Background: To determine the maximum tolerated dose (MTD), safety, potential pharmacokinetic (PK) interactions, and effect on liver histology of trabectedin in combination with pegylated liposomal doxorubicin (PLD) for advanced malignancies.
Patients and methods: Entry criteria for the 36 patients included normal liver function, prior doxorubicin exposure <250 mg/m2, and normal cardiac function. A 1-h PLD (30 mg/m2) infusion was followed immediately by one of six trabectedin doses (0.4, 0.6, 0.75, 0.9, 1.1, and 1.3 mg/m2) infused over 3 h, repeated every 21 days until evidence of complete response (CR), disease progression, or unacceptable toxicity. Plasma samples were obtained to assess PK profiles.
Results: The MTD of trabectedin was 1.1 mg/m2. Drug-related grade 3 and 4 toxic effects were neutropenia (31%) and elevated transaminases (31%). Six patients responded (one CR, five partial responses), with an overall response rate of 16.7%, and 14 had stable disease (less than a 50% reduction and less than a 25% increase in the sum of the products of two perpendicular diameters of all measured lesions and the appearance of no new lesions) >4 months (39%). Neither drug had its PK affected significantly by concomitant administration compared with trabectedin and PLD each given as a single agent.
Conclusion: Trabectedin combined with PLD is generally well tolerated at therapeutic doses of both drugs in pretreated patients with diverse tumor types and appears to provide clinical benefit. These results support the need for additional studies of this combination in appropriate cancer types.
ET-743; ovarian cancer; pegylated liposomal doxorubicin (PLD); sarcomas; trabectedin
To determine the dose of trabectedin plus doxorubicin with granulocyte colony stimulating factor (G-CSF) support associated with manageable neutropenia and acceptable dose-limiting toxicities (DLTs) in patients with recurrent or persistent soft tissue sarcoma (STS).
In this phase I, open-label, multicenter trial, patients previously treated with 0–1 prior chemotherapy regimens excluding doxorubicin, an ECOG performance status 0–1, and adequate organ function received a 10–15-minute intravenous (IV) infusion of doxorubicin 60 mg/m2 immediately followed by a 3-hour IV infusion of trabectedin 0.9–1.3 mg/m2 on day 1 of a 3-week cycle. Because four of the first six patients experienced DLT-defining neutropenia during cycle 1, all subsequent patients received primary prophylactic G-CSF. The maximum tolerated dose (MTD) was the highest dose level with ≥6 patients in which less than one third of the patients experienced severe neutropenia or DLT. Blood was collected during cycle 1 for pharmacokinetic analyses. Adverse events (AEs), tumor response, and survival were assessed.
Patients (N = 41) received a median of six cycles of treatment (range, 2–13). The MTD was trabectedin 1.1 mg/m2 and doxorubicin 60 mg/m2. Common grade 3/4 treatment-emergent AEs were neutropenia (71%), ALT increase (46%), and thrombocytopenia (37%). Overall, five (12%) patients achieved a partial response, and 34 (83%) maintained stable disease. Median progression-free survival was 9.2 months. Doxorubicin and trabectedin pharmacokinetics were not altered substantially with concomitant administration.
The combination of doxorubicin 60 mg/m2 followed by trabectedin 1.1 mg/m2 every 21 days is safe and active in patients with STS.
trabectedin; ET-743; doxorubicin; sarcoma; pharmacokinetics; YONDELIS
To determine the maximum tolerated dose (MTD) of trabectedin plus gemcitabine administered on a weekly schedule in patients with advanced solid tumors.
Patients with ECOG performance status 0–1 and adequate organ function were enrolled. On days 1, 8, and 15 of a 28-day cycle, patients received gemcitabine (starting dose, 800 mg/m2) followed by trabectedin (starting dose, 0.3 mg/m2). Strict liver function test treatment criteria were employed to avoid hepatic toxicity seen in previous trabectedin studies. Plasma samples were collected during cycles 1 and 2 for pharmacokinetic analyses.
Fifteen patients received ≥1 dose, with a median of two treatment cycles (range 1–10). The most common drug-related toxicity was hepatic. Dose reductions were required for trabectedin in four (27%) patients and gemcitabine in six (40%) patients. Cycle delays/dose holds were required in 11 (73%) patients and doses above trabectedin 0.4 mg/m2 and gemcitabine 1,000 mg/m2, which is the recommended phase II dose, were not feasible. Seven patients maintained stable disease after two cycles. Gemcitabine and trabectedin pharmacokinetics were not altered substantially with concomitant administration.
Given the lack of pharmacokinetic interaction and potential efficacy of trabectedin and gemcitabine combination therapy, further study is warranted with alternate schedules.
Dose-finding; Phase I; Gemcitabine; Pharmacokinetics; Trabectedin
The objectives of this phase I study were to determine the maximum tolerated dose (MTD), toxicity profile and pharmacokinetics of a 24-hour continuous intravenous infusion of trabectedin administered to children and adolescents with refractory or relapsed solid tumors.
Patients between the ages of 4 and 16 years old with refractory solid tumors received trabectedin as a 24-hour infusion every 21 days. Dexamethasone and prophylactic growth factor support were administered with each cycle. Pharmacokinetic studies were conducted during cycle 1.
