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Phase I pharmacokinetic study of a weekly liposomal paclitaxel formulation (Genexol®-PM) in patients with solid tumors
original article
Annals of Oncology 21: 382–388, 2010 doi:10.1093/annonc/mdp315 Published online 24 July 2009
Phase I pharmacokinetic study of a weekly liposomal paclitaxel formulation (Genexolâ-PM) in patients with solid tumors W. T. Lim1, E. H. Tan1, C. K. Toh1, S. W. Hee2, S. S. Leong1, P. C. S. Ang1, N. S. Wong1 & B. Chowbay3* 1
Department of Medical Oncology; 2Biostatistic Unit, Division of Clinical Trials and Epidemiological Sciences and 3Clinical Pharmacology Laboratory, Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore
Background: The aim of this study was to determine the maximum tolerated dose (MTD) and the pharmacokinetic profile of Genexol-PM in Asian cancer patients.
original article
Materials and methods: Patients (N = 24) refractory to previous chemotherapy received Genexol-PM as an 1-h infusion on a weekly basis for 3 weeks followed by a resting week. The starting dose was 80 mg/m2 and the maximum administered dose was 200 mg/m2. Results: The majority of patients had lung, nasopharyngeal and breast cancers and in eleven patients (46%), taxanebased chemotherapy had previously failed. The MTD was defined at 180 mg/m2. The most common grade 3 nonhematologic adverse events in cycle 1 were fatigue (4%) and neuropathy (4%) occurring mainly at 200 mg/m2. Five (21%) patients had partial response, nine (38%) had stable disease and seven (29%) had disease progression. Five of 11 previously taxane-refractory patients showed clinical benefit to Genexol-PM. The pharmacokinetics of Genexol-PM displayed dose-proportionality, with both the maximum concentration (Cmax) and the area under the concentrationtime curve from zero to infinity (AUC0–N) increasing by approximately four- and threefold, respectively, as the dose of Genexol-PM was escalated from 80 to 200 mg/m2. The median total-body clearance of Genexol-PM for all patients was 43.9 l/h. Conclusion: The weekly regimen of Genexol-PM was well tolerated and responses were observed in patients with refractory tumors, including patients who had failed taxane-based chemotherapy previously. Key words: Asian, Genexol-PM, pharmacokinetics, phase 1, weekly regime
introduction Paclitaxel is a taxane derived from the Pacific yew tree (Taxus brevifolia). It has a wide spectrum of antitumor activity when used as monotherapy or in combination chemotherapy regimens [1]. The drug is used extensively in the treatment of advanced carcinomas of the breast, ovary, head and neck and lung. In preclinical studies, paclitaxel produces a number of concentrationdependent effects, including acute cytotoxicity with and without apoptosis, radiosensitization, microtubule bundle formation, increase in tubulin polymer mass and stabilization of microtubules against depolymerization [2]. As paclitaxel concentration increases, its mechanism of cytotoxic action may also vary. Paclitaxel concentrations up to 330 nmol/l was shown to enhance polymerized microtubule mass and stabilize microtubule bundle formation in association with cell growth
*Correspondence to: Assoc. Prof. B. Chowbay, Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre, 11 Hospital Drive, Singapore 169610. Tel: +65-6436-8321; Fax: +65-6372-0161; E-mail: [email protected]
arrest [3]. At these high concentrations, paclitaxel-induced cell death occurred via a Raf-1-dependent pathway [4]. In contrast, at lower concentrations (<10 nmol/l), paclitaxel was shown to induce growth inhibition independent of microtubular mass [3] and caused mitotic arrest by a Raf-1-dependent pathway [4]. Paclitaxel exhibits nonlinear pharmacokinetics with saturable metabolism and distribution to tissues [5, 6]. The nonlinear behavior of paclitaxel has been attributed to the formulating reagent, cremophor-EL (Cr-EL), that is used to enhance its drug solubility [7]. In vitro studies indicated that Cr-EL reversed P-glycoprotein-mediated multidrug resistance [8, 9]; however, the low volumes of distribution of Cr-EL in vivo indicated that concentrations of Cr-EL would be too low to have any effect in solid tumors [10], negating any additional benefit of such a vehicle. Cr-EL also decreases the oral bioavailability of paclitaxel [11, 12], thereby limiting the usefulness of this formulation for oral use. Cr-EL systemic exposure is higher when this formulation is given over 1 h as compared with longer infusions [13]. This results in higher incidences of hypersensitivity reactions seen in shorter
ª The Author 2009. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
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Received 20 February 2009; revised 4 May 2009 & 7 May 2009; accepted 8 May 2009
original article
Annals of Oncology
materials and methods patients This was an open-label phase I dose-escalation study. Patients were eligible for the trial if they satisfied the following inclusion criteria: (i) cytologically or histologically confirmed solid tumors that were advanced and incurable; (ii) age between 21 and 70 years; (iii) Eastern Cooperative Oncology Group performance status of zero to two; (iv) life expectancy of at least 3 months; (v) adequate bone marrow function with absolute neutrophil count ‡1.5 · 103/ml, hemoglobin ‡9 g/dl and platelet count ‡100 · 103/ml; (vi) adequate hepatic function with serum total bilirubin level £2.0 mg/dl (34 mmol/l) and alanine transaminase and aspartate transaminase £2· the upper limit of normal; (vii) adequate renal function with serum creatinine £141 lmol/l; (viii) no chemotherapy or radiotherapy within 4 weeks before entry into the study. Previously irradiated patients with marker lesions not within the irradiated field were eligible for the study. Patients with controlled or asymptomatic brain metastases not requiring dexamethasone were eligible. Patients who had previous paclitaxel treatment were excluded but prior docetaxel (Taxotere, Aventis Pharma, UK) treatment was allowed. Exclusion criteria included the following: (i) active or uncontrolled infection; (ii) preexisting cardiac disease, including congestive heart failure, arrhythmias requiring treatment or myocardial infarction within the preceding 3 months and (iii) pneumonitis or uncontrolled large pleural effusions, uncontrolled diabetes mellitus (random blood glucose >11.0 mmol/l) and pregnancy, lactation or refusal to use effective contraception. Written informed consent was obtained from all study participants. The study was reviewed and approved by the Health Science Authority Singapore and the National Cancer Centre Singapore Institutional Review Board.
