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Cancer Therapy: Clinical
Phase I and Pharmacokinetic Study of Trabectedin as a 1- or 3-hour Infusion Weekly in Patients with Advanced Solid Malignancies Bahram Forouzesh,1 Manuel Hidalgo,1 Quincy Chu,1 Alain Mita,1 Monica Mita,1 Garry Schwartz,2 José Jimeno,3 Javier Gómez,3 Vicente Alfaro,3 Claudia Lebedinsky,3 Patrik Zintl,3 and Eric K. Rowinsky1
Purpose: This study was designed to determine the safety, tolerability, and pharmacokinetics, and to seek preliminary evidence of anticancer activity of trabectedin, a novel marine-derived DNA minor grove binder, when administered as a 1-hour or 3-hour i.v. infusion for 3 consecutive weeks every 4 weeks in patients with advanced solid malignancies. The study also sought to determine the maximum tolerated dose (MTD) levels of trabectedin on these schedules, as well as to recommend doses for disease-directed studies. Experimental Design: A total of 32 and 31 patients were treated in sequential cohorts with trabectedin on the 1-hour schedule (doses ranging from 0.46 to 0.80 mg/m2) and on the 3-hour schedule (doses ranging from 0.30 to 0.65 mg/m2). Results: Neutropenia, transient elevations in hepatic transaminases and creatine phosphokinase, and fatigue precluded dose escalation above 0.70 mg/m2 (1-hour schedule) and 0.65 mg/m2 (3-hour schedule), which were determined to be the MTD levels, respectively. The pharmacokinetics of trabectedin on both schedules were characterized by a high clearance rate, a long terminal half-life, and a large volume of distribution. A patient with soft tissue sarcoma had partial response, and several soft tissue sarcoma patients had prolonged (≥6 months) stable disease. Conclusions: The MTD levels of trabectedin given weekly for 3 weeks every 4 weeks is 0.61 mg/m2 as a 1-hour infusion and 0.58 mg/m2 as a 3-hour infusion. The manageable toxicities at the MTDs, preliminary evidence of antitumor activity, pharmacokinetic profile, and the unique mechanistic aspects of trabectedin warrant further disease-directed evaluations on weekly schedules.
Trabectedin is a marine-derived antineoplastic agent initially isolated from the tunicate Ecteinascidia turbinata and currently produced synthetically (1). Trabectedin is a first-in-class antitumor agent with a complex mechanism of action at the level of gene transcription. Trabectedin binds covalently to the minor DNA groove and alkylates the N2 amino group of a guanine residue, which bends towards the major groove (1). Cytotoxic concentrations of trabectedin delay cell cycle as progression
Authors' Affiliations: 1Institute for Drug Development, Cancer Therapy and Research Center, and 2Brook Army Medical Center, San Antonio, Texas; and 3PharmaMar Clinical R&D, Colmenar Viejo, Madrid, Spain Received 11/7/08; revised 2/6/09; accepted 2/17/09; published OnlineFirst 5/5/09. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Note: Current address for J. Jimeno: Pangaea Biotech S.A., Medical Oncology Service & Laboratory, USP Institut Universitari Dexeus, Barcelona, Spain. Requests for reprints: Eric K. Rowinsky, 33 ImClone Drive, Branchburg, NJ 08876. Phone: 1-908-203-6912; Fax: 1-908-231-9885; E-mail: [email protected] oncodrugs.com. F 2009 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-08-2889
through the S phase and produce arrest at G2/M, ultimately resulting in p53-independent apoptosis (2–5). Several phase I trials have extensively evaluated the safety and antitumor activity of trabectedin in patients with advanced solid malignancies using different rates of i.v. infusion on every-3week schedules: 1-hour (6, 7), 3-hour (6, 7), 24-hour (8, 9), and 72-hour i.v. infusion (10), as well as a daily 1-hour i.v. infusion for a 5-day schedule (11). Dose-limiting toxicities (DLT) noted with trabectedin every-3-week schedules included transient neutropenia, fatigue, and reversible transaminase elevations. In these phase I trials, trabectedin produced objective antitumor responses in heavily pretreated patients with diverse tumor types, including soft tissue sarcomas (STS) and bone sarcomas, melanoma, mesothelioma, and breast and ovarian cancers. Trabectedin every-3-week schedules were further evaluated in phase II studies involving STS patients (5, 12–16). Trabectedin (1.5 mg/m2 24-hour i.v. infusion every 3 weeks) received regulatory approval in Europe in 2007 for treatment of patients with advanced STS after failure of anthracyclines and ifosfamide or those who are not candidates for these agents. Trabectedin is currently being evaluated in other oncology indications, including ovarian, breast, lung, and prostate cancers. This phase I clinical trial was principally designed to evaluate the feasibility, safety profile, and pharmacokinetics of