Patients (n=12) median (range) age 14.5 (8–16) years received trabectedin at 1.1 (n=3), 1.5 (n=6) or 1.7 (n=3) mg/m2. At the 1.5 mg/m2 dose level, one patient had dose limiting anorexia and fatigue. At 1.7 mg/m2, 2 patients experienced dose limiting toxicity, dehydration and gamma-glutamyl transpeptidase (GGT) elevation. Non-dose limiting toxicities included elevated serum transaminases, myelosuppression, nausea, emesis and fatigue. Plasma pharmacokinetic parameters were similar to historical data in adults. One partial response (PR) was observed in a patient with neuroendocrine carcinoma. Stable disease (SD) (≥6 cycles) was achieved in 3 patients (osteosarcoma n=2, desmoplastic small round cell tumor n=1).
The MTD of trabectedin in pediatric patients with refractory solid tumors is 1.5 mg/m2 IV over 24 hours every 21 days. Dexamethasone to ameliorate hepatic toxicity and prophylactic growth factor support are required.
trabectedin; phase I clinical trial; pediatrics; pharmacokinetics
Soft tissue sarcoma accounts for less than 1% of all malignant neoplasms and is comprised of a very heterogeneous group of tumors with over 50 different subtypes. Due to its diversity and rarity, developing new therapeutics has been difficult, at best. The standard of care in the treatment of advanced and metastatic disease over the last 30 years has been doxorubicin and ifosfamide, either alone or in combination. There has been significant focus on developing new therapeutics to treat primary and metastatic disease. Trabectedin (ecteinascidin-743) is a tetrahydroiso-quinoline alkaloid which has been evaluated in the treatment of metastatic soft tissue sarcoma.
To review the current evidence for the therapeutic use of trabectedin in patients with soft tissue sarcoma.
Five phase I studies in patients with solid tumors, all of which include sarcoma patients, evaluating the dosing and toxicity of trabectedin were performed with efficacy being evaluated as a secondary endpoint. Additionally, there are four phase I trials evaluating trabectedin in combination with frontline therapeutic drugs in soft tissue sarcoma. Four phase II studies were performed in soft-tissue sarcoma patients with objective response rates ranging from 3.7% to 17.1%. Additionally, in two compassionate use trials, objective response rates between 14% and 51% were seen, the largest response resulting from a study specifically focusing on liposarcoma.
Place in therapy:
Trabectedin is a potential therapeutic option for the management of soft-tissue sarcoma. It appears to have specific activity in a select group of histologies, most notably myxoid/round cell liposarcoma. Although it would be helpful to study the use of trabectedin in a randomized, controlled fashion, the relative rarity of soft-tissue sarcoma, and heterogeneity of the histologic subtypes, makes phase III trials a difficult prospect.
soft tissue sarcoma; metastatic; trabectedin; ET-743; Yondelis®
Yondelis® (trabectedin, ET-743) is a novel marine-derived anticancer compound found in the ascidian Ecteinascidia turbinata. It is currently under phase II/III development in breast cancer, hormone refractory prostate cancer, sarcomas and ovarian cancer. Activity in breast cancer experimental models has been reported, and preliminary evidence of activity in this setting during the phase I programme has also been observed. The present study assessed the activity and feasibility of trabectedin in women with advanced breast cancer previously treated with conventional therapies. Patients with advanced disease previously treated with at least one but not more than two regimens that included taxanes or anthracyclines as palliative therapy were eligible. Trabectedin 1.5 mg m−2 was administered as a 24-h continuous infusion every 3 weeks. Patients were kept on therapy until disease progression, unacceptable toxicity or patient refusal. Twenty-seven patients were included between April 1999 and September 2000. Their median age was 54 years (range: 36–67) and 63% of them had two metastatic sites. Twenty-two patients were performance status 1. All patients had previously received anthracyclines, and 23 out of 27 patients had received taxanes. Of 21 patients with measurable disease, three confirmed partial responses, one unconfirmed partial response and two minor responses (49 and 32% tumour shrinkage) were observed; six patients had stable disease. Median survival was 10 months (95% confidence interval: 4.88–15.18). Transient and noncumulative transaminitis was observed in most of the patients. The pharmacokinetic profile of trabectedin in this patient's population is in line with the overall data available with this schedule. The policy of dose adjustments based on the intercycle peaks of bilirubin and alkaline phosphatase appears to have a positive impact in the therapeutic index of trabectedin. Trabectedin can induce response and tumour control in previously treated advanced breast cancer, with manageable toxicity, thus warranting further development as a single agent or in combination regimens.
Yondelis; trabectedin; breast cancer
A review of the literature was used to compare the tolerability, efficacy, and safety profiles of pegylated liposomal doxorubicin in combination with carboplatin with those of gemcitabine–carboplatin for the treatment of patients with platinum-sensitive recurrent ovarian cancer.
To compare the tolerability, efficacy, and safety profiles of pegylated liposomal doxorubicin in combination with carboplatin (PLD–Carbo) with those of gemcitabine–carboplatin (Gem–Carbo) for the treatment of patients with platinum-sensitive recurrent ovarian cancer (PSROC) by reviewing the published literature.