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drug administration and dose escalation Blood counts and a metabolic panel were checked every week during the course of treatment. Safety assessments were based on physical examinations, vital signs and laboratory tests, performance status, symptoms/toxicity and adverse events. Patients were treated to a maximum of six cycles of treatment. Patients were removed from the study if toxic effects did not resolve within 14 days, withdrew informed consent or due to progressive disease (PD). Toxic effects were assessed in this study using the National Cancer Institute—Common Toxicity Criteria (NCI-CTC) version 3.0. Although response was not the primary end point of this trial, patients with measurable disease were assessed after every two cycles of Genexol-PM using standard RECIST criteria [24]. In addition to a baseline/screening scan, confirmatory scans were obtained 4 weeks following initial documentation of either an objective response or a PD. Genexol-PM was supplied by Samyang Corporation, Seoul, South Korea. Genexol-PM was infused over 1 h without premedication and administered on a weekly schedule for three consecutive weeks, followed by 1 week of rest. This 4-week treatment schedule constituted one treatment cycle. In the event of hypersensitivity reactions, standard premedications were prescribed before Genexol-PM administration. A standard ‘3 + 3’ design was used for dose escalation. The starting dose of Genexol-PM was 80 mg/m2. Subsequent dose escalations were 100, 120, 140, 160, 180 and 200 mg/m2 in cohorts of three patients per level. If at any dose level, no patient experienced DLT within 28 days after receipt of Genexol-PM, then another cohort of three patients were enrolled to the next level. Three additional patients were entered at the same dose if one of three patients experienced DLT. If DLT occured in at least one of the additional three patients entered at a particular dose level, then the dose level before the current dose level at which DLT occurred was regarded as the MTD and further dose escalation was terminated. Intrapatient dose escalation was not allowed. DLT was defined as any of the following events occurring during the first cycle (28-day period): (i) grade 4 neutropenia lasting at least 4 days or grade 4 neutropenia associated with fever, (ii) grade 3 anemia, (iii) grade 4 thrombocytopenia, (iv) grade 4 elevation of total bilirubin or (v) any other grade 3 non-hematologic toxicity according to the NCI-CTC. Complete response (CR) was defined as the clinical absence of tumour; partial response (PR) as at least a 50% decrease in the sum of the product of the perpendicular diameters of the measurable lesions, taking as reference the baseline sum product of perpendicular diameters, without progression of any lesion or appearance of any new disease; stable disease as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum perpendicular diameters since the treatment started; and PD as at least a 25% increase in the sum of the product of the perpendicular diameters of the measurable lesion, taking as reference the smallest sum product perpendicular diameters recorded since the treatment started, and/or the appearance of new lesions.
pharmacokinetics Pharmacokinetics evaluation was carried out in all patients following administration of the first dose on day 1 of the first cycle. Blood samples (3 ml) were collected for determination of Genexol-PM concentrations just before the start of infusion and 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 24 h postinfusion. All blood samples were drawn from a vein in the arm opposite to that used for Genexol-PM infusion. The blood samples were immediately centrifuged at 1500 g for 15 min and stored at 220C until analyzed. Plasma concentrations of paclitaxel were estimated by reversed-phase highperformance liquid chromatography with UV detection as previously published [25]. The lower limit of quantitation was 20 ng/ml for paclitaxel. The calibration curves were linear over a concentration range of 20–250 000 ng/ml for paclitaxel. The average recovery was >90% and the within- and between-day coefficients of variations were <9%. Pharmacokinetic
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infusions of 1 h compared with 3-h and 24-h infusions. Complement activation by Cr-EL in vitro [14, 15] possibly explains the acute life-threatening hypersensitivity reactions experienced with paclitaxel [16, 17] in patients treated with this drug. Neurotoxicity resulting from axonal demyelination and swelling is also possibly an effect of Cr-EL. Cyclosporine formulated with Cr-EL causes a similar neurotoxicity as opposed to oral formulations of cyclosporine [18], and docetaxel formulated with Tween 80 has a much lower incidence of neurotoxicity [19]. Finally, rats treated with CrEL-free paclitaxel showed no distribution of paclitaxel to the peripheral nervous system [20]. All the aforementioned limitations of formulating paclitaxel with Cr-EL prompted the development of novel formulations of paclitaxel. One of these formulations is a sterile, lyophilized polymeric micellar formulation of paclitaxel, Genexol-PM. It consists of paclitaxel solubilized in methoxy polyethylene glycol-poly (D,Llactide) [21]. It has better tissue distribution in mouse models than paclitaxel Cr-EL with good antitumor efficacy [21]. In a phase I monotherapy study of Genexol-PM on a 3-weekly schedule, dose-limiting toxic effects (DLTs) of neuropathy and neutropenia were encountered at 390 mg/m2 [22]. A subsequent phase II study of Genexol-PM 300 mg/m2 3 weekly in metastatic breast cancer patients showed good efficacy with no febrile neutropenia but a high rate of grade 3 neuropathy (51.2%) and grade 3 and 4 neutropenia (68.3%) [23]. Different doses and scheduling needed to be evaluated to determine whether toxic effects and efficacies can be improved. To this end, we carried out a phase I study to determine the DLTs and maximum tolerated dose (MTD) of a weekly schedule of Genexol-PM.
original article
Annals of Oncology
parameters were calculated by noncompartmental analysis using WinNonlin software version 2.1 (Pharsight Corp., Mountain View, CA).
statistical analysis Categorical variables were summarized as frequency and percentage, and continuous variables were summarized as mean with standard deviation or median with range. All analyses were carried out on SAS 9.1.
results patient characteristics Table 1 depicts the characteristics of the patients accrued to this study. A total of 35 patients were screened for this trial and 24 Table 1. Patient demographics and clinical characteristics
No. of patients Screened Eligible Assessable for toxicity Assessable for response Assessable for pharmacokinetics Age (years) Median (range) Sex Female Male Performance status (ECOG) 0 1 2 Primary site Breast Head and neck Lung Nasopharyngeal Others No. of previous chemotherapies (n = 23) Median (range) Prior taxane-based chemotherapy Prior radiation
N
(%)
35 24 24 22 22
100.0 68.6 68.6 62.9 62.9
56
(39–67)
8 16
33.3 66.7
5 18 1
20.8 75.0 4.2
4 3 7 9 1
16.7 12.5 29.2 37.5 4.2
2 11 16
(1–7) 45.8 66.7
ECOG, Eastern Cooperative Oncology Group.
