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1.  A Phase I Study of the Safety and Pharmacokinetics of Trabectedin in Combination With Pegylated Liposomal Doxorubicin in Patients With Advanced Malignancies 
SUMMARY
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-hour PLD (30 mg/m2) infusion was followed immediately by 1 of 6 trabectedin doses (0.4, 0.6, 0.75, 0.9, 1.1, and 1.3 mg/m2) infused over 3 hours, repeated every 21 days until evidence of complete response (CR), disease progression, or unacceptable txicity. Plasma samples were obtained to assess PK profiles.
Results
The MTD of trabectedin was 1.1 mg/m2. Drug-related grade 3 and 4 toxicities were neutropenia (31%) and elevated transaminases (31%). Six patients responded (1 CR, 5 partial responses), with an overall response rate of 16.7%, and 14 had stable disease >4 months (39%). Neither drug had its PK affected significantly by concomitant administration compared to 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.
doi:10.1093/annonc/mdn363
PMCID: PMC2598415  PMID: 18497430
trabectedin; ET-743; pegylated liposomal doxorubicin (PLD); sarcomas; ovarian cancer
2.  New developments in treatment of ovarian carcinoma: focus on trabectedin 
Trabectedin is a new marine-derived compound that binds the DNA minor groove and interacts with proteins of the DNA repair machinery. Trabectedin has shown promising single-agent activity in pretreated patients with soft tissue sarcoma, and ovarian and breast cancer, and combination with various other chemotherapeutic drugs seems feasible. Toxicities are mainly hematologic 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. The recently reported results of a large Phase III trial comparing pegylated liposomal doxorubicin (PLD) alone with a combination of PLD and trabectedin in patients with recurrent ovarian cancer showed improved progression-free survival with the combination of trabectedin and PLD, albeit at the price of increased toxicity. Current research focuses on the identification of predictive factors for patients treated with trabectedin, as well as the development of other combinations.
doi:10.2147/CMR.S9459
PMCID: PMC3004573  PMID: 21188115
chemotherapy; ovarian cancer; combination; drug development; DNA repair
3.  A dose escalation and pharmacokinetic study of biweekly pegylated liposomal doxorubicin, paclitaxel and gemcitabine in patients with advanced solid tumours 
British Journal of Cancer  2007;97(1):43-49.
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.
doi:10.1038/sj.bjc.6603832
PMCID: PMC2359662  PMID: 17551496
doxorubicin; gemcitabine; paclitaxel; pharmacokinetics
4.  Phase I trial of weekly trabectedin (ET-743) and gemcitabine in patients with advanced solid tumors 
Purpose
To determine the maximum tolerated dose (MTD) of trabectedin plus gemcitabine administered on a weekly schedule in patients with advanced solid tumors.
Methods
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.
Results
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.
Conclusions
Given the lack of pharmacokinetic interaction and potential efficacy of trabectedin and gemcitabine combination therapy, further study is warranted with alternate schedules.
doi:10.1007/s00280-008-0733-7
PMCID: PMC3556988  PMID: 18379785
Dose-finding; Phase I; Gemcitabine; Pharmacokinetics; Trabectedin
5.  A Phase I Trial and Pharmacokinetic Study of a 24-hour Infusion of Trabectedin (Yondelis®, ET-743) in Children and Adolescents with Relapsed or Refractory Solid Tumors 
Pediatric blood & cancer  2012;59(5):865-869.
Background
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.
Procedure
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.
Results
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).
Conclusions
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.
doi:10.1002/pbc.24201
PMCID: PMC3442122  PMID: 22847981
trabectedin; phase I clinical trial; pediatrics; pharmacokinetics
6.  Phase I study of pegylated liposomal doxorubicin and the multidrug-resistance modulator, valspodar 
British Journal of Cancer  2005;93(1):46-53.