Using the PubMed database, a systematic review of peer-reviewed literature published between January 2000 and September 2009 was undertaken to identify studies related to the treatment of patients with PSROC with PLD–Carbo or Gem–Carbo. Studies reporting either response rate, progression-free survival (PFS), and/or overall survival (OS) were included. Treatment regimens, efficacy endpoints, and safety profiles were compared between the two combination therapies.
Ten studies evaluating 608 patients (PLD–Carbo: 5 studies, 278 patients; Gem–Carbo: 5 studies, 330 patients) were identified. The mean planned doses were: PLD, 34.8 mg/m2 and Gem, 993 mg/m2. The dose intensity reported in Gem trials was lower (75% of the planned dose) than the dose intensity reported in PLD trials (93.7% of the planned dose), suggesting better tolerability for the PLD–Carbo regimen. Among patients receiving PLD–Carbo, 60.2% achieved a response (complete, 27.0%; partial, 33.2%), versus 51.4% of patients treated with Gem–Carbo (complete, 19.2%; partial, 32.2%). The median PFS times were 10.6 months and 8.9 months in the PLD–Carbo and the Gem–Carbo populations, respectively. The median OS was longer for the PLD–Carbo regimen (27.1 months) than for the Gem–Carbo regimen (19.7 months). The hematological safety profiles were comparable in the two groups, although grade III or IV anemia (PLD–Carbo, 13.6%; Gem–Carbo, 24.5%) and neutropenia (PLD–Carbo, 45.5%; Gem–Carbo, 62.9%) were more common in patients receiving Gem–Carbo.
Results from this systematic analysis of peer-reviewed literature suggest that PLD–Carbo therapy is a rational alternative to Gem–Carbo for the treatment of patients with PSROC.
Ovarian cancer; Platinum; Pegylated liposomal doxorubicin; Gemcitabine; Carboplatin
A phase I clinical study was conducted to determine the maximum tolerated dose (MTD) and the recommended dose (RD) of irinotecan hydrochloride (CPT-11) in CPT-11/pegylated liposomal doxorubicin (PLD) combination therapy, a novel treatment regimen for platinum- and taxane-resistant recurrent ovarian cancer.
Pegylated liposomal doxorubicin was administered intravenously on day 3 at a fixed dose of 30 mg/m2. CPT-11 was administered intravenously on days 1 and 15, at a dose of 50 mg/m2 on both days. One course of chemotherapy was 28 days, and patients were given a maximum of six courses, with the CPT-11 dose being increased in increments of 10 mg/m2 (level 1, 50 mg/m2; level 2, 60 mg/m2; level 3, 70 mg/m2; level 4, 80 mg/m2) to determine MTD and RD.
During the period from April 2010 to March 2013, three patients were enrolled for each level. In the first course, no dose-limiting toxicity occurred in any of the patients. Grade 4 neutropenia was observed in two of three patients at level 4. At level 4, the antitumor effect was a partial response (PR) in two of the three patients and stable disease (SD) in one. At level 3, one of the three patients showed PR and two had SD. At level 4, the start of the next course was postponed in two of three patients. In addition, one patient at level 4 experienced hemotoxicity that met the criteria for dose reduction in the next course. The above results suggested that administration of CPT-11 at dose level 5 (90 mg/m2) would result in more patients with severe neutropenia and in more patients requiring postponement of the next course or a dose reduction. Based on the above, the RD of CPT-11 was determined to be 80 mg/m2.
The results suggest that CPT-11/PLD combination therapy for recurrent ovarian cancer is a useful treatment method with a high response rate and manageable adverse reactions. In the future phase II study, the safety and efficacy of this therapy will be assessed at 80 mg/m2 of CPT-11 and 30 mg/m2 of PLD.
Recurrent ovarian cancer; Chemotherapy; CPT-11; PLD
Trabectedin has mostly been studied in metastatic leiomyosarcoma and liposarcomas. Only limited data are available in other sarcoma subtypes, heavily pretreated and elderly patients. We retrospectively analyzed 101 consecutive sarcoma patients treated with trabectedin at our center. We recorded progression-free survival (PFS), clinical benefit rate (CBR, defined as complete or partial response or stable disease for at least 6 weeks) and toxicity. Covariates were sarcoma subtype, age and pretreatment. On average, trabectedin was administered for 2nd relapse/progression (range 1st to 12th line). A median of 2 cycles and a dose of 1.5 mg/m2 (range 1–21 cycles; 1.3–1.5 mg/m2) was administered. The median PFS under treatment with trabectedin was 2.1 months in the overall population. Different clinical outcomes were observed with respect to sarcoma subtypes: in patients with L-sarcoma [defined as leiosarcoma and liposarcoma (n=25)] the CBR was 55%. Notably, long lasting remissions were even observed in 7th-line treatment. In contrast, the majority of patients with non-L-sarcomas quickly progressed (median PFS 1.6 months). Nevertheless, a CBR of 34% was achieved, including long-lasting disease stabilization in subtypes such as rhabdomyosarcoma. Patients treated with trabectedin at 1st or 2nd line (n=16) achieved an improved PFS (median 5.7 months, range) and a CBR of 59%. No differences in terms of toxicity or efficacy were observed between patients older than 65 years (n=23) and younger patients (n=78). In this non-trial setting, port-associated complications were more frequent (14%) with trabectedin compared to other continuous infusion protocols administered at our outpatient therapy center. The majority of patients with relapsing L-sarcomas and a substantial fraction of patients with non-L-sarcomas derive a clinically meaningful benefit from trabectedin. Outpatient treatment is well tolerated also in elderly and heavily pretreated patients. Port-associated complications were observed at an unusually high rate. This suggests a drug-specific local toxicity that merits further investigation.
