/L, elevation of AP or bilirubin of any grade, a 2-week delay of recovery of AST or ALT, or grade 3 of any other toxicity on any weekly evaluation. A maximum of two dose reductions down to 900 µg/m² was allowed; if toxicity recurred, the patient was removed from the study.

Treatment was continued until tumor progression, development of unacceptable toxicity, request of the patient to withdraw, or investigator's decision. In patients who achieved a response or stable disease (SD), additional treatment after six and four cycles, respectively, was left to the discretion of the investigator.

Statistical Methods
Duration of response was calculated from the first evidence of response; progression-free survival was calculated from the day of first treatment to the first day of relapse. Patients lost to follow-up were censored at the day of the last visit.

A level of interest of antitumor activity of 15% and 20% was estimated for platinum-resistant and platinum-sensitive patients, respectively. A Gehan two-step study design was implemented with a type I and II error of 0.05 and 0.20, respectively. Nineteen platinum-resistant patients were to be treated in the first step, with a maximum of five additional patients to be entered if more than three responses were observed in the first 19. Fourteen patients experiencing disease relapse were to be treated in the first step, and additional patients were to be entered if one response occurred in the first 14 patients, up to a maximum of 11 additional patients.¹⁶

	RESULTS

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Patient Characteristics
Fifty-nine patients from four institutions entered onto the study between June 2000 and September 2003 (Table 1). Because the original recommended dose was reduced twice because of toxicity (see Treatment and Dosing), more patients than originally planned were accrued to ensure proper sample size at the newly defined recommended dose (RD). Twenty-nine patients (49%) were platinum-sensitive. PFI was between 6 and 12 months in 15 patients (52%) and longer than 12 months in 14 patients (48%). Thirty patients were classified as platinum resistant: seven patients (23%) had developed progressive disease while receiving prior therapy, four patients (13%) had achieved SD, and 19 patients (64%) had experienced disease relapse within 6 months after the last cycle of treatment.

Treatment and Dosing
A total of 259 cycles were administered with a median of four cycles per patient (range, one to 13 cycles). The first six patients were treated at the phase I RD of 1,650 µg/m².¹⁴ Three patients required a dose reduction at cycle 2. The next 12 patients were treated at 1,500 µg/m², corresponding to the level before the RD. Eleven were re-treated at cycle 2; six were re-treated at reduced doses. Overall, approximately 60% of the patients treated at the higher doses underwent a dose reduction mainly because of liver toxicity and/or asthenia (Table 2). The dose was further decreased to 1,300 µg/m². With this dose only 21% of patients required a dose reduction at cycle 2, all because of liver toxicity. Overall, 37% of cycles at 1,300 µg/m² were given at reduced doses and 37% were delayed because of toxicity (Table 2).

Toxicity
All 59 patients and all 259 cycles were assessable for toxicity. The most common toxicity was a severe but reversible dose-dependent increase of liver function tests, mainly AST or ALT and, to a lower degree, bilirubin and AP. The reduction from 1,650 to 1,500 µg/m² and then to 1,300 µg/m² resulted in a decreased incidence of grade 4 AST or ALT elevation at cycle 1 from 83%, to 42%, and to 17%, respectively. The incidence of grade 1 to 2 bilirubin decreased from 50%, to 42%, and to 12%, respectively. Alteration of liver function tests started within 72 hours after treatment and peaked at 5 days. The median number of days from zenith to recovery to 1.5x ULN of AST or ALT was similar across cycles: 7 and 11 days on cycle 1, and 5 and 11 days on subsequent cycles, respectively. Liver toxicity of trabectedin at different doses is shown in Figure 1.

View larger version (22K): [in this window] [in a new window]   Fig 1. Overall incidence of liver toxicity by patient (worst National Cancer Institute Common Toxicity Criteria grade) of trabectedin. ALP, alkaline phosphatase.

Severe neutropenia at cycle 1 occurred in 67% of patients at 1,650 µg/m², with one occurrence of febrile neutropenia, in 33% of patients at 1,500 µg/m², and in 12% of patients at 1,300 µg/m². At the latter dose the overall incidence of severe neutropenia throughout all cycles was 41% (median duration of grade 4 neutropenia, 3 days); severe thrombocytopenia occurred in three patients, and one patient developed a septic thrombosis with grade 4 neutropenia.

Trabectedin was given preferentially through a central catheter because of local toxicity. In the 26 patients without a permanent central venous line, local toxicity (consisting of painful erythema along the vein of injection and residual sclerotic phlebitis) occurred in five patients (19%). Table 3 summarizes the main toxicities of trabectedin in the 41 patients who started therapy at 1,300 µg/m².

