Purpose: This phase I study evaluated the feasibility, safety, pharmacokinetics (PK), and preliminary evidence of anticancer activity of the sequential administration of paclitaxel and trabectedin on an every-2-week schedule in patients with refractory solid malignancies. The study also sought to determine the maximum tolerated dose (MTD) level on this schedule, as well as to recommend doses for disease-directed studies.

Experimental Design: Twenty-seven patients were treated with paclitaxel (80-120 mg/m2; 1-hour i.v. infusion, day 1) and trabectedin (0.525-0.775 mg/m2; 3-hour i.v. infusion, day 2) with doses increased in successive cohorts. Blood sampling for PK and drug-drug interaction studies was done.

Results: Neutropenia, which resulted in treatment delay exceeding 1 week, was the principal dose-limiting toxicity for this paclitaxel-trabectedin regimen and precluded dose escalation above 120 mg/m2 paclitaxel and 0.650 mg/m2 trabectedin. At the MTD (120 mg/m2 paclitaxel and 0.650 mg/m2 trabectedin), the safety profile was favorable in patients receiving cumulative treatment. Relevant drug-drug PK interactions between paclitaxel and trabectedin were not identified. A patient with soft tissue sarcoma had a complete response and several patients with various refractory solid malignancies showed protracted stable disease as their best response.

Conclusions: The MTD level of sequential paclitaxel 1-hour infusion (day 1) and trabectedin 3-hour infusion (day 2) administered every 2 weeks is 120 and 0.650 mg/m2, respectively. The manageable toxicities at the MTD, preliminary evidence of antitumor activity, and lack of notable PK drug-drug interactions warrant further disease-directed studies of this regimen in relevant tumor types and settings. Clin Cancer Res; 16(9); 2656–65. ©2010 AACR.

This article is featured in Highlights of This Issue, p. 2483

Translational Relevance

This phase I study determined the feasibility, safety, pharmacokinetics, and preliminary anticancer activity of the sequential administration of paclitaxel as a 1-hour i.v. infusion (day 1) and trabectedin as a 3-hour i.v. infusion (day 2) on an every 2-week schedule in patients with refractory solid malignancies based on the results of preclinical studies. The maximum tolerated dose level of sequential paclitaxel 1-hour infusion (day 1) and trabectedin 3-hour infusion (day 2) administered every 2 weeks is 120 and 0.650 mg/m2, respectively. Because protracted administration of paclitaxel and trabectedin at the maximum tolerated dose level was shown to be well tolerated and feasible, it is recommended for subsequent disease-directed studies.

Trabectedin, a marine-derived antineoplastic agent initially isolated from the tunicate Ecteinascidia turbinata and currently produced synthetically, is a first-in-class antitumor agent with a complex mechanism of action at the level of transcription (13). As a single agent, trabectedin has shown antitumor activities in soft tissue sarcoma (STS; ref. 4) as well as in patients with several types of cancer, such as ovarian (57) and breast cancer (8), in which paclitaxel plays a principal role in therapeutic management and confers robust clinical benefit.

In addition to clinical pragmatism as support for evaluating the combination of trabectedin and paclitaxel in the clinical settings, in which there is relevant single-agent activity, several preclinical studies have shown favorable interactions between these agents. For example, treatment of human CALU-3 lung and MCF-7 breast carcinoma xenografts with the combination of trabectedin and paclitaxel resulted in at least additive cytotoxicity (9). Furthermore, sequence-dependent cytotoxic synergism between trabectedin and paclitaxel has been noted in human HT-1080 and HS-18 sarcoma in vitro (10). Cytotoxic synergism was apparent when paclitaxel treatment occurred before trabectedin treatment, whereas less than additive cytotoxicity or antagonism was noted when trabectedin treatment occurred concomitant or before paclitaxel (10). Cytotoxic synergism was also evident following treatment of several P-glycoprotein–overexpressing human breast cancer cell lines with paclitaxel and trabectedin, with superior activity noted when the tumor cells were treated with paclitaxel before trabectedin compared with the reverse sequence (11). The sequence of paclitaxel followed by trabectedin was also superior to the reverse treatment sequence against human MX-1 breast cancer xenografts, as manifested by the greater percentage reduction in tumor volume and the percentage of tumor-free mice than either paclitaxel or trabectedin alone (11).

Several mechanisms that may account for the favorable interactions between paclitaxel and trabectedin, as well as their sequence-dependent cytotoxic effects, have been proposed. Several explanations supported by experimental data have focused on the cell cycle–specific effects of these agents. In one experiment, cytotoxicity was maximal when paclitaxel treatment preceded trabectedin treatment, which was also associated with the maximal reentry of tumor cells from a mitotic block induced by paclitaxel to the G1 phase, thereby enabling trabectedin to induce maximal DNA damage as cells in G1 phase are more sensitive to trabectedin than cells in other phases of the cell cycle (11, 12). An alternative explanation proposed by Synold et al. (13) is based on the inhibitory effects of trabectedin on the orphan nuclear receptor SXR, which modulates paclitaxel metabolism and efflux through the effects on CYP34, CYP2C8, and Pg-p, and is, in turn, induced by paclitaxel treatment.