sarcoma; trabectedin; port complication
To determine the maximum tolerated doses (MTDs) and dose-limiting toxicities (DLTs) of pegylated liposomal doxorubicin (PLD), paclitaxel (PCX) and gemcitabine (GEM) combination administered biweekly in patients with advanced solid tumours. Twenty-two patients with advanced-stage solid tumours were treated with escalated doses of PLD on day 1 and PCX plus GEM on day 2 (starting doses: 10, 100 and 800 mg m−2, respectively) every 2 weeks. DLTs and pharmacokinetic (PK) parameters of all drugs were determined during the first cycle of treatment. All but six (73%) patients had previously received at least one chemotherapy regimen. The DLT dose level was reached at PLD 12 mg m−2, PCX 110 mg m−2 and GEM 1000 mg m−2 with neutropaenia being the dose-limiting event. Of the 86 chemotherapy cycles delivered, grade 3 and 4 neutropaenia occurred in 20% with no cases of febrile neutropaenia. Non-haematological toxicities were mild. The recommended MTDs are PLD 12 mg m−2, PCX 100 mg m−2 and GEM 1000 mg m−2 administered every 2 weeks. The PK data revealed no obvious drug interactions. Biweekly administration of PLD, PCX and GEM is a well-tolerated chemotherapy regimen, which merits further evaluation in various types of solid tumours.
doxorubicin; gemcitabine; paclitaxel; pharmacokinetics
This multicenter phase II trial evaluated the efficacy and safety of trabectedin in metastatic castration-resistant prostate cancer (CRPC).
Patients and methods:
Two schedules were evaluated in three cohorts: weekly as 3-h i.v. infusion at 0.58 mg/m2 for 3 out of 4 weeks (Cohort A, n = 33), and every 3 weeks (q3wk) as 24-h infusion at 1.5 mg/m2 (Cohort B1, n = 5) and 1.2 mg/m2 (Cohort B2, n = 20). The primary end point was prostate-specific antigen (PSA) response; secondary end points included safety, tolerability and time to progression (TTP).
Trabectedin resulted in PSA declines ≥50% in 12.5% (Cohort A) and 10.5% (Cohort B2) of patients. Among men pretreated with taxane-based chemotherapy, PSA response was 13.6% (Cohort A) and 15.4% (Cohort B2). PSA responses lasted 4.1–8.6 months, and median TTP was 1.5 months (Cohort A) and 1.9 months (Cohort B2). The dose of 1.5 mg/m2 (approved for soft tissue sarcoma) given as 24-h infusion q3wk was not tolerable in these patients. At 1.2 mg/m2 q3wk and 0.58 mg/m2 weekly, the most common adverse events were nausea, fatigue and transient neutropenia and transaminase increase.
Two different trabectedin schedules showed modest activity in metastatic CRPC. Further studies may require identification of predictive factors of response in prostate cancer.
chemotherapy; docetaxel; prostate cancer; second-line; trabectedin
Canfosfamide is a novel glutathione analog activated by glutathione S-transferase P1-1. This study evaluated the safety and efficacy of canfosfamide in combination with pegylated liposomal doxorubicin (PLD) in patients with platinum resistant ovarian cancer. Patients with platinum resistant ovarian carcinoma and measurable disease received canfosfamide at 960 mg/m2 in combination with PLD at 50 mg/m2, intravenously day 1 in every 28 day cycles until tumor progression or unacceptable toxicities. The primary endpoints were objective response rate (ORR) and progression-free survival (PFS).
Canfosfamide plus PLD combination therapy was administered at 960/50 mg/m2, respectively. Thirty-nine patients received a median number of 4 cycles (range 1.0-18.0). The ORR was 27.8% (95% CI, 14.2-45.2) with a disease stabilization rate of 80.6% (95% CI, 64.0-91.8) in the evaluable population. The CA-125 marker responses correlated with the radiological findings of complete response or partial response. The median PFS was 6.0 months (95% CI, 4.2-7.9) and median survival was 17.8 months. The combination was well tolerated. Myelosuppression was managed with dose reductions and growth factor support. Grade 3 febrile neutropenia was observed in 2 patients (5.1%). Non-hematologic adverse events occurred at the expected frequency and grade for each drug alone, with no unexpected or cumulative toxicities.
Canfosfamide in combination with PLD is well tolerated and active in platinum and paclitaxel refractory or resistant ovarian cancer. A randomized phase 3 study was conducted based on this supportive phase 2 study.
This study was registered at www.clinicaltrials.gov: NCT00052065.