Response
All patients defined by the study investigators to be either in response or with an SD lasting for 24 weeks or longer were submitted to independent peer review. Of the 59 patients entered, eight (two platinum-resistant and six platinum-sensitive patients) were considered not assessable according to RECIST criteria because of lack of histologic proof of solitary measurable lesion (n = 5), inadequate method of instrumental tumor assessment (n = 1), or not measurable disease (n = 2). Among the five patients with lack of histologic assessment of solitary lesions, one had a complete response (CR) according to peer review and all five had a 50% decrease of CA-125 from abnormal baseline values in two consecutive samples. This notwithstanding, the activity analysis reported is limited to the 51 patients deemed assessable by the reviewers (Table 4). Among the 28 assessable platinum-resistant patients, two patients (7%), both of whom experienced disease relapse within 6 months after treatment, achieved a partial response lasting 2 and 2.5 months and a time to progression of 4 and 4.6 months, respectively; eight patients (29%) had SD, and of these, one had a 50% decrease of CA-125. Progression while receiving trabectedin occurred in 64% of patients overall, and occurred after the first cycle in 22% of patients.

With all of the limitations of a small subgroup analysis, the rate of response was also apparently not affected by the initial dose, nor were platinum-sensitive patients affected by the extent of prior PFI (Table 5).

	DISCUSSION

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During phase I evaluation, trabectedin administered as a 1-hour infusion showed a unique pattern of liver toxicity associated with nausea, vomiting, and asthenia.¹² Prolonging the infusion to 24 hours improved hepatic and gastrointestinal toxicities, but was associated with myelosuppression.¹³ The intermediate 3-hour infusion combined a favorable toxicity profile with ease of administration, even though data on repeated cycles were limited.¹² From the above considerations, the latter schedule was adopted in the present trial. In the 3-hour schedule, the maximum-tolerated dose and RD of trabectedin were 1,850 and 1,650 µg/m², respectively.¹²

It is not uncommon that RDs defined during phase I trials undergo refinements during phase II trials, when longer durations of treatment are implemented while evidence of antitumor activity is sought. We observed early in the trial that the dose had to be reduced frequently at cycle 2 because of liver toxicity and asthenia. The observation prompted us to decrease the starting dose to 1,500 µg/m² and later to 1,300 µg/m², at which dose the majority of patients were treated. This dose refinement process (without compromising response) decreased the risk of severe toxicity and limited dose reductions, unlike what had occurred during the phase II evaluation of topotecan and liposomal doxorubicin. Clinical and experimental data in rats also became available during the study, suggesting a potential benefit of a premedication with corticosteroids to limit liver toxicity.¹⁸

The study therefore has the value of providing an in-depth assessment of the toxicity of trabectedin even after repeated administrations, and the measures adopted also allow for recommendations about prophylactic treatments and concomitant medications. In the 41 assessable patients initially treated at 1,300 µg/m², the main toxicities were asthenia (78%; 7% severe), nausea and vomiting (78%; 5% severe), and asymptomatic increase of AST or ALT (93%). Severe neutropenia was observed in 41% of patients, whereas severe thrombocytopenia occurred in three patients (7.5%); 19% of patients presented local toxicity; neurotoxicity and alopecia were not seen.

The toxicity profile of the 3-hour infusion at 1,300 µg/m² compares favorably with that of 1,500 µg/m² infused during 24 hours.¹³ With the latter dose and schedule, tested in patients with soft tissue sarcoma pretreated with at least one combination chemotherapy, 61% of patients developed severe neutropenia, 7% had febrile neutropenia, and 80% developed asthenia, which was severe in 15%.¹⁷

In the present study, at 1,300 µg/m², 37% of cycles were administered at a reduced dose, mainly because of a mild increase of AP and/or bilirubin, according to protocol. In addition, 37% of cycles were delayed, mainly because of lack of recovery of AST or ALT and/or absolute neutrophil count 1 week after the day scheduled for re-treatment. However, only two patients discontinued treatment because of lack of hematologic recovery, whereas none discontinued because of liver toxicity. Overall, the data on tolerability indicate that trabectedin at 1,300 µg/m² infused during 3 hours every 3 weeks with corticosteroid premedication is feasible and applicable for multiple cycles to the majority of patients already treated with one or more lines of chemotherapy.

The antitumor activity observed is notable. The 43% overall response rate (95% CI, 23% to 65%) assessed by independent peer review in platinum-sensitive patients, is in keeping with the preclinical antitumor activity in ovarian cancer models.¹¹ One patient achieved a CR of 8.7 months and nine patients achieved a PR, with a median time to progression of 7.9 months (95% CI, 7.5 to 14.1 months).