drug administration and toxicity A total of 87 cycles of Genexol-PM were administered. The median number of cycles of Genexol-PM administered was 4. The total number of cycles completed in each dose level is summarized in Table 2. Five patients (21%) completed the prescribed six cycles of Genexol-PM: one patient each from dose levels 1, 2 and 3 and two patients from dose level 7. In the 19 patients who did not complete treatment, the reasons for withdrawal were progressive disease (n = 7; 37%), adverse events/serious adverse events (n = 5; 26%), requested withdrawal (n = 3; 16%), death (n = 2; 11%) and worsening performance status (n = 2; 11%). DLT was reached at dose level 7 (200 mg/m2) and the MTD of Genexol-PM was declared at 180 mg/m2. Table 3 summarizes the frequency of occurrence of hematologic toxic effects in the cancer patients. Grade 3 neutropenia was the most common hematologic toxicity observed in patients receiving Genexol-PM at doses of ‡120 mg/ m2 in the first cycle. A similar hematologic toxicity profile was observed at subsequent cycles when the dose of Genexol-PM was escalated beyond dose level 3 (120 mg/m2). Anemia was not more than grade 2 for all cases. Thrombocytopenia was uncommon across all dose levels (Table 3). Grade 4 non-hematologic adverse events were uncommon in cycle 1 and subsequent cycles (Table 4). The most common grade 3 non-hematologic adverse events in cycle 1 were fatigue and neuropathy and occurred mainly at dose level 7 (200 mg/m2) in 4% and 4% of the patients, respectively. A similar toxicity profile was observed in subsequent cycles but tended to appear at dose level 4 (140 mg/m2) onward (Table 4). One patient experienced grade 3 dermatitis during cycle 1 at dose level 7 (200 mg/m2) due to radiation recall caused by the administration of Genexol-PM. The investigators agreed that this was a unique case and did not strictly constitute a DLT.
Table 2. Dose levels and administration n Dose Dose level (mg/m2)
No. of No. of No. of No. of patients No. of No. of patients Total no. No. of patients No. of patients patients with cycles of with dose delay cycles of cycles who completed of cycles with dose dose delay dose omission dose omission de-escalated of dose completed reduction six cycles reduction
Total 1 2 3 4 5 6 7
5 1 1 1 0 0 0 2
80 100 120 140 160 180 200
384 | Lim et al.
24 3 3 3 3 3 3 6
87 9 10 10 14 12 9 23
7
7
5
9
1 1
1 1
1
1
3 1
5 2
4
4
1
2
13
36
2 3 1 2 5
2 7 1 7 19
7 1 1 1 4
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Variables
were eligible. The median age was 56 years (range 39–67 years) and two-thirds of the enrolled patients were male (67%). Twenty-three patients (96%) had received prior chemotherapy, including 11 patients (46%) who had previously received taxane-based chemotherapy. The median number of prior chemotherapy regimens received per patient was 2 (range 1–7). Sixteen patients (67%) had prior radiotherapy.
original article
Annals of Oncology
Table 3. Hematologic adverse events by dose level in the first cycle and subsequent cycles in parenthesis, () Dose level, mg/m2 80 (n = 3) Grade 1/2 3 4 Adverse events
100 (n = 3) 1/2 3 4
120 (n = 3) 1/2 3
Anemia 3 (2) Thrombocytopenia Neutropenia 1
3 (3) (1) 1 (1)
3 (3)
4
140 (n = 3) 1/2 3 3 (2)
160 (n = 3) 4 1/2 3
(1)
1 (1) 1 (1) 1 (1)
180 (n = 3) 1/2 3
4
3 (3)
1 (3) 1 1
200 (n = 6) 4 1/2 3
3 (3)
4
4 (5)
(1)
1 (2) 1
2 (2) 1 (2)
Table 4. Maximum grade of non-hematologic adverse event by dose level in the first cycle and subsequent cycles in parenthesis, (). Dose level, mg/m2 Grade
100 (n = 3) 1/2 3
120 (n = 3) 1/2 3
140 (n = 3) 1/2 3
160 (n = 3) 1/2 3
180 (n = 3) 1/2 3
200 (n = 6) 1/2 3
2 (2)
3 (2)
3 (1)
1
2 (3)
2
1 (2) 5 (3) 1 (1)
(1)
1 1
Adverse events Hypersensitivity Fatigue Insomnia Non-neutropenic fever Febrile neutropenia Alopecia Pruritus/itch Rash Dermatitis associated with radiation Anorexia Constipation Diarrhea Mucositis Nausea Vomiting Edema: limb AST ALT Alkaline phosphatase Neuropathy (cranial) Neuropathy (motor) Neuropathy (sensory) Myalgia Cough Dyspnea
1
(1)
1
(2)
1 (1)
(1) (1) 1 (1)
1 (1) 1 2
(1)
1 (1)
1 (1)
1 (1)
1 1 1
3 (2) 2 (2)
(1)
(1) (1) (1)
(1) 1 (1) 2 (3) (1)
1 1 1 1 1
4 (2)
2 (1) 1
(2) (1) (1) (1) (1)
1 2 (2) 2 (1) 1 (2)
1 (1) 2 (1) 1
(1) 1 (1) 1 (1) 1 (1) 1 (1)
(2) (1) (1) (1) (1)
2 (1) 1 (2) (1)
1 (1) 1 (1) 2 (2)
(1)
2 (2) (2) 1 (1) (1)
1
(1)
2 2
1 (1) (2) 3 (3) 1 (2)
(1) 1 (2)
1
AST, aspartate aminotransferase; ALT, alanine aminotransferase.
antitumor response Table 5 summarizes the overall response of the patients. Twenty-one of 24 patients were assessable for response. Fourteen patients had clinical benefit. Five patients had partial response (PR) (21%), nine (38%) had stable disease at 16 weeks and seven patients (29%) had PD. Of the five patients with PR, two patients had head and neck squamous cell carcinomas, two had lung carcinomas and one had nasopharyngeal carcinoma. Five of 11 patients who had received taxane-based treatment previously also achieved clinical benefit. pharmacokinetics Complete plasma pharmacokinetic profiles were obtained from 23 patients. Two patients had extremely high values of Cmax
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and AUC0–N. The Cmax of each patient was 75 986.7 and 231 448.8 ng/ml, respectively, which were 27- and 81-fold greater than the median Cmax of the rest of the patients, respectively. The AUC0–N of these two patients were 49 528.6 ngh/ml and 157 194.8 ngh/ml, which were 9- and 30-fold greater than the median AUC0–N of the rest of the patients, respectively. These two patients were considered outliers and excluded from further pharmacokinetic analysis. Table 6 shows a summary of the pharmacokinetic parameters by dose levels in 21 patients. Figure 1 depicts the mean plasma concentration–time profiles of Genexol-PM in patients treated at different dose levels. The maximum concentration was reached at the end of the infusion and the decline in concentration during the terminal elimination phase was similar at the various dose levels after 8 h. At 24 h,
doi:10.1093/annonc/mdp315 | 385
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80 (n = 3) 1/2 3
original article
Annals of Oncology
Genexol-PM concentrations were <10% of Cmax, with a median terminal half-life (t½) of 8 h. The interpatient variability [as measured by the percent coefficient of variation (CV)] for Cmax and AUC0–N values were 54% and 45%, respectively. The pharmacokinetics of Genexol-PM displayed doseproportionality, with both Cmax and AUC0–N values increasing by approximately four- and threefold as the dose of GenexolPM was increased from 80 to 200 mg/m2 with no significant change in clearance (Figure 2A–C). The median total-body clearance of Genexol-PM for all patients was 43.9 l/h. The apparent volume of distribution (Vd) was >500 l, indicative of paclitaxel’s extensive tissue binding.