Rhabdomyolysis is an uncommon side effect of trabectedin which is used for the second line therapy of metastatic sarcoma after anthracycline and ifosfamide failure. This side effect may be due to pharmacokinetic interactions caused by shared mechanisms of metabolism involving the cytochrome P450 (CYP) system in the liver. Here, for the first time in literature, we describe the unexpected onset of heavy toxicity, including rhabdomyolysis, after the fourth course of trabectedin in a patient with retroperitoneal liposarcoma who at the same time was taking an alternative herbal medicine suspected of triggering this adverse event.
This is the case of a 56 year old Caucasian man affected by a relapsed de-differentiated liposarcoma who, after the fourth cycle of second-line chemotherapy with trabectedin, complained of sudden weakness, difficulty walking and diffuse muscle pain necessitating complete bed rest. Upon admission to our ward the patient showed grade (G) 4 pancytopenia and a marked increase in liver lytic enzymes, serum levels of myoglobin, creatine phosphokinase (CPK) and lactate dehydrogenase. No cardiac or kidney function injuries were present. Based on these clinical and laboratory features, our conclusive diagnosis was of rhabdomyolysis induced by trabectedin.
The patient did not report any trauma or muscular overexertion and no co-morbidities were present. He had not received any drugs during treatment with trabectedin, but upon further questioning the patient informed us he had been taking a folk medicine preparation of chokeberry (Aronia melanocarpa) daily during the last course of trabectedin and in the 2 subsequent weeks.
One week after hospitalization and cessation of intake of chokeberry extract, CPK and other markers of myolysis slowly returned to standard range, and the patient noted a progressive recovery of muscle strength.
The patient was discharged on day 14 when a blood transfusion and parenteral hydration gradually lowered general toxicity. Progressive mobilization of the patient was obtained as well as a complete normalization of the laboratory findings.
The level of evidence of drug interaction leading to the adverse event observed in our patient was 2 (probable). Thus our case underlines the importance of understanding rare treatment-related toxicities such as trabectedin-induced rhabdomyolysis and the possible role of the drug-drug interactions in the pathogenesis of this rare side effect. Furthermore, this report draws attention to a potential problem of particular concern, that of nutritional supplements and complementary and alternative drug interactions. These are not widely recognized and can cause treatment failure.
Trabectedin related rhabdomyolysis; Liposarcomas; Drug-drug interactions; Chokeberry (Aronia melanocarpa)-drugs interaction
Occurrences of oral squamous cell carcinoma in patients who received long-term pegylated liposomal doxorubicin for ovarian cancer are reported.
After completing this course, the reader will be able to:
Compare the risk of secondary cancer versus benefits of maintenance therapy for women with ovarian cancer who have a complete response to pegylated liposomal doxorubicin.Explain the need to perform regular and frequent oral examinations in women with ovarian cancer who received treatment with pegylated liposomal doxorubicin.
This article is available for continuing medical education credit at CME.TheOncologist.com
To describe occurrences of oral squamous cell carcinoma (SCC) in patients who had received long-term pegylated liposomal doxorubicin (PLD) for ovarian cancer.
Patients and Methods.
In our cohort of patients on maintenance PLD for ovarian and related mullerian epithelial malignancies, we encountered two patients with invasive SCC of the oral cavity (one of them multifocal) and one with high-grade squamous dysplasia. Review of patients at our institution receiving PLD for recurrent ovarian cancer identified three additional patients. The duration of treatment, cumulative PLD dose, human papillomavirus (HPV) positivity, BRCA status, stage at diagnosis, outcome, and other characteristics are reviewed.
All five cases were nonsmokers with no known risk factors for HPV and four were negative for p16 expression. Four of the patients had known BRCA mutations whereas one tested negative. Cumulative doses of PLD were >1,600 mg/m2 given over 30–132 months. Three had SCCs staged as T1N0 oral tongue, alveolar ridge (gingival), and multifocal oral mucosa; one had a T2N0 oral tongue; and one had dysplasia. After excision, two were given radiation but recurred shortly thereafter; the others remain well and have had no further exposure to cytotoxic drugs, including PLD.
Awareness of this possible long-term complication during PLD treatment should enhance the likelihood of early detection of oral lesions in these patients. Decisions to continue maintenance PLD after complete response of the original cancer should perhaps consider the benefits of delaying ovarian cancer recurrence versus the possible risk for a secondary cancer.
Head and neck secondary malignancies; Pegylated liposomal doxorubicin; Secondary malignancy; Oral SCC as side effect; Ovarian cancer
The primary objective of this study was to access the potential effects of trabectedin on the QT/QTc interval in patients with locally advanced or metastatic solid tumors.
Patients (n = 75) who had received ≤3 previous lines of chemotherapy and had either relapsed or had progressive disease were enrolled. Patients were administered 3-h intravenous infusions of placebo (saline) on day 1 and trabectedin (1.3 mg/m2) on day 2. Time-matched serial triplicate ECG recordings and pharmacokinetic blood samples were collected over 24 h on both days. Heart rate corrected mean QT intervals and changes from predose baseline in QTc (ΔQTc) were assessed. The difference in ΔQTc between trabectedin and placebo was calculated at each time point (ΔΔQTc).