Translational Relevance This phase I study determined the safety, tolerability, pharmacokinetics, and preliminary evidence of anticancer activity of trabectedin when administered as a 1-hour or 3-hour i.v. infusion for 3 consecutive weeks every 4 weeks in patients with advanced solid malignancies. Trabectedin 0.61 mg/m2 and trabectedin 0.58 mg/m2 are the respective maximum tolerated levels (MTD) for trabectedin administered as a 1-hour and 3-hour infusion in these weekly regimens. These respective MTD levels are also recommended for subsequent disease-directed studies as protracted administration has been determined to be feasible based on the present study, as well as in phase II studies in soft tissue sarcoma and ovarian carcinoma, which have confirmed the favorable safety profile and antitumor activity of trabectedin on a weekly administration schedule.
trabectedin given as a 1-hour or 3-hour i.v. infusion weekly for 3 consecutive weeks every 4 weeks in patients with advanced solid malignancies. It also sought to define the maximum tolerated dose (MTD) levels and to recommend doses of trabectedin on these schedules for subsequent diseasedirected studies. A once-weekly administration schedule could potentially confer antitumor activity with the benefit of improved patient tolerability and the convenience of a shorter time of administration compared with 24-hour infusion schedules.
Materials and Methods Study design and objectives. This dose-escalating phase I trial was conducted in patients with advanced solid malignancies for whom conventional therapies were not applicable. The main objectives were to characterize the principal DLTs and to determine the MTD and the recommended dose for trabectedin administered as a 1-h or 3-h i.v. infusion weekly for 3 consecutive wk every 4 wk. In addition, the study sought to describe the toxicities, document antitumor activity, and characterize the pharmacokinetics of trabectedin on these weekly administration schedules. The study was conducted at three clinical centers: Cancer Therapy and Research Center, San Antonio, Texas (61 patients); Beth Israel Deaconess Medical Center, Boston, Massachusetts (1 patient); and Brook Army Medical Center, San Antonio, Texas (1 patient). The study was carried out in accordance with the Declaration of Helsinki and guidelines for Good Clinical Practice, and approved by the institutional review boards. Informed written consent was obtained for all patients. Patients. Eligibility requirements included: age ≥18 y, a histologic or cytologic confirmation of cancer not amenable to conventional treatment, an Eastern Cooperative Oncology Group performance status ≤2, and either measurable or evaluable disease. The following laboratory values were required within 14 prior days: an absolute neutrophil count of ≥1.5 × 109/l; platelets ≥100 × 109/l; hemoglobin ≥ 9 g/dL; albumin ≥2.5 g/dL; creatinine clearance and bilirubin ≤ upper limit of normal (ULN); aspartate aminotransferase and alanine aminotransferase of ≤3 × ULN (≤ 5 × ULN, in case of documented liver metastases), and alkaline phosphatase ≤ 1.5 × ULN (if total alkaline phosphatase > 1.5 × ULN, the alkaline phosphatase liver fraction and 5′-nucleotidase were required to be within normal limits). Patients with a history of central
Clin Cancer Res 2009;15(10) May 15, 2009
nervous system metastases were eligible provided there was no progression from previous treatments, no requirement for corticosteroids, no evidence of peritumoral edema, and no evidence of progressive central nervous system symptoms. Patients with primary central nervous system malignancies were not eligible. Patients were excluded if they had acute or chronic leukemia, multiple myeloma, or serious nonmalignant systemic disease, e.g. active uncontrolled infection, myocardial infarction, unstable angina pectoris, or uncompensated congestive heart failure within the prios 6 mo. Chemotherapy, radiotherapy, or biologic therapy within 4 prior wk (mitomycin C or nitrosurea therapy, temozolamide, other minor groove binders within 6 prior wk) or prior allogenic, syngenic, or autologous bone marrow or stem cell transplantation were not allowed. Pregnant or breast-feeding women, or patients not using appropriate contraceptive measures, were excluded. Drug