Valspodar, a P-glycoprotein modulator, affects pharmacokinetics of doxorubicin when administered in combination, resulting in doxorubicin dose reduction. In animal models, valspodar has minimal interaction with pegylated liposomal doxorubicin (PEG-LD). To determine any pharmacokinetic interaction in humans, we designed a study to determine maximum tolerated dose, dose-limiting toxicity (DLT), and pharmacokinetics of total doxorubicin, in PEG-LD and valspodar combination therapy in patients with advanced malignancies. Patients received PEG-LD 20–25 mg m−2 intravenously over 1 h for cycle one. In subsequent 2-week cycles, valspodar was administered as 72 h continuous intravenous infusion with PEG-LD beginning at 8 mg m−2 and escalated in an accelerated titration design to 25 mg m−2. Pharmacokinetic data were collected with and without valspodar. A total of 14 patients completed at least two cycles of therapy. No DLTs were observed in six patients treated at the highest level of PEG-LD 25 mg m−2. The most common toxicities were fatigue, nausea, vomiting, mucositis, palmar plantar erythrodysesthesia, diarrhoea, and ataxia. Partial responses were observed in patients with breast and ovarian carcinoma. The mean (range) total doxorubicin clearance decreased from 27 (10–73) ml h−1 m−2 in cycle 1 to 18 (3–37) ml h−1 m−2 with the addition of valspodar in cycle 2 (P=0.009). Treatment with PEG-LD 25 mg m−2 in combination with valspodar results in a moderate prolongation of total doxorubicin clearance and half-life but did not increase the toxicity of this agent.
doi:10.1038/sj.bjc.6602653
PMCID: PMC2361488  PMID: 15942626
doxil; multidrug resistance; pegylated liposomal doxorubicin; PSC 833; valspodar
7.  A Phase I Combination Study of Trabectedin and Doxorubicin in Patients With Soft Tissue Sarcoma 
Purpose
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).
Methods
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.
Results
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.
Conclusion
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.
doi:10.1158/1078-0432.CCR-08-0336
PMCID: PMC2777645  PMID: 18927308
trabectedin; ET-743; doxorubicin; sarcoma; pharmacokinetics; YONDELIS
8.  Phase 2 study of canfosfamide in combination with pegylated liposomal doxorubicin in platinum and paclitaxel refractory or resistant epithelial ovarian cancer 
Background
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).
Results
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.
Conclusions
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.
Trial Registration
This study was registered at www.clinicaltrials.gov: NCT00052065.
doi:10.1186/1756-8722-3-9
PMCID: PMC2851575  PMID: 20222977
9.  Trabectedin plus pegylated liposomal doxorubicin in relapsed ovarian cancer delays third-line chemotherapy and prolongs the platinum-free interval 
Annals of Oncology  2010;22(1):49-58.
Background: OVA-301 is a large randomized trial that showed superiority of trabectedin plus pegylated liposomal doxorubicin (PLD; CentoCor Ortho Biotech Products L.P., Raritan, NJ, USA). over single-agent PLD in 672 patients with relapsed ovarian cancer, particularly in the partially platinum-sensitive subgroup [platinum-free interval (PFI) of 6–12 months]. This superiority has been suggested to be due to the differential impact of subsequent (platinum) therapy.
Patients and methods: A detailed analysis of subsequent therapies and survival outcomes in the overall population and in the subsets according to platinum sensitivity was therefore conducted.
Results: Similar proportions of patients received subsequent therapy in each arm (76% versus 77%), including further platinum-based regimens (49% versus 55%). Patients in the trabectedin/PLD arm received subsequent chemotherapy at a later time (median delay 2.5 months versus PLD arm). Overall survival from subsequent platinum was significantly prolonged in the partially platinum-sensitive disease subset (hazard ratio = 0.63; P = 0.0357).
Conclusion: The superiority of trabectedin/PLD over single-agent PLD in OVA-301 cannot be explained by differences in the extent or nature of subsequent therapies administered to these patients. On the other hand, these exploratory analyses support the hypothesis that the enhanced survival benefits in the partially platinum-sensitive subset might be due to an extended PFI leading to longer survival with subsequent platinum.
doi:10.1093/annonc/mdq353
PMCID: PMC3003617  PMID: 20643863
pegylated liposomal doxorubicin; platinum-free interval; relapsed ovarian cancer; trabectedin
10.  Trabectedin plus pegylated liposomal doxorubicin in relapsed ovarian cancer: outcomes in the partially platinum-sensitive (platinum-free interval 6–12 months) subpopulation of OVA-301 phase III randomized trial 
Annals of Oncology  2010;22(1):39-48.
Background: OVA-301 is a large randomized trial that showed superiority of trabectedin plus pegylated liposomal doxorubicin (PLD) over PLD alone in relapsed ovarian cancer. The optimal management of patients with partially platinum-sensitive relapse [6–12 months platinum-free interval (PFI)] is unclear.