The upper limits of the 90% confidence interval for ΔΔQTcF and ΔΔQTcB at all time points were less than the prespecified noninferiority margin of 10 ms (≤6.65 ms). No patient had a QTc > 500 ms or a time-matched increase from baseline in QTc > 60 ms at any time point. Regression analyses indicated ΔΔQTc was poorly correlated with trabectedin concentration. No adverse events suggestive of proarrhythmic potential were reported.
Trabectedin did not prolong the QTc interval. Safety and pharmacokinetic profiles of trabectedin were similar to that observed in other ovarian and breast cancer studies.
Anti-tumor; ECG; Malignancies; QTc interval; Trabectedin
Interest in marine natural products has allowed the discovery of new drugs and trabectedin (ET-743, Yondelis), derived from the marine tunicate Ecteinascidia turbinata, was approved for clinical use in 2007. It binds to the DNA minor groove leading to interferences with the intracellular transcription pathways and DNA-repair proteins. In vitro antitumor activity was demonstrated against various cancer cell lines and soft tissue sarcoma cell lines. In phase I studies tumor responses were observed also in osteosarcomas and different soft tissue sarcoma subtypes. The most common toxicities were myelosuppression and transient elevation of liver function tests, which could be reduced by dexamethasone premedication. The efficacy of trabectedin was established in three phase II studies where it was administered at 1.5 mg/m2 as a 24 h intravenous infusion repeated every three weeks, in previously treated patients. The objective response rate was 3.7%–8.3% and the tumor control rate (which included complete response, partial response and stable disease) was obtained in half of patients for a median overall survival reaching 12 months. In nonpretreated patients the overall response rate was 17%. Twenty-four percent of patients were without progression at six months. The median overall survival was almost 16 months with 72% surviving at one year. Predictive factors of response are being explored to identify patients who are most likely to respond to trabectedin. Combination with other agents are currently studied with promising results. In summary trabectedin is an active new chemotherapeutic agents that has demonstrated its role in the armamentarium of treatments for patients with sarcomas.
soft tissue sarcoma; trabectedin; chemotherapy; DNA-minor groove binder
AIM: To assess the efficacy and safety of the combination of pegylated liposomal doxorubicin (PLD) and carboplatin in patients with recurrent epithelial ovarian carcinoma (ROC), following disease progression on single agent PLD.
METHODS: An analysis of the medical records of 10 patients with ROC, treated in our institution with a combination of PLD and carboplatin following progression on single-agent PLD therapy was performed. The median age was 59.1 years (range, 45 to 77 years). All diagnoses were histological-proven. Eight of the 10 patients were platinum-resistant. Following disease progression on single-agent PLD treatment, carboplatin area under the curve (AUC)-5 was added to PLD in all 10 patients. In order to assess disease status, Ca-125 was assessed before each PLD/carboplatin treatment. Relative changes in Ca-125 values were calculated, and response defined as a greater than 50% reduction in Ca-125 from baseline. Radiographic studies were re-evaluated and responses to therapy based on computer tomography (CT) scans carried out on a regular basis every 2-3 mo in each patient. Statistical analysis was performed using SPSS (V19).
RESULTS: A median of 10 cycles (range, 2-26) of the carboplatin-PLD combination was given. Of the 10 treated patients, 6 had > 50% reduction in Ca-125 levels from baseline, 4 of these had a partial response according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria, and the other 2 patients had no measurable disease. In a further 2 patients with a best response of disease stabilization and < 50% reduction of Ca-125 levels, one had progression of disease after 26 cycles, and the second progressed with brain metastases following 12 cycles. Seven of the eight patients who were platinum-resistant showed evidence of clinical benefit on carboplatin-PLD combination therapy; 5 of these had > 50% reduction in Ca-125 level, 4 also showed a partial response on CT scan. The treatment was generally well-tolerated by the patients.
CONCLUSION: Addition of carboplatin to PLD, after disease progression on single-agent PLD therapy, is both effective and safe in patients with ROC, even in those with Platinum-resistant disease.
Pegylated liposomal doxorubicin; Carboplatin; Ovarian cancerchemotherapy; Platinum-resistant ovarian cancer; Platinum sensitive ovarian cancer
To determine how the accumulation of drug in mice bearing an extra-hepatic tumor and its therapeutic efficacy are affected by the type of PEGylated liposomal doxorubicin used, treatment modality, and rate of drug release from the liposomes, when combined with radiofrequency (RF) ablation.
Materials and Methods
Two nano-drugs, both long-circulating PEGylated doxorubicin liposomes, were formulated: (1) PEGylated doxorubicin in thermosensitive liposomes (PLDTS), having a burst-type fast drug release above the liposomes’ solid ordered to liquid disordered phase transition (at 42°C), and (2) non-thermosensitive PEGylated doxorubicin liposomes (PLDs), having a slow and continuous drug release. Both were administered intravenously at 8 mg/kg doxorubicin dose to tumor-bearing mice. Animals were divided into 6 groups: no treatment, PLD, RF, RF+PLD, PLDTS, and PLDTS+RF, for intra-tumor doxorubicin deposition at 1, 24, and 72 h post-injection (in total 41, mice), and 31 mice were used for randomized survival studies.