administration. Trabectedin (PharmaMar) was administered weekly as either a 1-h or 3-h infusion for 3 consecutive wk (days 1, 8, and 15) every 4 wk (1 cycle). Dexamethasone 20 mg i.v. was administered 30 min before trabectedin. The starting trabectedin dose was 0.46 mg/m2 (1-h schedule) and 0.30 mg/m2 (3-h schedule). DLTs were defined as follows: absolute neutrophil count <0.5 × 109/L lasting > 5 d; absolute neutrophil count <0.5 × 109/L with fever (≥38°C); platelets < 25 × 109/L; any other grade 3/4 nonhematologic toxicity (except for nausea/vomiting if not optimal prophylaxis/management); grade 3/4 transaminase elevations lasting > 28 d; inability to receive at least two scheduled treatments during a single course due to drug-related toxicity, and delay of 2 consecutive wk due to persistent toxicity. Initially, three patients were treated in each cohort. In case of no DLT, dose escalation proceeded and the next enrolled patients were treated at a higher dose level. If 1 of the first 3 patients in a cohort had a DLT, then the cohort was expanded to 6 patients; if no other patient in this cohort had a DLT, dose escalation proceeded as described above. The MTD was defined as the highest dose level at which <2 patients in a cohort of 6 patients experienced DLT in the first two cycles. Dose escalation was allowed if at least 1 of 3 patients completed the first cycle without DLT and the other 2 patients completed treatment on day 15. Study assessments. Assessments prior to, during, and after study treatment included a medical history, physical examination, electrocardiogram, complete blood counts, clotting studies, chemistries, chest radiographs, and relevant scanning to evaluate tumor status. Toxicity was assessed at baseline and during treatment. Safety parameters evaluated were frequency/severity of adverse events, occurrence of drugrelated treatment discontinuations, and frequency/severity of abnormal laboratory parameters. Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC) v.2.0 (17). Any tumor response to treatment was graded according to the WHO criteria (18), based on tumor size measurements made at least 4 wk apart. Pharmacokinetics. Blood samples for pharmacokinetic analysis were collected at predefined times on day 1 of cycle 1: baseline, 0.5, 0.83, 1.5, 2, 3, 7, 25, 49, and 97 h postinfusion (1-h schedule); and baseline, 1.5, 2.98, 3.5, 4, 5, 8, 27, and 49 h postinfusion (3-h schedule). Additional samples were collected prior to the second and third doses administered in cycle 1. Blood was sampled from the contralateral arm to the trabectedin infusion arm and collected into heparinized tubes. Samples were centrifuged at 1,000 × g for 15 min, and plasma was separated, placed in polypropylene tubes, and stored at −80°C until analysis. The concentrations of trabectedin in plasma samples from patients treated with the 1-h schedule were measured using a validated high-performance liquid chromatograph system coupled with electrospray ionization tandem mass spectrometry (LC/MS-MS method; Slotervaart Hospital, Amsterdam, the Netherlands). For the 3-h schedule, the concentration of trabectedin in plasma from the first 26 patients was measured using a validated LC-MS method (Massachusetts General Hospital Cancer Care, Boston, USA). For the remaining five patients, concentrations were measured using a validated LC/MS-MS method
Table 1. Patient characteristics 1-h schedule (32 patients) Numbers of patients Male/female Median age in y (range) ECOG performance status 0 1 2 Primary tumor type Soft tissue sarcoma Ovary Breast Melanoma Other Sites of metastasis Lung Soft tissue Liver Lymph nodes Other Prior treatment Surgery Radiotherapy Chemotherapy Number of prior chemotherapy regimens 0 1 2 ≥3
3-h schedule (31 patients) %
Numbers of patients
17/15 46 (23-75)
13/18 46 (21-77)
18 13 1
56.3 40.6 3.1
11 16 4
35.5 51.6 12.9
27 2 1 1 1*
84.4 6.3 3.1 3.1 3.1
20 3 2 2 4†
64.2 9.7 6.5 6.5 13.1
19 18 8 2 3‡
59.4 56.3 25.0 6.3 9.4
19 5 8 6 12§
61.3 16.1 25.8 19.4 38.7
32 21 31
100.0 65.6 96.9
31 19 30
100.0 61.2 96.8
1 7 9 15
3.1 21.9 28.1 46.9
1 4 26
3.2 12.9 83.9
NOTE: In both schedules, trabectedin is administered as an i.v. infusion weekly for 3 consecutive weeks every 4 wk. Abbreviation: ECOG, Eastern Cooperative Oncology Group. *Germ cell cancer (nonseminoma). † Colorectal (2) and non-small cell lung carcinoma (1), carcinoma of unknown origin (1). ‡ Bone, brain and right adrenal (n = 1 each). § Abdominal and pelvic metastases (10), and bone and breast (1 each).