Patients and methods: Within OVA-301, we therefore now report on the outcomes for the 214 cases in this subgroup.
Results: Trabectedin/PLD resulted in a 35% risk reduction of disease progression (DP) or death [hazard ratio (HR) = 0.65, 95% confidence interval (CI), 0.45–0.92; P = 0.0152; median progression-free survival (PFS) 7.4 versus 5.5 months], and a significant 41% decrease in the risk of death (HR = 0.59; 95% CI, 0.43–0.82; P = 0.0015; median survival 23.0 versus 17.1 months). The safety of trabectedin/PLD in this subset mimicked that of the overall population. Similar proportions of patients received subsequent therapy in each arm (76% versus 77%), although patients in the trabectedin/PLD arm had a slightly lower proportion of further platinum (49% versus 55%). Importantly, patients in the trabectedin/PLD arm survived significantly longer after subsequent platinum (HR = 0.63; P = 0.0357; median 13.3 versus 9.8 months).
Conclusion: This hypothesis-generating analysis demonstrates that superior benefits with trabectedin/PLD in terms of PFS and survival in the overall population appear particularly enhanced in patients with partially sensitive disease (PFI 6–12 months).
doi:10.1093/annonc/mdq352
PMCID: PMC3003616  PMID: 20643862
pegylated liposomal doxorubicin; platinum-free interval; relapsed ovarian cancer; trabectedin
11.  Multiscale Kinetic Modeling of Liposomal Doxorubicin Delivery Quantifies the Role of Tumor and Drug-Specific Parameters in Local Delivery to Tumors 
Nanoparticle encapsulation has been used as a means to manipulate the pharmacokinetic (PK) and safety profile of drugs in oncology. Using pegylated liposomal doxorubicin (PLD) vs. conventional doxorubicin as a model system, we developed and experimentally validated a multiscale computational model of liposomal drug delivery. We demonstrated that, for varying tumor transport properties, there is a regimen where liposomal and conventional doxorubicin deliver identical amounts of doxorubicin to tumor cell nuclei. In mice, typical tumor properties consistently favor improved delivery via liposomes relative to free drug. However, in humans, we predict that some tumors will have properties wherein liposomal delivery delivers the identical amount of drug to its target relative to dosing with free drug. The ability to identify tumor types and/or individual patient tumors with high degree of liposome deposition may be critical for optimizing the success of nanoparticle and liposomal anticancer therapeutics.
doi:10.1038/psp.2012.16
PMCID: PMC3600732  PMID: 23835797
12.  Phase I trial of ixabepilone plus pegylated liposomal doxorubicin in patients with adenocarcinoma of breast or ovary†‡ 
Annals of Oncology  2010;21(10):2075-2080.
Background: Ixabepilone is a semisynthetic epothilone B analogue that is active in taxane-resistant cell lines and has shown activity in patients with refractory breast and ovarian cancer. We carried out a phase I trial of ixabepilone plus pegylated liposomal doxorubicin (PLD) in patients with advanced taxane-pretreated ovarian and breast cancer.
Methods: Patients with recurrent ovarian or breast carcinoma received PLD every 3 or 4 weeks plus five different dose schemas of ixabepilone in cohorts of three to six patients.
Results: Thirty patients received a total of 142 treatment cycles of the PLD–ixabepilone combination. The recommended phase II dose and schedule of ixabepilone was 16 mg/m2 on days 1, 8, and 15 plus PLD 30 mg/m2 given on day 1, repeated every 4 weeks. Hand–foot syndrome and mucositis were dose limiting when both ixabepilone and PLD were given every 3 or 4 weeks. Objective responses were observed in 3 of 13 patients (23%) with breast cancer and 5 of 17 patients (29%) with ovarian cancer.
Conclusion: Ixabepilone may be safely combined with PLD, but tolerability is highly dependent upon the scheduling of both agents. This combination demonstrated efficacy in patients with breast and ovarian cancer and merits further evaluation in these settings.
doi:10.1093/annonc/mdq080
PMCID: PMC2980936  PMID: 20357034
breast cancer; ixabepilone; liposomal doxorubicin; ovarian cancer
13.  A multicentric observational trial of pegylated liposomal doxorubicin for metastatic breast cancer 
BMC Cancer  2010;10:2.
Background
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.
Methods
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.
Results
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%).