discussion
Table 5. Best overall response Clinical characteristics
Partial response
Primary sites Breast Head and neck 2 Lung 2 Nasopharyngeal 1 Others Previous taxane exposure No 3 Yes 2 Dose level (actual dose, mg/m2) 1 (80) 2 (100) 1 3 (120) 4 (140) 2 5 (160) 1 6 (180) 7 (200) 1
Stable disease
Progressive disease
Not evaluable
2
1 1 1 4
1
6 3
3 4
1 2
1 1 2
2 1 1 1 1
2 4 1
1 2 2
1
2
1 2
Table 6. Pharmacokinetic parameters of Genexol-PM at different dose levels in Asian cancer patients (N = 21) Dose level (mg/m2)
No. of patients
Median (range) Cmax (ng/ml)
AUC0–N (ngh/ml)
t½ (h)
Vd (l)
CL (l/h)
80 100 120 140 160 180 200
3 3 3 2 3 3 4
1187.5 1857.7 2584.2 2775.6 3017.6 4675.8 4704.6
2249.8 2925.3 4867.1 5062.6 5212.1 7470.2 7610.2
10.9 11.3 7.5 8.1 7.2 7.8 7.6
760.6 698.3 435.2 485.7 527.6 362.5 491.8
49.7 42.9 40.4 41.9 48.8 37.6 43.7
(976.8–1644.6) (1244.0–2691.1) (1938.2–4209.1) (2575.1–2976.2) (2716.1–7882.4) (2405.5–6167.5) (4183.2–5000.5)
(2058.8–2673.2) (2890.7–4917.7) (4747.9–6013.1) (4734.8–5390.4) (4134.6–7863.3) (5523.6–11011.8) (7003.4–11008.6)
(7.95–14.1) (6.0–18.6) (7.5–9.1) (7.8–8.3) (7.2–9.5) (6.7–8.3) (6.2–8.7)
(569.8–1434.2) (248.8–1512.6) (306.9–578.0) (445.2–526.1) (271.5–665.7) (259.5–634.9) (293.2–595.0)
(48.3–70.7) (28.6–56.4) (28.3–43.9) (37.1–46.7) (26.1–51.0) (21.6–56.1) (32.7–50.0)
t½, half-life; Vd, volume of distribution.
386 | Lim et al.
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Microtubule stabilizers such as paclitaxel and docetaxel, either alone or in combination, represent an important class of drugs in the treatment of various cancers. The major limitation associated with the use of paclitaxel concerns the hypersensitivity reactions commonly encountered during treatment which is mainly due to the presence of Cr-EL in the
formulation. The Cr-EL is also responsible for alterations in the pharmacokinetics of paclitaxel and limits the administration of higher doses that may be therapeutically advantageous. The shortcomings associated with the conventional formulation of paclitaxel has seen the development of several novel formulations of paclitaxel that are either free of Cr-EL such as ABI-007 (nanoparticle formulation of paclitaxel) and GenexolPM or are formulated with smaller amounts of Cr-EL to improve safety and feasibility of shorter administration schedules such as BMS-184476. The safety profile of a 3-weekly schedule of Genexol-PM in a phase I setting has been reported previously [22] and found to be tolerable with neuropathy, myalgia and neutropenia being the main DLTs. The recommended phase II dose of the 3-weekly regimen of Genexol-PM was 300 mg/m2. This 3-weekly dose of Genexol-PM has been safely combined with cisplatin 60 mg/m2 as first-line chemotherapy in non-small-cell lung cancer [26]. Patients were initially started at 230 mg/m2 of Genexol-PM and this was successfully dose escalated to 300 mg/m2 in cycle 2 in 46% of patients. There was no excess toxicity seen with this combination and the response rates were promising. Further promise was seen in a phase II study of advanced pancreatic cancer that attempted monotherapy dosing of patients at 435 mg/m2 every 3 weeks [27]. This was not well tolerated in the first 11 patients and a permanent dose reduction to 300–350 mg/m2 was required for the subsequent 45 patients. The overall clinical benefit rate was 60% and the median progression-free survival is at least comparable to historical controls of single-agent gemcitabine. The weekly regimen of Genexol-PM has not been previously reported. The present phase I and pharmacokinetic study investigating the weekly regimen of Genexol-PM demonstrated that doses exceeding 180 mg/m2 were associated with increased incidence of hematologic and non-hematologic toxic effects in patients with advanced malignancies. Therefore, the weekly regimen of Genexol-PM 180 mg/m2 is the recommended phase II dose. The severity of neutropenia varied with the dose of GenexolPM, with grade 3 neutropenia being more common between dose levels 3 and 6 (120 and 180 mg/m2) and grade 4 neutropenia occurring more frequently at dose level 7 (200 mg/m2). These variations in the hematologic pharmacodynamics of Genexol-PM mirrored similar variations in the exposure levels of Genexol-PM at the different dose levels. Both Cmax and AUC0–N fluctuated minimally between
original article
Annals of Oncology
dose levels 3 and 5 (120 and 160 mg/m2) but increased 30% at dose levels 6 and 7 (180 and 200 mg/m2). The clearance of Genexol-PM, however, remained constant throughout the different dose levels and may partly account for the noncumulative hematologic toxicity observed at the different dose levels. Significant thrombocytopenia and anemia were uncommon. The incidence of non-hematologic toxicity was mild and manageable and mostly limited to grade 1 or 2. Fatigue, myalgia and peripheral neuropathy were the most common non-hematologic toxic effects observed with a trend of increased frequency and severity observed at dose levels exceeding 160 mg/m2. Although the incidence of neutropenia was similar to that observed in the study by Kim et al. [22], the non-hematologic toxic effects were less severe in the present study utilizing the weekly regimen of Genexol-PM. This improvement in the toxicity profile may be attributed to the lower exposure levels of paclitaxel associated with the weekly regimen as compared with the 3-weekly regimen [22]. While response was not a primary end point, the response rate in this heavily pretreated population was 21% with an additional 38% of patients achieving disease stabilization of at least 12 weeks. Furthermore, discernible clinical benefit was observed in 5 of 11 patients who had prior exposure to taxanes. These findings indicate that the weekly regimen of Genexol-PM should be explored further in formal phase II studies. Sixteen patients had received previous radiation therapy either as primary treatment or as palliation. The single patient who suffered radiation recall was a patient who had recent thoracic radiation for palliation of hemoptysis. The skin erythema and desquamation corresponded exactly to the radiation port. As radiation recall is known to recur on repeat exposure, no further drug challenge was attempted. This is a rare phenomenon albeit more common with taxanes and adriamycin [28] and should not restrict the use of this drug in future studies. In conclusion, the weekly regimen of Genexol-PM was found to be safe at a MTD of 180 mg/m2 with predictable pharmacokinetic characteristics. Preliminary clinical benefits were observed in patients with head and neck, lung and nasopharyngeal cancers as well as in patients in whom prior
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Figure 1. Mean plasma concentration–time profiles of Genexol-PM in Asian cancer patients (N = 21) treated at different dose levels.