(Slotervaart Hospital). Plasma concentration-time profiles of trabectedin were analyzed by standard noncompartmental methods. The phenotypic activity of cytochrome P450 3A4 (CYP3A4), which is the principal enzyme responsible for the hepatic metabolism of trabectedin at clinically relevant concentrations (19), was evaluated prior to and during treatment using the erythromycin breath test (ERMBT) in patients receiving trabectedin on the 3-h schedule (20). Patients were evaluated in cycle 1 on day 1 (prior to trabectedin) and again on day 15 (after trabectedin). Following administration of 14C-erythromycin, breath samples were analyzed for 14CO2 content and the percentage of 14C metabolized per hour was calculated. Correlation analysis between the 14C metabolized per hour and trabectedin clearance was done. Log-transformation or nonparametric correlation tests were to be carried out in case of nonnormal data distribution. A mixed model was used to fit the data, with exhaled 14 CO2 percentage as dependent variable, day as fixed effect, and subject as random effect. The 90% confidence intervals for the ratio of the individual percentage of 14CO2 after and before trabectedin administration were calculated. All statistical analyses were done using SAS SYSTEM, release 8.02.
Results Patient characteristics Sixty-three patients were enrolled in the study, with 32 and 31 patients treated with the 1-hour and 3-hour schedules, respectively (Table 1). The most common tumor types were
STS (41 patients; 65%) and ovarian cancer (5 patients; 8%). All patients had undergone prior surgery, and almost all patients (61 patients; 97%) had received prior chemotherapy (65% of these patients with ≥3 prior regimens). The median number of prior chemotherapeutic agents was 3 (range, 1-9) for patients treated with the 1-hour schedule and 5 (range, 1-11) for patients treated with the 3-hour schedule: anthracyclines (76%) and nitrogen mustard analogues (68%) were the most common.
Trabectedin treatment All patients received at least one complete 4-week trabectedin cycle. The dose escalation scheme for both schedules, cycles, and patients at each dose level, and principal DLTs are depicted in Table 2. Trabectedin 1-hour schedule. A total of 109 cycles (median of 2 cycles per patient; range 1-14) were administered at doses ranging from 0.46 to 0.80 mg/m2. Overall 16.7% of infusions were delayed (median delay of 7 days; range, 1-35 days), with transient neutropenia as the most common cause in drug-related cases. At the MTD, 0.61 mg/m2, the median dose intensity was 0.394 mg/m2/week and the median relative dose intensity was 83% (range, 60-100%). Trabectedin 3-hour schedule. A total of 75 cycles (median of 2 cycles per patient, range 1-7) were administered at doses ranging from 0.30 to 0.65 mg/m2. Overall, 17.7% of infusions were
3 fatigue 3/4 neutropenia >5 d 3 AP 3 ALT 3 bilirubin 4 CPK 3 neutropenia >5 d 4 neutropenia with fever 3 AST 3 CPK 3 LDH 3 fatigue 4 thrombophlebitis 3 myalgia
Abbreviations: ALT, alanine aminotransferase; AP, alkaline phosphatase; AST, aspartate aminotransferase; CPK, creatine phosphokinase; LDH, lactate dehydrogenase; RD, recommended dose. *MTD and dose recommended dose on indicated schedule. † Two additional patients were recruited after the first cohort of patients had been evaluated and one DLT was found.
delayed (median delay of 7 days; range, 1-35 days), with most delays (69%) unrelated to trabectedin. At the MTD, 0.58 mg/m2, the median dose intensity was 0.435 mg/m2/week and the median relative dose intensity was 100% (range, 52-100%).