Conclusions
This observational study supports the activity and tolerability of PLD in metastatic breast cancer as demonstrated in PLD clinical trials.
doi:10.1186/1471-2407-10-2
PMCID: PMC2806246  PMID: 20047698
14.  Phase 1/2 Study of Atrasentan Combined with Pegylated Liposomal Doxorubicin in Platinum-Resistant Recurrent Ovarian Cancer1 
Neoplasia (New York, N.Y.)  2010;12(11):941-945.
Background
Ovarian cancer overexpresses ET-1, and in vitro studies have shown that ET-1 confers resistance to anthracycline-containing chemotherapy. Atrasentan has been developed as an oral selective endothelin-A receptor antagonist. The objective of the study was to investigate the feasibility and toxicity of adding increasing doses of atrasentan (to a maximum of 10 mg/d) and liposomal doxorubicin in patients with progressive ovarian cancer, refractory for platinum and paclitaxel.
Methods
Patients with platinum-resistant ovarian cancer were treated with pegylated liposomal doxorubicin (PLD) 50 mg/m2 on day 1 (and repeated every 4 weeks) in combination with escalating doses of atrasentan once daily. The starting dose was 2.5 mg and escalated in cohorts of three patients from 5 to 10 mg.
Results
Twenty-six patients (mean age = 60 years, range = 42–74 years) were treated at the three dose levels. Atrasentan could be safely administered in combination at a dose of 10 mg. All patients were evaluable for toxicity, and 19 patients, included in the phase 2 period, were evaluable for response. Adverse events included nausea, vomiting, mucositis, skin toxicity, and rhinitis. Clinical cardiac toxicity, intensively monitored, was not observed, although two patients had a decrease in cardiac ejection fraction. Three objective responses were observed and another six patients had stable disease with a median time to progression of 14 weeks and an overall survival of 13.1 months.
Conclusions
The addition of atrasentan to standard dose PLD in platinum-resistant ovarian cancer is feasible with some suggestion of prolonged survival.
PMCID: PMC2978916  PMID: 21076619
15.  Trabectedin: the evidence for its place in therapy in the treatment of soft tissue sarcoma 
Core evidence  2010;4:191-198.
Introduction:
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.
Aims:
To review the current evidence for the therapeutic use of trabectedin in patients with soft tissue sarcoma.
Evidence review:
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.
PMCID: PMC2899778  PMID: 20694075
soft tissue sarcoma; metastatic; trabectedin; ET-743; Yondelis®
16.  Phase II Clinical Trial With Pegylated Liposomal Doxorubicin (CAELYX®/Doxil®) and Quality of Life Evaluation (EORTC QLQ-C30) in Adult Patients With Advanced Soft Tissue Sarcomas: A study of the Spanish Group for Research in Sarcomas (GEIS) 
Sarcoma  2005;9(3-4):127-132.
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.
doi:10.1080/13577140500287024
PMCID: PMC2395634  PMID: 18521419
17.  Randomized Trial of Paclitaxel versus Pegylated Liposomal Doxorubicin for Advanced Human Immunodeficiency Virus-associated Kaposi’s Sarcoma: Evidence for Symptom Palliation from Chemotherapy 
Cancer  2010;116(16):3969-3977.
Background
Paclitaxel (PTX) and pegylated liposomal doxorubicin (PLD) are active cytotoxic agents for the treatment of human immunodeficiency (HIV) associated Kaposi’s sarcoma (KS). We performed a randomized trial comparing the efficacy and toxicity of PTX and PLD, and determine the effects of therapy on symptom palliation and quality of life.
Methods
Patients with advanced HIV-associated KS were randomly assigned to receive PTX (100 mg/m2) IV every 2 weeks, or PLD 20 mg/m2 IV every 3 weeks. The KS Functional Assessment of HIV (FAHI) Quality of Life instrument was used before and after every other treatment cycle.
Results
The study included 73 analyzable patients enrolled between 1998 and 2002, including 36 in the PTX arm and 37 in the PLD arm; 73% received highly active antiretroviral therapy (HAART) and 32% had undetectable viral load (<400 copies/mL). Treatment was associated with significant improvement in pain (P=0.024) and swelling (P<0.001). Of the 36 patients who reported that pain interfered with their normal work or activities at baseline, 25 (69%) improved. Of the 41 patients who reported swelling at baseline, 38 (93%) improved. Comparing the PTX and PLD arms revealed comparable response rates (56% vs. 46%; p=0.49), median progression free survival (17.5 vs. 12.2 months; p=0.66), and 2-year survival (79% vs. 78%; p=0.75), but somewhat more grade 3–5 toxicity for PTX (84% vs. 66%, p=0.077).