Based on the results of the aforementioned preclinical studies suggesting favorable antitumor interactions with the combination of trabectedin and paclitaxel, as well as their overlapping antitumor spectra, particularly with regard to breast and ovarian cancer (14), this phase I study sought to evaluate the feasibility, safety, pharmacokinetics (PK), drug-drug PK interactions, and preliminary antitumor activity of paclitaxel and trabectedin administered on an every-2-week schedule in patients with advanced solid malignancies. It was elected to administer trabectedin 24 hours after the paclitaxel treatment based on the superior antitumor activity shown with this sequence in preclinical studies, particularly when treatment with trabectedin occurred 24 hours after paclitaxel (9, 10).

Study design and objectives

This phase I and pharmacokinetic trial was conducted in patients with advanced solid malignancies for whom conventional therapy did not exist. The main objectives were to characterize the principal dose-limiting toxicities (DLT) and to determine the maximum tolerated dose (MTD) and the recommended dose for sequential administration of paclitaxel (1-hour i.v. infusion) on day 1, followed 24 hours later by trabectedin (3-hour i.v. infusion; day 2). In addition, the study sought to describe the toxicities, document preliminary anticancer activity, and characterize the PK of paclitaxel and trabectedin on this sequential every-2-week administration schedule. The study was conducted in accordance with the Declaration of Helsinki and guidelines for Good Clinical Practice and was approved by the institutional review board. Informed written consent was obtained for all patients.

Patients

Eligibility requirements included the following: age of ≥18 years, a histologic confirmation of cancer not amenable to conventional treatment, an Eastern Cooperative Oncology Group performance status of ≤2, life expectancy of ≥3 months, and either measurable or evaluable disease. The following laboratory values were required within 14 days of study treatment: an absolute neutrophil count (ANC) of ≥1.5 × 109/L, platelets of ≥100 × 109/L, hemoglobin of ≥8.5 g/dl, albumin of ≥2.5 g/dl, calculated creatinine clearance of ≥50 mL/min, bilirubin of less than or equal to the upper limit of normal (ULN), aspartate aminotransferase and alanine aminotransferase of ≤3× ULN, and alkaline phosphatase (AP) ≤1.5× ULN (if total AP is >1.5× ULN, the AP liver fraction and/or 5′-nucleotidase and/or γ glutamyltransferase were required to be within normal limits). Patients with a history of central nervous system metastases were eligible provided that a radiographic study showed no progression from previous treatments and no evidence of peritumoral edema, there was no requirement for corticosteroids, and there was no evidence of progressive central nervous system symptoms. Patients with primary central nervous system malignancies were not eligible.

Patients were excluded if they had serious nonmalignant systemic disease, e.g., active uncontrolled infection, uncontrolled diabetes mellitus, recent (within 6 months before study entry) myocardial infarction, unstable angina pectoris, or life-threatening ventricular arrhythmia requiring treatment. Chemotherapy, radiotherapy (wide-field with >25% bone marrow reserve), or biological therapy within 4 weeks before administration of trabectedin (mitomycin C or nitrosurea therapy within 6 weeks) were not allowed. Immunocompromised patients, including patients known to be HIV positive, were not eligible. Patients with peripheral neuropathy exceeding the National Cancer Institute Common Toxicity Criteria grade 2 in severity were also excluded from enrollment. Patients were also excluded if they were pregnant or breastfeeding women, or if they were not using appropriate contraceptive measures.

Drug administration

Paclitaxel (Taxol, Bristol-Myers Squibb) was administered using commercially available single vials of 300 mg through either a peripheral or a central venous catheter. Trabectedin (Yondelis, PharmaMar) was supplied as a sterile lyophilized product in glass vials containing two strengths (0.25 or 1 mg), which was reconstituted with 5 mL (0.25-mg vials) or 20 mL (1-mg vials) of sterile water. The total amount of trabectedin was diluted in 500 mL of 0.9% normal saline. Trabectedin was infused through a central venous catheter.

In the first cycle, the lapse in the administration of both agents, paclitaxel (1-hour i.v. infusion) and trabectedin (3-hour i.v. infusion), was different from that used in subsequent cycles to evaluate drug-drug pharmacokinetic interactions. In the first cycle, paclitaxel was administered 8 days before trabectedin (day −7). In subsequent cycles, paclitaxel was administered on day 1, 24 hours before the start of trabectedin infusion (day 2). Treatment cycles were repeated every 2 weeks. Twenty milligrams of dexamethasone i.v., 50 mg diphenhydramine i.v., and 50 mg ranitidine i.v. were administered 30 to 60 minutes before paclitaxel. Ten milligrams of dexamethasone i.v and standard dosage of an antiserotonin (HT3) i.v. were administered 30 to 60 minutes before trabectedin followed by standard dosage of anti-HT3 orally every 12 hours, starting 24 hours after trabectedin. The use of dexamethasone as a premedication 24 hours before trabectedin was based on reductions in the incidence and severity of drug-induced toxicities, particularly nausea and vomiting, in preclinical and previous clinical studies (15, 16).

The starting dose of paclitaxel administered on this every-2-week regimen was 80 mg/m2, which is 100% of the recommended dose of paclitaxel on a weekly schedule (17). The starting dose of trabectedin was 0.525 mg/m2, which is 9% lower than that recommended for trabectedin on a weekly 3-hour schedule (14). The planned dose escalation scheme (designated as paclitaxel/trabectedin in mg/m2) based on the incidence of DLT at each proceeding dose level, as discussed below, was as follows: level 2, 80/0.58 mg/m2; level 3, 120/0.58 mg/m2; level 4, 120/0.65 mg/m2; level 5, 120/0.775 mg/m2; level 6, 140/0.9 mg/m2; and level 7, 140/1 mg/m2.