Figure 2. Box Whisker Plots of Genexol-PM. (A) Cmax, (B) AUC0–N and (C) clearance at various dose levels in Asian cancer patients.
taxane-based chemotherapy had failed. Future phase II studies should be conducted to validate these findings.
funding Singapore Cancer Syndicate Grant (SCS-PS0023).
doi:10.1093/annonc/mdp315 | 387
original article disclosures The authors declare absence of conflict of interest as well as financial interest in the conduct of this study.
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388 | Lim et al.
14. Szebeni J, Muggia FM, Alving CR. Complement activation by Cremophor EL as a possible contributor to hypersensitivity to paclitaxel: an in vitro study. J Natl Cancer Inst 1998; 90: 300–306. 15. Szebeni J, Alving CR, Savay S et al. Formation of complement-activating particles in aqueous solutions of Taxol: possible role in hypersensitivity reactions. Int Immunopharmacol 2001; 1: 721–735. 16. Weiss RB, Donehower RC, Wiernik PH et al. Hypersensitivity reactions from taxol. J Clin Oncol 1990; 8: 1263–1268. 17. Khan A, McNally D, Tutschka PJ, Bilgrami S. Paclitaxel-induced acute bilateral pneumonitis. Ann Pharmacother 1997; 31: 1471–1474. 18. Windebank AJ, Blexrud MD, de Groen PC. Potential neurotoxicity of the solvent vehicle for cyclosporine. J Pharmacol Exp Ther 1994; 268: 1051–1056. 19. Verweij J, Clavel M, Chevalier B. Paclitaxel (Taxol) and docetaxel (Taxotere): not simply two of a kind. Ann Oncol 1994; 5: 495–505. 20. Lesser GJ, Grossman SA, Eller S, Rowinsky EK. The distribution of systemically administered [3H]-paclitaxel in rats: a quantitative autoradiographic study. Cancer Chemother Pharmacol 1995; 37: 173–178. 21. Kim SC, Kim DW, Shim YH et al. In vivo evaluation of polymeric micellar paclitaxel formulation: toxicity and efficacy. J Control Release 2001; 72: 191–202. 22. Kim TY, Kim DW, Chung JY et al. Phase I and pharmacokinetic study of GenexolPM, a cremophor-free, polymeric micelle-formulated paclitaxel, in patients with advanced malignancies. Clin Cancer Res 2004; 10: 3708–3716. 23. Lee KS, Chung HC, Im SA et al. Multicenter phase II trial of Genexol-PM, a Cremophor-free, polymeric micelle formulation of paclitaxel, in patients with metastatic breast cancer. Breast Cancer Res Treat 2008; 108: 241–250. 24. Therasse P, Arbuck SG, Eisenhauer EA et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000; 92: 205–216. 25. Willey TA, Bekos EJ, Gaver RC et al. High-performance liquid chromatographic procedure for the quantitative determination of paclitaxel (Taxol) in human plasma. J Chromatogr 1993; 621: 231–238. 26. Kim DW, Kim SY, Kim HK et al. Multicenter phase II trial of Genexol-PM, a novel Cremophor-free, polymeric micelle formulation of paclitaxel, with cisplatin in patients with advanced non-small-cell lung cancer. Ann Oncol 2007; 18: 2009–2014. 27. Saif MW, Rubin MS, Figueroa JA, Kerr RO. Multicenter phase II trial of GenexolPM (GPM), a novel Cremophor-free, polymeric micelle formulation of paclitaxel in patients with advanced pancreatic cancer (APC): final results. In ASCO 2008 Gastrointestinal Cancers Symposium, Orlando, FL, USA (Abstr 269). 28. Azria D, Magne´ N, Zouhair A et al. Radiation recall: a well recognized but neglected phenomenon. Cancer Treat Rev 2005; 31: 555–570.
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1. Crown J, O’Leary M. The taxanes: an update. Lancet 2000; 355: 1176–1178. 2. Rowinsky EK. The taxanes: dosing and scheduling considerations. Oncology 1997; 11: 07–19. 3. Jordan MA, Toso RJ, Thrower D et al. Mechanism of mitotic block and inhibition of cell proliferation by Taxol at low concentrations. Proc Natl Acad Sci U S A 1993; 90: 9552–9556. 4. Torres K, Horwitz SB. Mechanisms of Taxol-induced cell death are concentration dependent. Cancer Res 1998; 58: 3620–3626. 5. Sonnichsen DS, Hurwitz CA, Pratt CB et al. Saturable pharmacokinetics and paclitaxel pharmacodynamics in children with solid tumours. J Clin Oncol 1994; 12: 532–538. 6. Gianni L, Kearns CM, Gianni A et al. Nonlinear pharmacokinetics and metabolism of paclitaxel and its pharmacokinetic/pharmacodynamic relationships in humans. J Clin Oncol 1995; 13: 180–190. 7. Gelderblom H, Verweij J, Nooter K, Sparreboom A. Cremophor EL: the drawbacks and advantages of vehicle selection for drug formulation. Eur J Cancer 2001; 37: 1590–1598. 8. Webster L, Linsenmeyer M, Millward M et al. Measurement of cremophor EL following taxol: plasma levels sufficient to reverse drug exclusion mediated by the multidrug-resistant phenotype. J Natl Cancer Inst 1993; 85: 1685–1690. 9. Rischin D, Webster LK, Millward MJ et al. Cremophor pharmacokinetics in patients receiving 3-, 6-, and 24-hour infusions of paclitaxel. J Natl Cancer Inst 1996; 88: 1297–1301. 10. Sparreboom A, Verweij J, van der Burg ME et al. Disposition of Cremophor EL in humans limits the potential for modulation of the multidrug resistance phenotype in vivo. Clin Cancer Res 1998; 4: 1937–1942. 11. Bardelmeijer HA, Ouwehand M, Malingre MM et al. Entrapment by Cremophor EL decreases the absorption of paclitaxel from the gut. Cancer Chemother Pharmacol 2002; 49: 119–125. 12. Malingre MM, Schellens JH, Van Tellingen O et al. The co-solvent Cremophor EL limits absorption of orally administered paclitaxel in cancer patients. Br J Cancer 2001; 85: 1472–1477. 13. Gelderblom H, Mross K, ten Tije AJ et al. Comparative pharmacokinetics of unbound paclitaxel during 1- and 3-hour infusions. J Clin Oncol 2002; 20: 574–581.