Conclusion
Treatment with either PTX or PLD produces significant improvement in pain and swelling in patients with advanced, symptomatic, HIV-associated KS treated in the early HAART era.
doi:10.1002/cncr.25362
PMCID: PMC3157242  PMID: 20564162
HIV infection; AIDS; Kaposi’s sarcoma; paclitaxel; pegylated liposomal doxorubicin
18.  Pegylated liposomal doxorubicin/carboplatin combination in ovarian cancer, progressing on single-agent pegylated liposomal doxorubicin 
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.
doi:10.5306/wjco.v3.i10.137
PMCID: PMC3509111  PMID: 23198277
Pegylated liposomal doxorubicin; Carboplatin; Ovarian cancerchemotherapy; Platinum-resistant ovarian cancer; Platinum sensitive ovarian cancer
19.  Radiofrequency ablation of small hepatocellular carcinoma with intravenous pegylated liposomal doxorubicin 
Hepatology International  2010;5(1):567-574.
Purpose
Synergy between radiofrequency ablation (RFA) and chemotherapy was demonstrated for liver malignancy. We assess the efficacy of intravenous pegylated liposomal doxorubicin (PLD) for RFA in patients with small hepatocellular carcinoma (HCC).
Methods
This study was designed as a non-randomized control trial. Patients received either PLD (20 mg) intravenously before RFA, or standard RFA alone. Computed tomography was performed immediately and 4 weeks after RFA to obtain ablative diameter, area and volume for each tumor. The changes in ablation size were analyzed by paired images for each tumor. All patients were followed up regularly.
Results
A total of 24 patients with 29 HCCs, including 12 patients with 16 tumors (mean 2.2 cm ± 0.9) in the PLD and RFA group, and 12 patients with 13 tumors (2.4 cm ± 0.5) in the RFA alone group, were enrolled. The ablative diameter, area and volume significantly decreased 4 weeks after RFA. The ablative volume decrease was significantly greater for the RFA alone group than for the combination group (26.1 vs. 12.1%, p = 0.018). The 3-year cumulative tumor progression and survival rates did not differ significantly between the two groups.
Conclusion
Intravenous PLD before RFA reduced contraction of ablative volume and might have no impact on tumor progression and survival in patients with small HCC after RFA.
doi:10.1007/s12072-010-9215-1
PMCID: PMC3034003  PMID: 21442054
Hepatocellular carcinoma; Radiofrequency ablation; Pegylated liposomal doxorubicin
20.  Tolerability, Efficacy, and Safety of Pegylated Liposomal Doxorubicin in Combination with Carboplatin Versus Gemcitabine–Carboplatin for the Treatment of Platinum-Sensitive Recurrent Ovarian Cancer: A Systematic Review 
The Oncologist  2010;15(10):1073-1082.
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.
Objective.
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.
Methods.
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.
Results.
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.
Conclusion.
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.
doi:10.1634/theoncologist.2009-0331
PMCID: PMC3227899  PMID: 20930103
Ovarian cancer; Platinum; Pegylated liposomal doxorubicin; Gemcitabine; Carboplatin
21.  A phase II study of Yondelis® (trabectedin, ET-743) as a 24-h continuous intravenous infusion in pretreated advanced breast cancer 
British Journal of Cancer  2006;94(11):1610-1614.
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.
doi:10.1038/sj.bjc.6603142
PMCID: PMC2361304  PMID: 16736024
Yondelis; trabectedin; breast cancer
22.  Phase I dose-escalating study of docetaxel in combination with 5-day continuous infusion of 5-fluorouracil in patients with advanced gastric cancer 
BMC Cancer  2005;5:87.
Background
Published data suggests that docetaxel combined with 5-fluorouracil (5-FU) may have synergistic activity in treating advanced gastric cancer. We performed a phase I study of docetaxel and 5-FU to determine the maximum tolerated dose (MTD), the recommended dose for phase II studies, and the safety of this combination.