DLTs were defined as: ANC of <0.5 × 109/L for longer than 5 days; ANC of <1.0 × 109/L with fever (≥38.5°C); platelets of <25 × 109/L; grade 3 transaminitis for >7 days resulting in cycle delay or grade 4 transaminitis; any other grade 3/4 nonhematologic toxicity, except for nausea and/or vomiting (in the absence of optimal prophylaxis and/or management), and treatment delay exceeding 1 week due to treatment-induced toxicity. Only DLTs occurring during the first two cycles were used to determine the MTD.

At least three patients were to be treated in each cohort. If none of these patients had DLT, dose escalation proceeded for next patients. If one of the first three patients in a cohort experienced DLT, then the cohort was expanded to six patients; if no other patients in this cohort had DLT, dose escalation proceeded as described above. The MTD was defined as the highest dose level at which less than two patients in a cohort of six patients experienced DLT in the first two cycles.

Study assessments

Assessments before, 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 pretreatment and during treatment. Safety parameters evaluated were the frequency and severity of adverse events (AE), the occurrence of study drug–related treatment discontinuations, and the frequency and severity of abnormal laboratory parameters. Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria, v. 2.0 (18). Objective anticancer responses were graded according to the WHO criteria (19), based on tumor assessments made at least 4 weeks apart.

Pharmacokinetics

Blood samples (5-10 mL) for PK analysis were collected at predefined times on day 1 of cycles 1 and 2. Blood for paclitaxel concentration measurements was sampled before treatment; at the end of infusion and at 0.5, 1, 2, 4.5, 7, 10.5, 24, and 48 hours postinfusion in cycle 1, and 1, 2, 4.5, 7, 10.5, 20 to 28, 44 to 52, 66 to 78, 90 to 102, and 162 to 174 hours postinfusion in cycle 2. Blood samples for measurement of trabectedin were collected before treatment, at the end of infusion and 30 minutes and 3, 3.5, 4, 5, 11, 21 to 27, 43 to 53, 67 to 77, 139 to 149, and 324 to 348 hours postinfusion in cycle 1, and 30 minutes, 3, 3.5, 4, 5, 11, 24, 48, 72, 144, and 324-348 hours postinfusion in cycle 2. Blood was sampled from the contralateral arm to the treatment infusion arm and collected into heparinized tubes. Samples for plasma concentration measurements were centrifuged immediately after sampling, at 1,000× g for 15 minutes. After centrifugation, plasma was separated, placed in polypropylene tubes, and stored at −80°C until analysis. The concentrations in plasma samples were measured using a validated high-performance liquid chromatograph (HPLC) system coupled with an electrospray ionization tandem mass spectrometry (liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods] as previously described (20). Two methods were used for the analysis of paclitaxel samples in this study. The first was a validated liquid chromatography/mass spectrometry assay (21). This assay was used to analyze the samples from patients 1 to 17. The second analytic method was a validated liquid chromatography-tandem mass spectrometry assay, which was switched to improve precision (a partial cross-validation between both methods was done with positive results). Patients 18 to 29 were analyzed using the modified liquid chromatography-tandem mass spectrometry assay. The complete plasma concentration–time profiles of both drugs were analyzed by standard noncompartmental methods.

The effect of paclitaxel on trabectedin PK was evaluated in each individual patient. Paired sample t test was used to compare each individual patient's values for maximal concentration (Cmax), area under the plasma concentration-time curve (AUC), and half-life for trabectedin in both the first cycle (paclitaxel treatment 1 week before trabectedin treatment) and second cycle (paclitaxel treatment 1 day before trabectedin treatment). Although the study was not specifically designed to study the effect of trabectedin on paclitaxel PK because paclitaxel was administered before trabectedin in all occasions, trabectedin could still potentially affect paclitaxel clearance if administered 1 day following paclitaxel. Therefore, the effect of trabectedin on paclitaxel PK parameters were also evaluated in each individual patient who received both agents administered 1 week (cycle 1) and 1 day (cycle 2) apart.

Patient characteristics

Twenty-nine patients were enrolled into this study. Data from 27 of the 29 patients, whose relevant characteristics are shown in Table 1, were included in the analyses of toxicity, dose definition, and activity. Two patients were not evaluable for these analyses as they did not receive trabectedin following their first paclitaxel infusion as one subject had insufficient blood counts (grade 2 neutropenia) and another refused trabectedin treatment. The most common malignancy was STS [21 (77.8%) patients]. All patients had undergone prior surgery and almost all of them [24 (89%) patients] had received prior chemotherapy, with 67% of the patients having received at least three prior regimens. The median number of prior lines of chemotherapy was 3 (range, 0-11). Doxorubicin (78%), ifosfamide (67%), cyclophosphamide (33%), and gemcitabine (33%) were the most common chemotherapy agents used in prior treatment regimens.

Table 1.