Non-thermosensitive PLD combined with RF had the least tumor growth and the best end-point survival, better than PLDTS+RF (p<0.005) or all individual therapies (p<0.001). Although at 1 h post-treatment the greatest amount of intra-tumoral doxorubicin was seen following PLDTS+RF (p<0.05), by 24 and 72 h the greatest doxorubicin amount was seen for PLD+RF (p<0.05); in this group the tumor also has the longest exposure to doxorubicin.
Optimizing therapeutic efficacy of PLD requires a better understanding of the relationship between the effect of RF on tumor microenvironment and liposome drug release profile. If drug release is too fast, the benefit of changing the microenvironment by RF on tumor drug localization and therapeutic efficacy may be much smaller than for PLDs having slow and temperature-independent drug release. Thus the much longer circulation time of doxorubicin from PLD than from PLDTS may be beneficial in many therapeutic instances, especially in extra-hepatic tumors.
Trabectedin, a new antitumor compound originally derived from a marine tunicate, is clinically effective in soft tissue sarcoma. The drug has shown a high selectivity for myxoid liposarcoma, characterized by the translocation t(12;16)(q13; p11) leading to the expression of FUS-CHOP fusion gene. Trabectedin appears to act interfering with mechanisms of transcription regulation. In particular, the transactivating activity of FUS-CHOP was found to be impaired by trabectedin treatment. Even after prolonged response resistance occurs and thus it is important to elucidate the mechanisms of resistance to trabectedin. To this end we developed and characterized a myxoid liposarcoma cell line resistant to trabectedin (402-91/ET), obtained by exposing the parental 402-91 cell line to stepwise increases in drug concentration. The aim of this study was to compare mRNAs, miRNAs and proteins profiles of 402-91 and 402-91/ET cells through a systems biology approach. We identified 3,083 genes, 47 miRNAs and 336 proteins differentially expressed between 402-91 and 402-91/ET cell lines. Interestingly three miRNAs among those differentially expressed, miR-130a, miR-21 and miR-7, harbored CHOP binding sites in their promoter region. We used computational approaches to integrate the three regulatory layers and to generate a molecular map describing the altered circuits in sensitive and resistant cell lines. By combining transcriptomic and proteomic data, we reconstructed two different networks, i.e. apoptosis and cell cycle regulation, that could play a key role in modulating trabectedin resistance. This approach highlights the central role of genes such as CCDN1, RB1, E2F4, TNF, CDKN1C and ABL1 in both pre- and post-transcriptional regulatory network. The validation of these results in in vivo models might be clinically relevant to stratify myxoid liposarcoma patients with different sensitivity to trabectedin treatment.
Among the pharmaceutical options available for treatment of ovarian cancer, increasing attention has been progressively focused on pegylated liposomal doxorubicin (PLD), whose unique formulation prolongs the persistence of the drug in the circulation and potentiates intratumor accumulation. Pegylated liposomal doxorubicin (PLD) has become a major component in the routine management of epithelial ovarian cancer. In 1999 it was first approved for platinum-refractory ovarian cancer and then received full approval for platinum-sensitive recurrent disease in 2005. PLD remains an important therapeutic tool in the management of recurrent ovarian cancer in 2012. Recent interest in PLD/carboplatin combination therapy has been the object of phase III trials in platinum-sensitive and chemonaïve ovarian cancer patients reporting response rates, progressive-free survival, and overall survival similar to other platinum-based combinations, but with a more favorable toxicity profile and convenient dosing schedule. This paper summarizes data clarifying the role of pegylated liposomal doxorubicin (PLD) in ovarian cancer, as well as researches focusing on adding novel targeted drugs to this cytotoxic agent.
Trabectedin is a new marine-derived compound that binds the DNA minor groove and interacts with proteins of the DNA repair machinery. Phase I trials have established the standard regimen as 1500 μg/m2 24-hour continuous infusion repeated every 3 weeks. Several phase II trials have shown response in 5%–10% of unselected patients with soft tissue sarcoma failing prior chemotherapy and disease stabilisation in 30%–40%. Furthermore, prolonged disease control has been described in 15%–20% of patients. Toxicities are mainly haematological and hepatic with grade 3–4 neutropenia and thrombocytopenia observed in approximately 50% and 20% of patients respectively, and grade 3–4 elevation of liver enzymes observed in 35%–50% of patients treated with trabectedin. Current research focuses on the identification of predictive factors for patients with soft tissue sarcoma treated with trabectedin.
chemotherapy; sarcoma; drug development; DNA repair
Pegylated liposomal doxorubicin (PLD) is active in metastatic breast cancer. This observational study evaluated the efficacy and safety of PLD in patients treated during routine clinical practice.
Eligible patients had metastatic breast cancer and were treated with PLD according to the dose and schedule determined by their physician as part of routine practice. The primary objectives were to analyze the efficacy and toxicity of PLD therapy.
125 patients were assessable. Median age was 62 years, 78% had performance status 0-1, and 60% had estrogen-receptor-positive disease. PLD treatment was second- or third-line in 69% of patients. Prior anthracyclines (adjuvant or metastatic) had been used in 56% of patients. The majority of patients (79%) received PLD every 4 weeks at a median dose of 40 mg/m2. Overall response rate was 43% in all patients and 34% in those previously treated with anthracyclines. The most common grade 3/4 adverse events were skin toxicity/hand-foot syndrome (6%), and leukopenia (3%).