Definition of the MTD Trabectedin 1-hour schedule. A single patient experienced DLT, characterized by grade 4 neutropenia >7 days in cycle 1 at the first dose level (0.46 mg/m2) and therefore cohort recruitment was expanded (Table 2). No further DLT was observed and dose escalation ensued. At dose level III (0.61 mg/ m2), one patient had grade 3 neutropenia in cycle 1, with a protracted 35-day recovery. Again, the dosing cohort was expanded, but no further DLT was observed. At dose level IV (0.70 mg/m 2 ), 2 of the first 3 patients experienced DLT. One of these patients developed grade 4 neutropenia >10 days and a subsequent grade 3 creatine phosphokinase elevation in cycle 2, whereas the second subject developed grade 3 fatigue in cycle 1. Additional dose-limiting events, consisting of grade 4 neutropenia with fever, and grade 3 lactate dehydrogenase and grade 3 aspartate aminotransferase elevations, were
Clin Cancer Res 2009;15(10) May 15, 2009
experienced by a single patient in the expanded 0.70 mg/m2 cohort. With the 0.70 mg/m2 dose level being associated with an unacceptably high incidence of DLTs, the next lower dose level, 0.61 mg/m2, was declared the MTD for subsequent studies of trabectedin on the 1-hour dosing schedule. The study protocol included the determination of the MTD for heavily pretreated and minimally pretreated patients. However, although eight patients were recruited at dose level 0.80 mg/m2 (Table 2), there were insufficient data to provide determinations based on the extent of prior treatment. One patient at this dose level experienced DLT (grade 4 neutropenia and thrombocytopenia, grade 3 alanine aminotransferase increase, and grade 4 rhabdomyolysis) that led to study discontinuation. Trabectedin 3-hour schedule. No patient had DLT until a patient treated with trabectedin at dose level III, 0.525 mg/m2, experienced grade 3 fatigue in cycle 1. After the cohort was expanded with no further episodes of DLT, the dose was escalated. At dose level IV (0.65 mg/m2), four patients experienced DLT. Two patients in the first cohort developed protracted grade 3 neutropenia and grade 3 alkaline phosphatase elevation (one
schedule) or 0.58 mg/m2 (3-hour schedule) were mild or moderate (Table 3). The most common were fatigue, myalgia, and nausea (three patients each) for the 1-hour schedule, and fatigue (six patients), nausea (six patients) and vomiting (five patients) for the 3-hour schedule. One patient with high-grade sarcoma of the left thigh had grade 3 fatigue and grade 3 myalgia with trabectedin 0.61 mg/m2 on the schedule. This patient discontinued treatment and soon after died due to disease progression. With respect to trabectedin 0.58 mg/m2 as a 3-hour infusion, one patient experienced grade 3 fatigue and grade 3 myalgia, and a second subject developed a grade 3 injection site reaction in cycle 1. These events did not preclude further treatment with trabectedin at the same dose level. Frequent hematologic abnormalities irrespective of grade were anemia, leucopenia, and neutropenia for both schedules (most grade 1 or 2). Frequent biochemical abnormalities were elevations in transaminases and alkaline phosphatase (grade 3/4 events were uncommon).
patient each). Two patients in the expanded cohort experienced DLT: one of these two patients developed grade 3 alanine aminotransferase increase; the other patient had grade 4 neutropenia, grade 3 bilirubin increase, and grade 4 creatine phopho‐ kinase increase. Because the 0.65 mg/m2 dose level was associated with an unacceptably high incidence of DLT, and the 0.525 mg/m2 dose level was associated with negligible toxicity, an intermediate dose level (dose level V, 0.58 mg/m2) was next evaluated. Five of 15 enrolled patients had DLTs in the first or second treatment cycle, which consisted of grade 3 aspartate aminotransferase increase (two patients), and protracted grade 3 neutropenia, grade 4 neutropenia with fever, grade 3 creatine phophokinase increase, grade 3 lactate dehydrogenase increase, grade 3 fatigue, grade 3 myalgia, and grade 4 thrombophlebitis of the forearm associated with an injection site reaction (one patient each). These toxicities did not lead to patient withdrawal, and all patients were treated without delay until disease progression. Because the median relative dose intensity at this dose level was 100% and there was no evidence of cumulative toxicity, with patients receiving as many as 7 cycles, 0.58 mg/m2 was declared the MTD for trabectedin on the 3-hour dosing schedule.