Patient characteristics (N = 27)

No. of patientsPercentage
Male/female 15/12 56/44 
Median age in y (range) 49 (19-82) 
ECOG performance status 
    0 13 48.1 
    1 13 48.1 
    2 3.8 
Primary tumor type 
    STS 21 77.8 
    Breast 7.4 
    Other 4* 14.8 
Tumor stage 
    Locally advanced 11.1 
    Metastatic 24 88.9 
Prior treatment 
    Surgery 27 100.0 
    Radiotherapy 20 74.1 
    Biological therapy 3 11.1 
    Chemotherapy 24 88.9 
No. of prior chemotherapy regimens 
    0 11.1 
    1 3.7 
    2 18.5 
    ≥3 18 66.7 
No. of patientsPercentage
Male/female 15/12 56/44 
Median age in y (range) 49 (19-82) 
ECOG performance status 
    0 13 48.1 
    1 13 48.1 
    2 3.8 
Primary tumor type 
    STS 21 77.8 
    Breast 7.4 
    Other 4* 14.8 
Tumor stage 
    Locally advanced 11.1 
    Metastatic 24 88.9 
Prior treatment 
    Surgery 27 100.0 
    Radiotherapy 20 74.1 
    Biological therapy 3 11.1 
    Chemotherapy 24 88.9 
No. of prior chemotherapy regimens 
    0 11.1 
    1 3.7 
    2 18.5 
    ≥3 18 66.7 

Abbreviation: ECOG, Eastern Cooperative Oncology Group.

*One patient each with non–small cell lung cancer, ovarian cancer, osteosarcoma, and melanoma.

IFN α-2b, granulocyte colony-stimulating factor, and interleukin-2 for the treatment of malignant melanoma; autologous stem cell transplant for the treatment of Ewing's sarcoma of the right leg and hip; and imatinib mesylate and TRM-1 for the treatment of spindle cell leiomyosarcoma.

Trabectedin treatment

All patients received at least one complete 2-week cycle of sequential paclitaxel for 1 hour and trabectedin for 3 hours (designated as paclitaxel in mg/m2/trabectedin in mg/m2) and a total of 243 cycles at doses ranging from 80/0.525 to 120/0.775 mg/m2 were administered in five dosing iterations as shown in Table 2. The median number of cycles administered was 4 (range, 1-28). Overall, 33.3% of cycles were delayed, with a median delay of 7 days (range, 5-28 days). The most common cause of treatment-related delay was neutropenia, which was generally short (<7 days). At the MTD, 120/0.650 mg/m2, the median dose intensity for paclitaxel and trabectedin was 45.3 and 0.3 mg/m2/week, respectively. The median relative dose intensity for paclitaxel and trabectedin was 81% (range, 66-105%) and 80% (range, 65-102%).

Table 2.

Dose escalation scheme and DLTs with sequential paclitaxel (1-h i.v. infusion) and trabectedin (3-h i.v. infusion) administered every 2 wk

Dose levelDose paclitaxel (mg/m2)/trabectedin (mg/m2)No. of patientsNo. of cyclesNo. of patients with DLTs in cycle 1 or 2Description of DLTs
80/0.525 36 
II 80/0.580 45 
III 120/0.580 16 Grade 2 neutropenia lasting 8 d (beyond day 21) 
IV* 120/0.650 11 120 1 Grade 4 neutropenia lasting 3 d 
Delay of 13 d due to hematologic toxicity (ANC decrease). 
120/0.775 26 Grade 4 neutropenia lasting 4-5 d. 
Delay of 13-14 d due to hematologic toxicity (ANC decrease). 
Total  27 243   
Dose levelDose paclitaxel (mg/m2)/trabectedin (mg/m2)No. of patientsNo. of cyclesNo. of patients with DLTs in cycle 1 or 2Description of DLTs
80/0.525 36 
II 80/0.580 45 
III 120/0.580 16 Grade 2 neutropenia lasting 8 d (beyond day 21) 
IV* 120/0.650 11 120 1 Grade 4 neutropenia lasting 3 d 
Delay of 13 d due to hematologic toxicity (ANC decrease). 
120/0.775 26 Grade 4 neutropenia lasting 4-5 d. 
Delay of 13-14 d due to hematologic toxicity (ANC decrease). 
Total  27 243   

*MTD and dose recommended for phase II trials.

This patient had two DLTs.

Definition of the MTD

The dose escalation scheme and numbers of patients, cycles, and DLT per dose level are shown in Table 2. The first DLT, grade 2 neutropenia in cycle 1 that lasted 8 days and resulted in a treatment delay exceeding 1 week, was experienced by a patient treated at dose level III (120/0.580 mg/m2). After the cohort was expanded with no further episodes of DLT observed, the dose was escalated to the next level (dose level IV, 120/0.650 mg/m2). Because none of the first three patients experienced DLT, dose escalation proceeded to dose level V (120/0.775 mg/m2), which was associated with dose-limiting neutropenia during cycles 1 or 2 in two of four total patients. One patient in the first cohort of three patients developed grade 4 neutropenia lasting 4 days; however, its slow resolution resulted in a 13-day treatment delay. The second DLT involved a patient in the expanded cohort who experienced grade 4 neutropenia that lasted 5 days and resulted in a 14-day treatment delay. Because the 120/0.775 mg/m2 dose level was associated with an unacceptably high incidence of DLT, dose level IV (120/0.650 mg/m2) was further evaluated. At this dose level, one of 11 patients had DLT, consisting of grade 4 neutropenia that lasted 3 days and resulted in a 13-day treatment delay due to slow resolution, in the first or second treatment cycle. Based on the criteria determined a priori, the dose level consisting of paclitaxel 120 and trabectedin 0.650 mg/m2 was determined to be the MTD level for the regimen evaluated.