Annals of Oncology
Annals of Oncology 21: 382–388, 2010 doi:10.1093/annonc/mdp315 Published online 24 July 2009
Phase I pharmacokinetic study of a weekly liposomal paclitaxel formulation (Genexolâ-PM) in patients with solid tumors W. T. Lim1, E. H. Tan1, C. K. Toh1, S. W. Hee2, S. S. Leong1, P. C. S. Ang1, N. S. Wong1 & B. Chowbay3* 1
Department of Medical Oncology; 2Biostatistic Unit, Division of Clinical Trials and Epidemiological Sciences and 3Clinical Pharmacology Laboratory, Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore
Background: The aim of this study was to determine the maximum tolerated dose (MTD) and the pharmacokinetic profile of Genexol-PM in Asian cancer patients.
original article
Materials and methods: Patients (N = 24) refractory to previous chemotherapy received Genexol-PM as an 1-h infusion on a weekly basis for 3 weeks followed by a resting week. The starting dose was 80 mg/m2 and the maximum administered dose was 200 mg/m2. Results: The majority of patients had lung, nasopharyngeal and breast cancers and in eleven patients (46%), taxanebased chemotherapy had previously failed. The MTD was defined at 180 mg/m2. The most common grade 3 nonhematologic adverse events in cycle 1 were fatigue (4%) and neuropathy (4%) occurring mainly at 200 mg/m2. Five (21%) patients had partial response, nine (38%) had stable disease and seven (29%) had disease progression. Five of 11 previously taxane-refractory patients showed clinical benefit to Genexol-PM. The pharmacokinetics of Genexol-PM displayed dose-proportionality, with both the maximum concentration (Cmax) and the area under the concentrationtime curve from zero to infinity (AUC0–N) increasing by approximately four- and threefold, respectively, as the dose of Genexol-PM was escalated from 80 to 200 mg/m2. The median total-body clearance of Genexol-PM for all patients was 43.9 l/h. Conclusion: The weekly regimen of Genexol-PM was well tolerated and responses were observed in patients with refractory tumors, including patients who had failed taxane-based chemotherapy previously. Key words: Asian, Genexol-PM, pharmacokinetics, phase 1, weekly regime
introduction Paclitaxel is a taxane derived from the Pacific yew tree (Taxus brevifolia). It has a wide spectrum of antitumor activity when used as monotherapy or in combination chemotherapy regimens [1]. The drug is used extensively in the treatment of advanced carcinomas of the breast, ovary, head and neck and lung. In preclinical studies, paclitaxel produces a number of concentrationdependent effects, including acute cytotoxicity with and without apoptosis, radiosensitization, microtubule bundle formation, increase in tubulin polymer mass and stabilization of microtubules against depolymerization [2]. As paclitaxel concentration increases, its mechanism of cytotoxic action may also vary. Paclitaxel concentrations up to 330 nmol/l was shown to enhance polymerized microtubule mass and stabilize microtubule bundle formation in association with cell growth
*Correspondence to: Assoc. Prof. B. Chowbay, Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre, 11 Hospital Drive, Singapore 169610. Tel: +65-6436-8321; Fax: +65-6372-0161; E-mail: [email protected]
arrest [3]. At these high concentrations, paclitaxel-induced cell death occurred via a Raf-1-dependent pathway [4]. In contrast, at lower concentrations (<10 nmol/l), paclitaxel was shown to induce growth inhibition independent of microtubular mass [3] and caused mitotic arrest by a Raf-1-dependent pathway [4]. Paclitaxel exhibits nonlinear pharmacokinetics with saturable metabolism and distribution to tissues [5, 6]. The nonlinear behavior of paclitaxel has been attributed to the formulating reagent, cremophor-EL (Cr-EL), that is used to enhance its drug solubility [7]. In vitro studies indicated that Cr-EL reversed P-glycoprotein-mediated multidrug resistance [8, 9]; however, the low volumes of distribution of Cr-EL in vivo indicated that concentrations of Cr-EL would be too low to have any effect in solid tumors [10], negating any additional benefit of such a vehicle. Cr-EL also decreases the oral bioavailability of paclitaxel [11, 12], thereby limiting the usefulness of this formulation for oral use. Cr-EL systemic exposure is higher when this formulation is given over 1 h as compared with longer infusions [13]. This results in higher incidences of hypersensitivity reactions seen in shorter
ª The Author 2009. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
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Received 20 February 2009; revised 4 May 2009 & 7 May 2009; accepted 8 May 2009
original article
Annals of Oncology
materials and methods patients This was an open-label phase I dose-escalation study. Patients were eligible for the trial if they satisfied the following inclusion criteria: (i) cytologically or histologically confirmed solid tumors that were advanced and incurable; (ii) age between 21 and 70 years; (iii) Eastern Cooperative Oncology Group performance status of zero to two; (iv) life expectancy of at least 3 months; (v) adequate bone marrow function with absolute neutrophil count ‡1.5 · 103/ml, hemoglobin ‡9 g/dl and platelet count ‡100 · 103/ml; (vi) adequate hepatic function with serum total bilirubin level £2.0 mg/dl (34 mmol/l) and alanine transaminase and aspartate transaminase £2· the upper limit of normal; (vii) adequate renal function with serum creatinine £141 lmol/l; (viii) no chemotherapy or radiotherapy within 4 weeks before entry into the study. Previously irradiated patients with marker lesions not within the irradiated field were eligible for the study. Patients with controlled or asymptomatic brain metastases not requiring dexamethasone were eligible. Patients who had previous paclitaxel treatment were excluded but prior docetaxel (Taxotere, Aventis Pharma, UK) treatment was allowed. Exclusion criteria included the following: (i) active or uncontrolled infection; (ii) preexisting cardiac disease, including congestive heart failure, arrhythmias requiring treatment or myocardial infarction within the preceding 3 months and (iii) pneumonitis or uncontrolled large pleural effusions, uncontrolled diabetes mellitus (random blood glucose >11.0 mmol/l) and pregnancy, lactation or refusal to use effective contraception. Written informed consent was obtained from all study participants. The study was reviewed and approved by the Health Science Authority Singapore and the National Cancer Centre Singapore Institutional Review Board.