Methods
Eligible patients had recurrent and/or metastatic advanced gastric cancer with normal cardiac, renal and hepatic function. Traditional phase I methodology was employed in assessing dose-limiting toxicity (DLT) and MTD. On day 1 every 3 weeks, docetaxel 75 mg/m2 (fixed dose) was infused over 1-h, followed immediately by 5-FU as a 5-day continuous infusion.
Results
Dose escalation schema was as follows: dose level (DL) 1 (5-FU 250 mg/m2/day), 2 (500), 3 (750), and 4 (1000). Three patients were enrolled on DL1, without DLT. On DL2, 1 DLT (grade 3 stomatitis) was developed in first 3 patients, and this cohort was expanded to 6 patients. Three patients had been enrolled on DL3. Because two out of 3 patients had DLTs, the MTD was reached at DL3.
Conclusion
The recommended phase II dose of this combination is 75 mg/m2 docetaxel on day 1 immediately followed by a 5-day continuous infusion of 5-FU 500 mg/m2/day.
doi:10.1186/1471-2407-5-87
PMCID: PMC1183196  PMID: 16042786
23.  Effect of trabectedin on the QT interval in patients with advanced solid tumor malignancies 
Purpose
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.
Methods
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).
Results
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.
Conclusion
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.
doi:10.1007/s00280-011-1697-6
PMCID: PMC3265736  PMID: 21739119
Anti-tumor; ECG; Malignancies; QTc interval; Trabectedin
24.  A Phase I Study of Heat Deployed Liposomal Doxorubicin during Radiofrequency Ablation for Hepatic Malignancies 
PURPOSE
A phase I dose escalation study was performed with systemically delivered lyso-thermosensitive liposomal doxorubicin (LTLD) (Celsion Corp., Columbia, MD). The primary objectives were to determine the safe maximum tolerated dose (MTD), pharmacokinetic (PK) properties, and dose limiting toxicity (DLT) of LTLD during this combination therapy.
MATERIALS AND METHODS
Subjects eligible for percutaneous or surgical RFA with primary (n=9) or metastatic (n=15) tumors of the liver, with lesions 4 or less in number and up to 7 cm in diameter were included. RFA was initiated 15 minutes after starting a 30 minute intravenous LTLD infusion. Dose levels between 20 and 60 mg/m2 were evaluated. MRI, PET and CT scans were performed at predetermined intervals pre and post-treatment until evidence of recurrence, administration of additional antitumor treatment, or a total of 3 years.
RESULTS
DLT criteria were met at 60 mg/m2, and the MTD was defined as 50 mg/m2. RFA was performed during the peak of the plasma concentration-time curve, in an effort to yield maximal drug deposition. LTLD produced reversible, dose-dependent neutropenia and leukopenia.
CONCLUSION
LTLD can be safely administered systemically at the MTD (50 mg/m2) in combination with RFA, with limited and manageable toxicity. Further evaluation of this agent combined with RFA is warranted to determine its role in the management of liver tumors.
doi:10.1016/j.jvir.2011.10.018
PMCID: PMC3264789  PMID: 22178041
25.  Adjuvant pegylated liposomal doxorubicin for older women with endocrine nonresponsive breast cancer who are NOT suitable for a “standard chemotherapy regimen”: the CASA randomized trial 
Breast (Edinburgh, Scotland)  2013;22(2):130-137.
Summary
There is no optimal treatment for breast cancers lacking estrogen (ER) and progesterone (PgR) receptors in elderly women with co-morbidities that prevent use of “standard chemotherapy regimens” such as AC or CMF. The CASA trial studied pegylated liposomal doxorubicin (PLD) and low dose, metronomic cyclophosphamide+ methotrexate (CM) for older (>65), vulnerable women with operable, ER and PgR-negative breast cancer. After two years the trial closed early, due to slow and inadequate accrual, with 77 patients (38:PLD, 36:CM, 3:nil). Sixty-eight percent completed PLD; 83% completed CM (both 16-weeks). Patients on PLD reported worse quality of life, cognitive and physical functioning than non-PLD regimens (primarily CM). At a median follow-up of 42 months, 78% of randomized patients remained free of any breast cancer recurrence. Based on our limited experience, PLD and CM may be reasonable options for further study for elderly vulnerable patients with endocrine non-responsive breast cancer.
doi:10.1016/j.breast.2013.01.015
PMCID: PMC3613787  PMID: 23453899
adjuvant treatment; endocrine non-responsive; chemotherapy; pegylated liposomal doxorubicin; elderly; breast cancer

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