Toxicity profile at the MTD

Nausea, fatigue, myalgia, arthralgia, and vomiting were the most common nonhematologic toxicities experienced in the study. These AEs were not related to dose level and were almost always mild to moderate (i.e., grade 1-2). Of 11 total patients treated at the MTD level, 120/0.650 mg/m2, the following grade 1 to 2 nonhematologic toxicities noted were as follows: fatigue (eight patients), nausea (eight patients), arthralgia (six patients), and myalgia (5 patients; Table 3). One patient each experienced grade 3 nausea and vomiting during one cycle. A 60-year-old male with a metastatic liposarcoma involving the abdomen who was receiving anticoagulant treatment to maintain patency of a central venous catheter developed a grade 3 gastrointestinal hemorrhage, which was determined endoscopically to be due to duodenal ulcers.

Table 3.

Treatment-related AEs (≥10% of patients) at the MTD level of sequential paclitaxel (120 mg/m2 1-h i.v. infusion) followed by trabectedin (0.650 mg/m2 3-h i.v. infusion) administered every 2 wk

AEs at the MTD*Per patient (n = 11)Per cycle (n = 120)
NCI-CTC gradeGrade 1-2Grade 3-4Grade 1-2Grade 3-4
ALT elevation — 52 — 
Alopecia — 16 — 
Anemia 10 87 
Anorexia — — 
AP elevation — 22 — 
Arthralgia — 27 — 
AST elevation — 21 — 
CPK elevation — — 
Creatinine elevation — 27 — 
Diarrhea — — 
Hypersensitivity reaction — — 
Fatigue — 61 — 
LDH elevation — 11 — 
Leukopenia 55 20 
Myalgia — 26 — 
Nausea 31 
Neutropenia 51 26 
Oral candidiasis — — 
Peripheral sensory neuropathy — 14 — 
Stomatitis — — 
Thrombocytopenia — 25 — 
Vomiting 
AEs at the MTD*Per patient (n = 11)Per cycle (n = 120)
NCI-CTC gradeGrade 1-2Grade 3-4Grade 1-2Grade 3-4
ALT elevation — 52 — 
Alopecia — 16 — 
Anemia 10 87 
Anorexia — — 
AP elevation — 22 — 
Arthralgia — 27 — 
AST elevation — 21 — 
CPK elevation — — 
Creatinine elevation — 27 — 
Diarrhea — — 
Hypersensitivity reaction — — 
Fatigue — 61 — 
LDH elevation — 11 — 
Leukopenia 55 20 
Myalgia — 26 — 
Nausea 31 
Neutropenia 51 26 
Oral candidiasis — — 
Peripheral sensory neuropathy — 14 — 
Stomatitis — — 
Thrombocytopenia — 25 — 
Vomiting 

Abbreviations: NCI-CTC, National Cancer Institute Common Toxicity Criteria; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CPK, creatine phosphokinase; LDH, lactate dehydrogenase.

*Depicted are the numbers of patients/cycles with the specified AE.

Of grade 3 to 4 AEs, grade 4 AEs included the following laboratory abnormalities (anemia, n = 1 patient; leukopenia, n = 1, and neutropenia, n = 4). Other grade 3 to 4 AEs were grade 3.

The most common hematologic AEs, irrespective of grade, were anemia, leukopenia, and neutropenia, which were generally grade 1 to 2 in severity. The severity of hematologic toxicities did not seem to be dose related within the narrow dosing range evaluated; however, the incidence of unresolved neutropenia, resulting in treatment delay, increased as a function of dose level and was the principal toxicity that ultimately precluded dose escalation in the study. Instead, the extent of prior myelosuppressive treatment related to the severity of hematologic toxicities. Effects on WBC and neutrophils were generally reversible and rarely resulted in treatment delay. At the MTD level, grade 3 to 4 neutropenia was generally noted on day 14 (range, 7-19) and usually resolved to grade ≤2 on day 21 (range, 9-26). One patient each had grade 4 anemia and leukopenia, whereas four patients developed grade 4 neutropenia. A 53-year-old female with metastatic breast cancer who had previously received high dose chemotherapy with autologous bone marrow support experienced grades 3 and 4 neutropenia in 3 and 12 cycles, respectively, but she was able to receive 18 total cycles, which occasionally required treatment delays of up to 7 days. A single patient developed neutropenia complicated by fever lasting 1 day in her fourth cycle administered at the 120/650 mg/m2 dose level.

The most frequent biochemical AEs were self-limited elevations in transaminases and AP. No grade 3 or 4 events occurred.