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drug administration and dose escalation Blood counts and a metabolic panel were checked every week during the course of treatment. Safety assessments were based on physical examinations, vital signs and laboratory tests, performance status, symptoms/toxicity and adverse events. Patients were treated to a maximum of six cycles of treatment. Patients were removed from the study if toxic effects did not resolve within 14 days, withdrew informed consent or due to progressive disease (PD). Toxic effects were assessed in this study using the National Cancer Institute—Common Toxicity Criteria (NCI-CTC) version 3.0. Although response was not the primary end point of this trial, patients with measurable disease were assessed after every two cycles of Genexol-PM using standard RECIST criteria [24]. In addition to a baseline/screening scan, confirmatory scans were obtained 4 weeks following initial documentation of either an objective response or a PD. Genexol-PM was supplied by Samyang Corporation, Seoul, South Korea. Genexol-PM was infused over 1 h without premedication and administered on a weekly schedule for three consecutive weeks, followed by 1 week of rest. This 4-week treatment schedule constituted one treatment cycle. In the event of hypersensitivity reactions, standard premedications were prescribed before Genexol-PM administration. A standard ‘3 + 3’ design was used for dose escalation. The starting dose of Genexol-PM was 80 mg/m2. Subsequent dose escalations were 100, 120, 140, 160, 180 and 200 mg/m2 in cohorts of three patients per level. If at any dose level, no patient experienced DLT within 28 days after receipt of Genexol-PM, then another cohort of three patients were enrolled to the next level. Three additional patients were entered at the same dose if one of three patients experienced DLT. If DLT occured in at least one of the additional three patients entered at a particular dose level, then the dose level before the current dose level at which DLT occurred was regarded as the MTD and further dose escalation was terminated. Intrapatient dose escalation was not allowed. DLT was defined as any of the following events occurring during the first cycle (28-day period): (i) grade 4 neutropenia lasting at least 4 days or grade 4 neutropenia associated with fever, (ii) grade 3 anemia, (iii) grade 4 thrombocytopenia, (iv) grade 4 elevation of total bilirubin or (v) any other grade 3 non-hematologic toxicity according to the NCI-CTC. Complete response (CR) was defined as the clinical absence of tumour; partial response (PR) as at least a 50% decrease in the sum of the product of the perpendicular diameters of the measurable lesions, taking as reference the baseline sum product of perpendicular diameters, without progression of any lesion or appearance of any new disease; stable disease as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum perpendicular diameters since the treatment started; and PD as at least a 25% increase in the sum of the product of the perpendicular diameters of the measurable lesion, taking as reference the smallest sum product perpendicular diameters recorded since the treatment started, and/or the appearance of new lesions.
pharmacokinetics Pharmacokinetics evaluation was carried out in all patients following administration of the first dose on day 1 of the first cycle. Blood samples (3 ml) were collected for determination of Genexol-PM concentrations just before the start of infusion and 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 24 h postinfusion. All blood samples were drawn from a vein in the arm opposite to that used for Genexol-PM infusion. The blood samples were immediately centrifuged at 1500 g for 15 min and stored at 220C until analyzed. Plasma concentrations of paclitaxel were estimated by reversed-phase highperformance liquid chromatography with UV detection as previously published [25]. The lower limit of quantitation was 20 ng/ml for paclitaxel. The calibration curves were linear over a concentration range of 20–250 000 ng/ml for paclitaxel. The average recovery was >90% and the within- and between-day coefficients of variations were <9%. Pharmacokinetic
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infusions of 1 h compared with 3-h and 24-h infusions. Complement activation by Cr-EL in vitro [14, 15] possibly explains the acute life-threatening hypersensitivity reactions experienced with paclitaxel [16, 17] in patients treated with this drug. Neurotoxicity resulting from axonal demyelination and swelling is also possibly an effect of Cr-EL. Cyclosporine formulated with Cr-EL causes a similar neurotoxicity as opposed to oral formulations of cyclosporine [18], and docetaxel formulated with Tween 80 has a much lower incidence of neurotoxicity [19]. Finally, rats treated with CrEL-free paclitaxel showed no distribution of paclitaxel to the peripheral nervous system [20]. All the aforementioned limitations of formulating paclitaxel with Cr-EL prompted the development of novel formulations of paclitaxel. One of these formulations is a sterile, lyophilized polymeric micellar formulation of paclitaxel, Genexol-PM. It consists of paclitaxel solubilized in methoxy polyethylene glycol-poly (D,Llactide) [21]. It has better tissue distribution in mouse models than paclitaxel Cr-EL with good antitumor efficacy [21]. In a phase I monotherapy study of Genexol-PM on a 3-weekly schedule, dose-limiting toxic effects (DLTs) of neuropathy and neutropenia were encountered at 390 mg/m2 [22]. A subsequent phase II study of Genexol-PM 300 mg/m2 3 weekly in metastatic breast cancer patients showed good efficacy with no febrile neutropenia but a high rate of grade 3 neuropathy (51.2%) and grade 3 and 4 neutropenia (68.3%) [23]. Different doses and scheduling needed to be evaluated to determine whether toxic effects and efficacies can be improved. To this end, we carried out a phase I study to determine the DLTs and maximum tolerated dose (MTD) of a weekly schedule of Genexol-PM.
original article
Annals of Oncology
parameters were calculated by noncompartmental analysis using WinNonlin software version 2.1 (Pharsight Corp., Mountain View, CA).
statistical analysis Categorical variables were summarized as frequency and percentage, and continuous variables were summarized as mean with standard deviation or median with range. All analyses were carried out on SAS 9.1.