Anticancer activity Anticancer activity with both trabectedin weekly schedules is shown in Table 4. In this series of patients, a high number of disease stabilizations (SD) occurred with the 1-hour schedule (12 SD versus 6 SD with the 3-hour schedule).
Toxicity profile at the MTD Most drug-related adverse events experienced by patients receiving trabectedin at the MTD of 0.61 mg/m 2 (1-hour
Table 3. Drug-related adverse events (≥10% of patients) at the maximum tolerated dose levels 0.61 mg/m2 (1-h schedule)
NOTE: In both schedules, trabectedin iv infusion for 3 consecutive weeks every 4 wk. Abbreviations: AE, adverse event; GGT, gamma-glutamyltransferase; LDH, lactate dehydrogenase; NCI-CTC, National Cancer Institute Common Toxicity Criteria; NOS, not otherwise specified. *Depicted are the numbers of patients/cycles with the specified adverse events.
Thigh Arm (brachioradialis muscle) Stomach Gluteal muscle Uterus Arm Scrotum Brachial plexus Uterus Thigh Stomach
4 6 7 2 9 5 4 2 4 4 4
SD SD SD SD PR SD SD SD SD SD SD
3.6 6.2 5.8+ 1.8+ 11.2 6.0 7.4 1.7+ 3.9 3.2 3.7
Abdomen and retroperitoneum Ovary
Lung Retroperitoneum Thigh
7 5 6
SD SD SD
7.1 2.3+ 7.4
NOTE: In both schedules, trabectedin iv infusion for 3 consecutive weeks every 4 wk. Abbreviations: PR, partial response; PS, performance status; SD, stable disease; TTP, time to progression. *Recommended dose for phase II trials. † Global tumor decrease = 32.2%. ‡ Global tumor decrease = 25.5%.
Trabectedin 1-hour schedule. A 43-year-old female patient with a uterine leiomyosarcoma with metastases to the lungs and pelvis who was treated with nine cycles experienced a partial response lasting 11.2 months. The patient had previously under-
gone chemotherapy with lometrexol, temozolomide, and folic acid, which culminated in a partial response with subsequent disease progression. The partial response was achieved after two cycles of trabectedin 0.61 mg/m2 (total of nine cycles
Table 5. Non-compartmental pharmacokinetic parameters of trabectedin Dose (mg/m2)
NOTE: In both schedules, trabectedin i.v. infusion for 3 consecutive weeks every 4 wk. Results shown are mean ± SD. Data obtained during the first cycle. Abbreviations: AUC, area under the curve; CL, clearance; Cmax, maximum plasma concentration; t1/2, half-life; Vss, volume of distribution in steady state. *For the 3-h schedule, the concentration of trabectedin in plasma from the first 26 patients was measured using a validated LC-MS method. For the remaining five patients, concentrations were measured using a validated LC/MS-MS method.
Fig. 1. Typical transient, noncumulative time-course of hepatic function tests in a patient treated with the MTD of trabectedin, 0.65 mg/m2, administered as a 3-h i.v. infusion weekly for 3 consecutive weeks every 4 wk (MTD).
received). Additionally, 12 patients had SD, including SD ≥6 months in 4 patients with STS: leiomyosarcoma (2 patients), liposarcoma and fibrosarcoma. Trabectedin 3-hour schedule. No objective responses were documented. Six patients had SD, including two patients with fibrosarcoma and synovial sarcoma who had SD ≥ 6 months. Two additional STS patients (one patient with a metastatic liposarcoma treated at 0.30 mg/m2 and one patient with ovarian carcinoma of the mesodermal subtype treated at 0.58 mg/m2) had tumor decrements of 32.2% and 25.5%, respectively.