Pharmacokinetics

Relevant pharmacokinetic parameter values for sequential paclitaxel and trabectedin are shown in Table 4. At the recommended dose for trabectedin in this sequential schedule (0.650 mg/m2), Cmax and AUC values averaged 3.53 (1.41) ng/mL and 23.39 (9.67) h*ng/mL, respectively, during the first cycle, and 3.23 (1.13) ng/mL and 21.55 (7.92) h*ng/mL, respectively, during the second cycle. Paired sample t test of each individual patients' Cmax and AUC values in cycles 1 and 2 (all level doses) did not show significant differences in these parameters (P = 0.80 and 0.98, respectively). With respect to paclitaxel recommended dose (120 mg/m2), Cmax and AUC were 5,099 (2,133) ng/mL and 8,482 (3,402) h*ng/mL, respectively, during the first cycle, and 4,963 (2,238) ng/mL and 8,693 (3,691) h*ng/mL, respectively, during the second cycle. AUC was calculated excluding those points beyond 48 hours, as the sampling schedule was different in cycle 1 and cycle 2. Paired sample t test (each individual patient, all level doses) did not show significant differences (P = 0.29 and 0.69 for Cmax and AUC, respectively).

Table 4.

Noncompartmental pharmacokinetic parameters of sequential paclitaxel (1-h i.v. infusion) and trabectedin (3-h i.v. infusion)

Dose level (mg/m2)Cycle (n)Total dose (mg)Cmax (ng/mL)AUC (h*ng/mL)t1/2 (h)CL (l/h)Vss (l)
Paclitaxel 1-h i.v. infusion* 
80 Cycle 1 (n = 6) 158.2 (25.6) 2,282 (1,053) 4,892 (2,146) 17.4 (5.2) 37.2 (14.8) 450 (193) 
Cycle 2 (n = 6) 158.8 (24.7) 2,058 (645) 4,554 (1,087) 14.8 (2.0) 36.9 (11.5) 412 (165) 
120 Cycle 1 (n = 23) 219.7 (37.2) 5,099 (2,133) 8,482 (3,402) 15.9 (3.5) 29.8 (11.9) 273 (153) 
Cycle 2 (n = 18) 217.8 (37.1) 4,963 (2,238) 8,693 (3,691) 16.2 (3.4) 29.7 (13.0) 299 (257) 
Trabectedin 3-h i.v. infusion 
0.525 Cycle 1 (n = 3) 1.039 (0.114) 2.83 (0.40) 20.88 (4.40) 86.8 (23.7) 51.83 (14.6) 3,702 (1,012) 
Cycle 2 (n = 3) 1.045 (0.114) 3.59 (1.70) 23.97 (6.06) 77.0 (65.6) 46.03 (14.5) 3,481 (4,134) 
0.580 Cycle 1 (n = 8) 1.139 (0.221) 3.61 (1.43) 27.62 (19.45) 52.4 (20.9) 57.38 (27.9) 2,535 (2,082) 
Cycle 2 (n = 7) 1.159 (0.232) 3.08 (1.40) 28.15 (16.52) 74.6 (27.5) 48.85 (17.7) 3,370 (2,081) 
0.650 Cycle 1 (n = 11) 1.198 (0.153) 3.53 (1.41) 23.39 (9.67) 69.8 (34.9) 60.18 (28.8) 3,308 (2,127) 
Cycle 2 (n = 11) 1.201 (0.155) 3.23 (1.13) 21.55 (7.92) 69.9 (46.0) 63.81 (29.5) 3,740 (3,150) 
0.775 Cycle 1 (n = 4) 1.281 (0.343) 1.95 (0.60) 14.80 (5.20) 59.2 (24.9) 89.07 (16.6) 4,761 (2,005) 
Cycle 2 (n = 3) 1.338 (0.409) 2.61 (0.26) 23.98 (11.49) 75.25 (40.3) 59.72 (12.4) 3,973 (1,853) 
Dose level (mg/m2)Cycle (n)Total dose (mg)Cmax (ng/mL)AUC (h*ng/mL)t1/2 (h)CL (l/h)Vss (l)
Paclitaxel 1-h i.v. infusion* 
80 Cycle 1 (n = 6) 158.2 (25.6) 2,282 (1,053) 4,892 (2,146) 17.4 (5.2) 37.2 (14.8) 450 (193) 
Cycle 2 (n = 6) 158.8 (24.7) 2,058 (645) 4,554 (1,087) 14.8 (2.0) 36.9 (11.5) 412 (165) 
120 Cycle 1 (n = 23) 219.7 (37.2) 5,099 (2,133) 8,482 (3,402) 15.9 (3.5) 29.8 (11.9) 273 (153) 
Cycle 2 (n = 18) 217.8 (37.1) 4,963 (2,238) 8,693 (3,691) 16.2 (3.4) 29.7 (13.0) 299 (257) 
Trabectedin 3-h i.v. infusion 
0.525 Cycle 1 (n = 3) 1.039 (0.114) 2.83 (0.40) 20.88 (4.40) 86.8 (23.7) 51.83 (14.6) 3,702 (1,012) 
Cycle 2 (n = 3) 1.045 (0.114) 3.59 (1.70) 23.97 (6.06) 77.0 (65.6) 46.03 (14.5) 3,481 (4,134) 
0.580 Cycle 1 (n = 8) 1.139 (0.221) 3.61 (1.43) 27.62 (19.45) 52.4 (20.9) 57.38 (27.9) 2,535 (2,082) 
Cycle 2 (n = 7) 1.159 (0.232) 3.08 (1.40) 28.15 (16.52) 74.6 (27.5) 48.85 (17.7) 3,370 (2,081) 
0.650 Cycle 1 (n = 11) 1.198 (0.153) 3.53 (1.41) 23.39 (9.67) 69.8 (34.9) 60.18 (28.8) 3,308 (2,127) 
Cycle 2 (n = 11) 1.201 (0.155) 3.23 (1.13) 21.55 (7.92) 69.9 (46.0) 63.81 (29.5) 3,740 (3,150) 
0.775 Cycle 1 (n = 4) 1.281 (0.343) 1.95 (0.60) 14.80 (5.20) 59.2 (24.9) 89.07 (16.6) 4,761 (2,005) 
Cycle 2 (n = 3) 1.338 (0.409) 2.61 (0.26) 23.98 (11.49) 75.25 (40.3) 59.72 (12.4) 3,973 (1,853) 

NOTE: Results shown are mean (SD).