This observational study supports the activity and tolerability of PLD in metastatic breast cancer as demonstrated in PLD clinical trials.
Background: Pegylated liposomal doxorubicin (PLD), a formulation with pharmacokinetic differences with respect
to doxorubicin (DXR), might benefit patients with advanced soft tissue sarcoma (STS) pretreated with DXR.
Patients and methods: Patients with measurable and progressive STS received PLD at 35 mg/2 every 3 weeks. Quality of life before and during treatment was assessed with EORTC QLQ-C30.
Results: Twenty-eight patients, 22 DXR-pretreated, were given 140 cycles (median 3, range 1–18). Activity in 27 patients
(5 GIST): one complete and one partial remission (both non-GIST and without prior DXR), 12 stabilizations and
13 progressions (response rate 7.4%, 95% CI: 0–17%). Grade 3 toxicity: palmar-plantar erythrodysesthesia (19% of
patients), stomatitis (4%) or cutaneous (4%). Neutropenia grade≥3 was detected in 16% of patients. Median relative
dose intensity was 95%. Progression-free rate at 3 and 6 months was, respectively, 48 and 22%, median progression-free
survival 5.8 months and median overall survival 8.7 months. QLQ-C30 at baseline and at weeks 6–11 in 23 and 13 patients,
respectively, showed good reliability and validity. Quality of life did not seem to worsen during therapy.
Conclusions: PLD did not induce objective remissions in 22 STS patients pretreated with DXR, but progression-free
rate figures support the use of this agent in patients who have not progressed under a DXR-containing regimen.
The toxicity observed was comparable to that of other PLD schedules.
We report the case of a 60-year-old woman with metastatic high-grade uterine leiomyosarcoma who achieved a delayed response to second-line therapy with the marine-derived drug trabectedin (Yondelis®, PharmaMar). We used 2-deoxy-2-[18F] fluorodeoxyglucose (FDG)-positron emission tomography (PET-CT) imaging as a tool for response monitoring in parallel with conventional re-staging according to Response Evaluation Criteria in Solid Tumours (RECIST) using computed tomography (CT). We illustrate the role of serial 18FDG-PET-CT imaging in the functional assessment of tumour response. Three cycles after commencement of trabectedin treatment, a reduction of the maximum standardized uptake value (SUVmax) of the solid component of the pelvic mass was observed, indicating a cystic or necrotic response in the tumour to trabectedin. After 7 cycles of treatment, on 18FDG-PET-CT there was clear evidence of ongoing disease improvement: the solid pelvic components were at worst stable, with an unchanged SUVmax, and possibly marginally reduced in size, while the pulmonary metastases had further reduced in size and become FDG negative; the bony metastases were stable. After a total of 13 cycles of treatment, administered over 13 months, the patient showed signs of progression on an 18FDG-PET-CT scan. The safety profile of trabectedin remained manageable, showing no evidence of cumulative toxicity and being associated with a preserved quality of life. This report illustrates potential limitations of RECIST in response assessments and the critical role of serial 18FDG-PET-CT imaging in assessing response to trabectedin treatment. Therefore, we propose that 18FDG-PET-CT may improve the assessment of response to trabectedin in selected patients.
Sarcoma; Trabectedin; Delayed response; 18FDG-PET-CT; Uterine leiomyosarcoma
Previously, we have shown that the intraductal (i.duc) administration of pegylated liposomal doxorubicin (PLD) to Her2/neu transgenic mice is associated with mammary tumor regression and prevention. Exploring the mechanism underlying the protection afforded by PLD, we studied: the effects of i.duc PLD-treatment with a subsequent pregnancy on outgrowth of tumors in Her2/neu mice; whether the i.duc PLD antitumor effect was mediated partially through changes in normal mammary stem cells (MaSCs); and the long-term safety of i.duc PLD into the normal mouse mammary gland. Her2/neu mice were treated with two i.duc injections of PLD given four weeks apart; pregnancy was induced and mice were followed up for changes in physiology, and tumor formation. We found that all pups born to i.duc PLD-treated Her2/neu mice died without weight gain within 7 days after birth. Despite an additional pregnancy, compared to vehicle control PLD-treated Her2/neu mice had a significantly longer latency and lower frequency of tumor development. Mammary epithelial cells isolated from untreated and i.duc PLD-treated 6–8 months-old multiparous FVB/N mice were analyzed for their repopulating ability in mammary fat pads of naïve recipients. Mice were also monitored for abnormalities in mammary gland morphology and function, including tumor formation. PLD-treated FVB/N mice displayed histomorphologic changes and a significant reduction in the outgrowth potential of cells from the mammary glands. Thus, i.duc PLD administration altered the mammary gland structurally and functionally by reducing the MaSC population, which could compromise milk production. Followed long term, i.duc PLD-treated FVB/N mice developed malignant mammary tumors, confirming similar published findings on doxorubicin injected into the mammary gland of rats. Unless there are fundamental species differences in PLD metabolism in rodents and humans, this finding seriously limits the consideration of i.duc PLD use in the clinic for treatment or prevention of breast cancer.
Intraductal; Mammary; Carcinogenesis; Doxorubicin; Stem cell