Pharmacokinetics Relevant pharmacokinetic data for trabectedin administered on 1-hour and 3-hour schedules are shown in Table 5. Trabectedin 1-hour schedule. The pharmacokinetic profile was characterized by a high plasma clearance rate, with mean values ranging from 49.3 to 135.8 L/hour across the range of doses evaluated. Volume of distribution (Vss) values were large with mean values as a function of dose level ranging from 1,434 to 3,025 L, whereas mean terminal half-life values ranged from 17.2 to 100.1 hours. Although mean plasma trabectedin concentration values increased proportionately with dose, the assessment of linearity was inconclusive due to a high degree of intersubject variability in peak plasma concentration (Cmax) and area under the curve (AUC∞) values. Trabectedin 3-hour schedule. Relevant pharmacokinetic parameters were similar to those with the 1-hour infusion schedule (Table 5). The coefficient of variability in plasma Cmax and AUC∞ values in cycle 1 ranged from 18.2 to 70.7%. In general, mean plasma Cmax and AUC∞ values increased proportionately with dose in the dosing range evaluated. ERMBT data were obtained in all patients treated with the 3-hour infusion schedule; however, paired samples (day 1 and 15) were obtained in 25 of 31 patients. The intrasubject coefficient of variation for %14CO2 was 22.95%, and the im-
pact on in vivo CYP3A4 activity was minimal, with a ratio after/before trabectedin of 83.62% (90% confidence interval, 74.93-93.31%). Trabectedin clearance roughly correlated with phenotypic CYP3A4 activity using nonparametric methods (Spearman’s test; r = 0.405; P = 0.045); however, no significant relationships were shown using parametric methods with both log-transformed and non–log-transformed data.
Discussion This phase I study determined the feasibility of administering trabectedin on both 1-hour and 3-hour infusion schedules weekly for 3 weeks every 4 weeks in patients with advanced solid malignancies, and determined the MTD levels for both schedules. Severe neutropenia was the most common DLT on both dose schedules; however, neutropenia was rarely severe or protracted. Furthermore, neutropenia generally resolved to acceptable levels prior to the next scheduled dose. The most common nonhematologic toxicities included elevations in liver function enzymes, creatine phophokinase, and lactate dehydrogenase, which were generally transient, noncumulative, and did not preclude repetitive dosing at the MTD levels. A typical course of liver function test fluctuations during multiple cycles of treatment is displayed in Fig. 1. Fatigue, myalgia, and injection site reactions were also noted infrequently. Based on the results of the present study, there were unacceptably high incidences of DLTs at trabectedin doses exceeding 0.61 mg/m2 and 0.58 mg/m2 on the 1-hour and 3-hour weekly schedules, respectively. In contrast, these dose levels were associated with acceptable toxicity following repetitive treatment, and are recommended for further disease-directed evaluations of trabectedin on these respective schedules. The safety profile and the DLTs of trabectedin administered as 1-hour and 3-hour infusions weekly for 3 weeks every 4 weeks were similar to those noted with the agent administered on
alternate dosing schedules in advanced cancer patients (5, 8, 9, 11–15, 21). As reported with other schedules, fatigue and nausea were common adverse events at the MTD levels in the present study; however, only 2 (9.5%) of 21 patients experienced severe treatment-related fatigue. Also similar to that reported with other schedules, neutropenia and hepatic transaminase elevations were common laboratory abnormalities with both the 1hour and the 3-hour weekly schedules, but these effects were transient, manageable, and rarely resulted in delays in treatment and/or required subsequent dose reduction. The current safety results have also been corroborated in two subsequent disease-directed phase II studies (22, 23). Trabectedin 0.58 mg/m2 3-hour weekly schedule was used as the control arm of a randomized phase II study involving 130 patients with recurrent or refractory liposarcoma or leiomyosarcoma who received 523 total cycles (22). The most common severe toxicities were transient, noncumulative elevations in transaminases. Less common severe toxicities (<5% of patients and <2% of cycles) included fatigue, nausea, and vomiting. The rarity of many unpleasant and/or life-threatening effects commonly found with classic cytotoxics (e.g., alopecia, mucositis, skin/nail toxicities, neurotoxicity, or cardiac toxicity) was particularly remarkable. The 3-hour weekly trabectedin schedule also showed a similar safety profile in 147, heavily pretreated, advanced ovarian cancer patients who received 588 total cycles in a phase II study (23). Despite being heavily pretreated, the median dose intensity was 85.9% and only 7% of patients discontinued treatment due to toxicity. The objective activity and relatively protracted duration of SD in several heavily patients with highly