Abbreviations: CL, total body clearance; t1/2, terminal half-life; Vss, volume of distribution at steady-state.

*To evaluate any possible drug-drug pharmacokinetic interaction when trabectedin and paclitaxel are administered concomitantly, their pharmacokinetic characteristics were evaluated independently during the first cycle [in this cycle, paclitaxel was to be given 8 days (i.e., on day −7) before trabectedin] and concomitantly during the second cycle (paclitaxel and trabectedin administered within a 24-hour period). Therefore, the sampling schedule was different in cycle 1 and 2. For measurement of paclitaxel PK, only samples limited to 48 h postinfusion were used.

Recommended dose for phase II trials.

Antitumor activity

Details regarding the potential anticancer activity of the paclitaxel/trabectedin regimen are shown in Table 5. A 33-year-old male with a poorly differentiated primitive neuroectodermal tumor with metastases to peritracheal and perivascular lymph nodes and the lung achieved a complete response after treatment with paclitaxel/trabectedin at the MTD (120/0.650 mg/m2). The patient's pertinent prior medical history included a primary resection of a right thigh mass followed by adjuvant ifosfamide and radiation therapy, neoadjuvant chemotherapy (consisting of vincristine, doxorubicin, and cyclophosphamide), and a second resection at first recurrence. Treatment was discontinued after 28 total cycles, at which time he had no evidence of disease. At the time of last follow-up, the duration of his complete response, time-to-progression, and overall survival were 5.4+, 18.5+, and 18.7+ months, respectively. In addition, a 53-year-old female with metastatic breast cancer who had received six lines of prior treatment, including taxanes, had a partial response (4.1 months), which was not confirmed by subsequent imaging and therefore considered to have had stable disease (SD) as the best response. She received 18 cycles of paclitaxel/trabectedin at the MTD. Overall, 10 patients had SD as their best response, including 6 patients with STS, 5 of whom had SD exceeding 6 months, 2 heavily pretreated breast cancer patients, both of whom had progressed on prior taxane treatment in the metastatic setting, and 1 patient each with non–small cell lung cancer and melanoma.

Table 5.

Characteristics of patients showing objective activity or SD as their best response

Dose (paclitaxel/trabectedin; mg/m2)GenderAge(y)PSPrimary tumor typePrior chemotherapy linesTreatment cycles receivedBest responseTTP (mo)
80/0.525 Male 58 STS 28 SD 14.6 
80/0.580 Male 35 STS 16 SD 7.9 
Female 48 Melanoma 26 SD 12.6 
120/0.650* Male 60 STS 23 SD 11.6 
Male 33 STS 28 CR 18.5+ 
Female 53 Breast 18 SD 4.1 
Male 65 Lung SD 4.3 
Female 57 Breast SD 2.0+ 
Male 82 STS 22 SD 11.9+ 
120/0.775 Female 56 STS SD 3.8 
Male 59 STS 12 SD 7.9 
Dose (paclitaxel/trabectedin; mg/m2)GenderAge(y)PSPrimary tumor typePrior chemotherapy linesTreatment cycles receivedBest responseTTP (mo)
80/0.525 Male 58 STS 28 SD 14.6 
80/0.580 Male 35 STS 16 SD 7.9 
Female 48 Melanoma 26 SD 12.6 
120/0.650* Male 60 STS 23 SD 11.6 
Male 33 STS 28 CR 18.5+ 
Female 53 Breast 18 SD 4.1 
Male 65 Lung SD 4.3 
Female 57 Breast SD 2.0+ 
Male 82 STS 22 SD 11.9+ 
120/0.775 Female 56 STS SD 3.8 
Male 59 STS 12 SD 7.9 

Abbreviations: CR, complete response; TTP, time to progression.

*Recommended dose for phase II trials.

Poorly differentiated primitive neuroectodermal tumor. Duration of response = 5.4+ mo and overall survival of 18.7+ mo.

Unconfirmed partial response.