Although sporadic responses were observed in platinum-resistant patients, the 15% activity threshold required by the trial's design was not reached, suggesting that trabectedin might not have an important role as salvage treatment in this category. However, recent mechanistic and experimental data indicate that the combination of cisplatin and trabectedin could overcome platinum resistance in vitro and in vivo.¹¹ A 2-weeks-on and 2-weeks-off combination of trabectedin and cisplatin is currently in a phase I trial, and three objective responses were observed in 10 platinum-resistant ovarian cancer patients.¹⁹

Recently, a new schedule of weekly trabectedin was tested,¹⁴ and results indicated that a higher dose-intensity per cycle can be administered. In an ongoing multicenter, single-arm, phase II study, the interim response rate of weekly trabectedin in ovarian cancer patients with characteristics comparable to those of our study was 22% in platinum-sensitive patients and 5% in platinum-resistant patients.²⁰

The observation that antitumor activity of weekly trabectedin in platinum-resistant patients with soft tissue sarcoma was somewhat lower than that reported with the once-every-3-weeks schedule infused over 24 hours lends weight to the hypothesis that the schedule not only influences tolerability but also might affect the antitumor activity.²¹

Salvage treatment of women with ovarian carcinoma who experience treatment failure after platinum and taxane is limited. Liposomal doxorubicin may be considered the drug of choice, although its use is hampered by a 49% incidence of hand-foot syndrome (severe in 22% of patients).²² The response rate in platinum-sensitive patients is 28%, with a median progression-free survival of 28.9 weeks,²³ whereas in platinum- and paclitaxel-refractory ovarian cancer patients, liposomal doxorubicin is 19%.²²,²³

Topotecan is also commonly used for salvage therapy, with a reported antitumor activity ranging between 13% and 33%, depending on sensitivity to prior platinum; only limited data are available in platinum- and taxane-resistant patients.²⁴,²⁵ Approximately 70% of patients treated with topotecan experienced severe neutropenia requiring treatment delays and/or dose reductions,²⁴,²⁵ which eventually led to the use of a dose in daily practice lower than the registered dose.

Finally, the good tolerability and second-line activity data prompted the inclusion of gemcitabine in front-line combinations, even though confirmatory results of antitumor activity in platinum- and paclitaxel-pretreated patients are not available.²⁶

In summary, when considering the results reported in this trial within the context of available knowledge on activity of established second- or third-line therapies for ovarian carcinoma, trabectedin stands as a drug that may play a definite therapeutic role. In addition, trabectedin does not cause adverse effects such as hair loss, stomatitis, and diarrhea, which can be clinically relevant for its use in combination with other therapies. The 20% occurrence of painful erythema at the injection site with residual sclerotic phlebitis after repeated administrations suggests that a central permanent venous access be positioned once lack of early disease progression is established in patients likely to continue treatment. The low incidence of hematologic toxicity and the absence of neurologic toxicity make trabectedin a suitable candidate for combinations with drugs active in ovarian cancer, such as platinum compounds and liposomal doxorubicin. A phase I study with cisplatin will be completed soon,¹⁹ and phase I combinations with liposomal doxorubicin and doxorubicin are ongoing in selected tumor types.

In conclusion, trabectedin is a new, active, and well-tolerated treatment for patients with epithelial ovarian cancer who experience disease relapse after platinum and taxanes. Combination studies with known active agents are justified by the toxicity profile and novel mechanism of action of trabectedin.

The 7% single-agent activity in platinum-resistant patients, although less encouraging, is also of interest in light of the experimental and preliminary clinical results suggesting a synergistic effect of the platinum and trabectedin combination in platinum-insensitive disease.

	Authors' Disclosures of Potential Conflicts of Interest

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The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Employment: José Jimeno, PharmaMar. Leadership position: José Jimeno, Zeltia/PharmaMar. Consultant/advisory role: Luca Gianni, PharmaMar; Maurizio D'Incalci, PharmaMar. Stock ownership: José Jimeno, Zeltia/PharmaMar. Honoraria: Luca Gianni, PharmaMar; Maurizio D'Incalci, PharmaMar. Other remuneration: Maurizio D'Incalci, PharmaMar. For a detailed description of these categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and Disclosures of Potential Conflicts of Interest found in Information for Contributors in the front of each issue.

	Acknowledgment

 
We thank Irene Corradino, Angelo Tinazzi, Annamalia Bartosek, Southern Europe New Drugs Organization (SENDO); the peer reviewers Stephen J. Gwyther and Jan P. Neijt, MD, PhD; and the Swiss League Against Cancer for their contribution to the SENDO.

	NOTES

 
Supported by PharmaMar, Madrid, Spain.

Presented in part at the 38th Annual Meeting of the American Society of Clinical Oncology, May 18-21, 2002, Orlando, FL.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
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Submitted September 7, 2004; accepted December 20, 2004.

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