refractory STS (fibromyxoid sarcoma, leiomyosarcoma, liposarcoma), osteosarcoma, and ovarian cancer are encouraging and consistent with findings in previous phase I evaluations of trabectedin on alternate administration schedules, including 1-hour to 72-hour infusions every 3 weeks and 1-hour infusions daily for 5 consecutive days (7, 9). In these studies, objective activity was shown in previously treated patients with breast and ovarian carcinomas, STS, osteosarcoma, and mesothelioma, resulting in more comprehensive disease-directed evaluations (7, 9–11). Results from the aforementioned randomized phase II trial in pretreated STS patients documented superior disease control with an every-3week 24-hour regimen, but the weekly 3-hour regimen seemed efficacious and an active control relative to historical progression-free survival data (16, 24). The weekly 3-hour regimen had progression-free survival rates of 45.1% at 3 months and of 26.9% at 6 months (25). These progression-free survival results were superior to those required for an active agent in STS (i.e., progression-free survival of 39% and 14% at 3 and 6 months, respectively) according to the criteria of the Soft Tissue and Bone Sarcoma Group of the European Organization for Research and Treatment of Cancer (STBSG EORTC; ref. 26). Furthermore, these results formed the basis for the marketing authorization of trabectedin in STS in Europe, being the first agent approved in non-GIST (gastrointestinal stromal tumor) sarcomas for two decades and the first successful cytotoxic derived from a marine organism.
The pharmacokinetics of trabectedin after administration of a weekly schedule (1-hour or 3-hour) revealed a high clearance rate, a long terminal half-life, and a large volume of distribution. With respect to dose proportionality, no major deviations from linearity were apparent. A population pharmacokinetics review of trabectedin including 603 patients (945 cycles) who received single-agent trabectedin as an i.v. infusion on various schedules, showed a linear pharmacokinetics with dose-proportionality at doses up to 1.8 mg/m2, and time-independent pharmacokinetics (27). In this population pharmacokinetic analysis, the terminal half-life was determined to be 180 hours, independent of the infusion length or the interval of administration. The lower value reported in the present study likely reflects the shorter plasma sampling periods used in the evaluation of weekly compared with every-3-week schedules. In the same population pharmacokinetic analysis, a significant relationship between clearance and body surface area was not found. However, due to the significant effect of gender on the central volume of distribution, the body surface area dose-normalization of trabectedin is used to equalize the expected peak concentration between genders. In the future, the decision whether or not to adjust the dose based on body surface area should be guided by these pharmacokinetic principles together with a better understanding of the exposure-response relationships and the relative importance of Cmax for efficacy and toxicity. CYP3A4 phenotypic activity was evaluated prior to and during trabectedin treatment using ERMBT. Trabectedin clearance was found to be related to CYP3A4 activity, but the relationship was not as strong as expected, even in light of CYP3A4 being the principal metabolizing enzyme involved in trabectedin clearance (19). This weak relationship may have been due to other factors contributing to the large variability in trabectedin clearance and a limited number of patients with evaluable ERMBT data. Differences in ERMBT done before and after two trabectedin doses were minimal, suggesting a limited influence of trabectedin on CYP3A4 activity, although the low sample size and the relatively short period of time between both measurements do not allow the drawing of definitive conclusions. Results from in vitro studies are consistent in that trabectedin does not affect the activity of the main CYP isoforms (28). In conclusion, trabectedin 0.61 mg/m 2 and trabectedin 0.58 mg/m2 are the respective MTD levels for trabectedin administered as a 1-hour and 3-h infusion weekly for 3 consecutive weeks every 4 weeks. These respective MTD levels are also recommended for subsequent disease-directed studies because protracted administration has been determined to be feasible based on the present study, as well as in phase II studies in STS and ovarian carcinoma, which have confirmed the favorable safety profile and antitumor activity of trabectedin on a weekly administration schedule.
Disclosure of Potential Conflicts of Interest J. Jimeno, J. Gomez, C. Lebedinsky, V. Alfaro, ownership interest, Zeltia (PharmaMar).
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Phase I and Pharmacokinetic Study of Trabectedin as a 1- or 3-hour Infusion Weekly in Patients with Advanced Solid Malignancies Bahram Forouzesh, Manuel Hidalgo, Quincy Chu, et al. Clin Cancer Res 2009;15:3591-3599.
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