Based on experimental data indicating that the magnitude of cytotoxicity produced by paclitaxel and trabectedin was maximal when paclitaxel treatment preceded trabectedin treatment, and the overlapping antitumor spectra of these agents, particularly in ovarian and breast cancer (10, 11, 14, 22, 23), this phase I study evaluated the feasibility of administering paclitaxel and trabectedin in a sequential manner, simulating optimal preclinical conditions. The principal hematologic toxicity of both trabectedin (24, 25) and paclitaxel (2628) when administered as single agents was neutropenia, which was the main DLT, thus precluding further dose escalation of paclitaxel/trabectedin above 120/0.650 mg/m2 on a treatment schedule of paclitaxel as a 1-hour i.v. infusion followed 24 hours later by trabectedin 3-hour i.v. every 2 weeks. Although the duration of grade 4 neutropenia was generally brief (<7 days), unresolved neutropenia resulted in protracted (>7 days) delays in the administration of the next cycle. Furthermore, the dose intensities for paclitaxel (60 mg/m2/week) and trabectedin (0.325 mg/m2/week) in this combination regimen are similar to the dose intensities for both paclitaxel and trabectedin administered as single agents on conventional dosing schedules: 175 mg/m2 paclitaxel every 3 weeks (58.3 mg/m2/week; refs. 2931) and 0.58 mg/m2/week × 3 every 4 weeks trabectedin (0.435 mg/m2/week; refs. 4, 7).

At the MTD dose level, 120/0.650 mg/m2, the paclitaxel/trabectedin regimen lacked relevant cumulative toxicity and was well tolerated when administered repeatedly. Although severe neutropenia was the principal DLT, its duration was rarely associated with complications. In 29 of 41 total cycles associated with grade 3 or 4 neutropenia at all dose levels, treatment delay by ≤1 week was required due to the lack of toxicity resolution to a level permitting retreatment on day 15; however, both protracted (>5 days) grade 4 neutropenia and febrile neutropenia were rare. A single patient experienced grade 4 neutropenia associated with fever. As expected, based on the lack of relevant thrombocytopenia associated with administration of paclitaxel and trabectedin as single agents (2428), severe (grade 3-4) thrombocytopenia did not occur and severe anemia was uncommon. In addition, no unexpected nonhematologic toxicities were observed. The most common nonhematologic AEs consisted of grade 1 to 2 fatigue, nausea, arthralgia, and myalgia, but all were manageable and none led to treatment delay or discontinuation. Elevations in hepatic transaminases, which have been reported previously with trabectedin (3235), were also noted in the present study, but transaminitis was always mild to moderate in severity and never resulted in treatment delay.

PK studies of both paclitaxel and trabectedin revealed high clearance rates, long half-lives, and large volumes of distribution, and PK parameters were within the range of those reported in prior single-agent studies (14, 36, 37). Both paclitaxel and trabectedin are substrates of cytochrome P450 metabolism (CYP3A4 and CYP2C8 for paclitaxel; CYP3A4 for trabectedin) that may be induced or inhibited by other drugs. However, the principal goal of PK assessments in the present study was to identify clinically relevant drug-drug interactions that might limit the administration of relevant doses of either agent in combination. The PK behavior of both agents was evaluated independently during the first cycle, in which paclitaxel was administered 8 days before trabectedin, and concurrently during the second cycle, in which drug treatment was separated by 24 hours. PK parameters indicative of exposure did not differ between first and second cycles, suggesting a lack of major interactions, particularly for trabectedin. In a recent study in which CYP3A4 phenotypic activity was evaluated before and during trabectedin treatment using the erythromycin breath test, trabectedin clearance was found to be related to CYP3A4 activity, but the relationship was not as strong as expected based on the importance of CYP3A4 in trabectedin clearance (14). Perhaps more interesting was the fact that differences in erythromycin breath test done before and after two trabectedin doses were minimal, suggesting a limited influence of trabectedin on CYP3A4 activity. The results of in vitro studies are consistent in that trabectedin does not inhibit the activity of the main CYP isoforms (38).

A patient with STS had a complete response and several patients with various refractory solid malignancies, including melanoma and breast and lung cancers, had protracted SD as their best response. These findings are consistent with in vitro or in vivo results for sequential paclitaxel and trabectedin in human STS and breast and lung adenocarcinoma (911), as well as with findings of previous clinical trials with single-agent trabectedin (4, 8, 24, 3942), and provide the rationale for phase II evaluations in relevant disease settings.

It was elected to develop the combination of trabectedin and paclitaxel on an every-2-week dosing schedule instead of the more common every-1-week and every-3-week dosing schedules. This decision reflected the results of previous phase II studies of trabectedin, as well as toxicity and feasibility considerations. In a pivotal randomized phase II study of trabectedin in previously patients with STS, an every-3-week schedule possessed greater antitumor activity than a weekly schedule (4). Nevertheless, a more frequent dosing schedule was considered to reduce overlapping toxicity, particularly neutropenia, which has been noted for each of the agents when administered on a weekly dosing schedule. However, the weekly sequential administration of paclitaxel followed 24 hours later by trabectedin is cumbersome for patients and was not considered logistically feasible for chronic administration. Therefore, an every-2-week dosing schedule, which has been previously evaluated for the development of paclitaxel-based combination regimens (4348), was used in the present study.

In conclusion, 120 mg/m2 paclitaxel and 0.650 mg/m2 trabectedin is the MTD level for these agents administered sequentially every 2 weeks, with neutropenia that resulted in treatment delay exceeding 1 week as the principal DLT. At this dose level, toxicity was manageable and repeated administration for protracted periods was also feasible. The administered dose intensity of each agent in combination being similar to that of each agent administered alone, single agent is consistent with the lack of major drug-drug PK interactions. Based on the favorable safety and PK behavior, as well as the preliminary activity noted with the combination of paclitaxel and trabectedin administered every 2 weeks, further disease-directed studies in patients with relevant solid malignancies are warranted.

No potential conflicts of interest were disclosed.

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.

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