results patient characteristics Table 1 depicts the characteristics of the patients accrued to this study. A total of 35 patients were screened for this trial and 24 Table 1. Patient demographics and clinical characteristics
No. of patients Screened Eligible Assessable for toxicity Assessable for response Assessable for pharmacokinetics Age (years) Median (range) Sex Female Male Performance status (ECOG) 0 1 2 Primary site Breast Head and neck Lung Nasopharyngeal Others No. of previous chemotherapies (n = 23) Median (range) Prior taxane-based chemotherapy Prior radiation
N
(%)
35 24 24 22 22
100.0 68.6 68.6 62.9 62.9
56
(39–67)
8 16
33.3 66.7
5 18 1
20.8 75.0 4.2
4 3 7 9 1
16.7 12.5 29.2 37.5 4.2
2 11 16
(1–7) 45.8 66.7
ECOG, Eastern Cooperative Oncology Group.
drug administration and toxicity A total of 87 cycles of Genexol-PM were administered. The median number of cycles of Genexol-PM administered was 4. The total number of cycles completed in each dose level is summarized in Table 2. Five patients (21%) completed the prescribed six cycles of Genexol-PM: one patient each from dose levels 1, 2 and 3 and two patients from dose level 7. In the 19 patients who did not complete treatment, the reasons for withdrawal were progressive disease (n = 7; 37%), adverse events/serious adverse events (n = 5; 26%), requested withdrawal (n = 3; 16%), death (n = 2; 11%) and worsening performance status (n = 2; 11%). DLT was reached at dose level 7 (200 mg/m2) and the MTD of Genexol-PM was declared at 180 mg/m2. Table 3 summarizes the frequency of occurrence of hematologic toxic effects in the cancer patients. Grade 3 neutropenia was the most common hematologic toxicity observed in patients receiving Genexol-PM at doses of ‡120 mg/ m2 in the first cycle. A similar hematologic toxicity profile was observed at subsequent cycles when the dose of Genexol-PM was escalated beyond dose level 3 (120 mg/m2). Anemia was not more than grade 2 for all cases. Thrombocytopenia was uncommon across all dose levels (Table 3). Grade 4 non-hematologic adverse events were uncommon in cycle 1 and subsequent cycles (Table 4). The most common grade 3 non-hematologic adverse events in cycle 1 were fatigue and neuropathy and occurred mainly at dose level 7 (200 mg/m2) in 4% and 4% of the patients, respectively. A similar toxicity profile was observed in subsequent cycles but tended to appear at dose level 4 (140 mg/m2) onward (Table 4). One patient experienced grade 3 dermatitis during cycle 1 at dose level 7 (200 mg/m2) due to radiation recall caused by the administration of Genexol-PM. The investigators agreed that this was a unique case and did not strictly constitute a DLT.
Table 2. Dose levels and administration n Dose Dose level (mg/m2)
No. of No. of No. of No. of patients No. of No. of patients Total no. No. of patients No. of patients patients with cycles of with dose delay cycles of cycles who completed of cycles with dose dose delay dose omission dose omission de-escalated of dose completed reduction six cycles reduction
Total 1 2 3 4 5 6 7
5 1 1 1 0 0 0 2
80 100 120 140 160 180 200
384 | Lim et al.
24 3 3 3 3 3 3 6
87 9 10 10 14 12 9 23
7
7
5
9
1 1
1 1
1
1
3 1
5 2
4
4
1
2
13
36
2 3 1 2 5
2 7 1 7 19
7 1 1 1 4
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Variables
were eligible. The median age was 56 years (range 39–67 years) and two-thirds of the enrolled patients were male (67%). Twenty-three patients (96%) had received prior chemotherapy, including 11 patients (46%) who had previously received taxane-based chemotherapy. The median number of prior chemotherapy regimens received per patient was 2 (range 1–7). Sixteen patients (67%) had prior radiotherapy.
original article
Annals of Oncology
Table 3. Hematologic adverse events by dose level in the first cycle and subsequent cycles in parenthesis, () Dose level, mg/m2 80 (n = 3) Grade 1/2 3 4 Adverse events
100 (n = 3) 1/2 3 4
120 (n = 3) 1/2 3
Anemia 3 (2) Thrombocytopenia Neutropenia 1
3 (3) (1) 1 (1)
3 (3)
4
140 (n = 3) 1/2 3 3 (2)
160 (n = 3) 4 1/2 3
(1)
1 (1) 1 (1) 1 (1)
180 (n = 3) 1/2 3
4
3 (3)
1 (3) 1 1
200 (n = 6) 4 1/2 3
3 (3)
4
4 (5)
(1)
1 (2) 1
2 (2) 1 (2)
Table 4. Maximum grade of non-hematologic adverse event by dose level in the first cycle and subsequent cycles in parenthesis, (). Dose level, mg/m2 Grade
100 (n = 3) 1/2 3
120 (n = 3) 1/2 3
140 (n = 3) 1/2 3
160 (n = 3) 1/2 3
180 (n = 3) 1/2 3
200 (n = 6) 1/2 3
2 (2)
3 (2)
3 (1)
1
2 (3)
2
1 (2) 5 (3) 1 (1)
(1)
1 1
Adverse events Hypersensitivity Fatigue Insomnia Non-neutropenic fever Febrile neutropenia Alopecia Pruritus/itch Rash Dermatitis associated with radiation Anorexia Constipation Diarrhea Mucositis Nausea Vomiting Edema: limb AST ALT Alkaline phosphatase Neuropathy (cranial) Neuropathy (motor) Neuropathy (sensory) Myalgia Cough Dyspnea
1
(1)
1
(2)
1 (1)
(1) (1) 1 (1)
1 (1) 1 2
(1)
1 (1)
1 (1)
1 (1)
1 1 1
3 (2) 2 (2)
(1)
(1) (1) (1)
(1) 1 (1) 2 (3) (1)
1 1 1 1 1
4 (2)
2 (1) 1
(2) (1) (1) (1) (1)
1 2 (2) 2 (1) 1 (2)
1 (1) 2 (1) 1
(1) 1 (1) 1 (1) 1 (1) 1 (1)
(2) (1) (1) (1) (1)
2 (1) 1 (2) (1)
1 (1) 1 (1) 2 (2)
(1)
2 (2) (2) 1 (1) (1)
1
(1)
2 2
1 (1) (2) 3 (3) 1 (2)
(1) 1 (2)
1
AST, aspartate aminotransferase; ALT, alanine aminotransferase.
antitumor response Table 5 summarizes the overall response of the patients. Twenty-one of 24 patients were assessable for response. Fourteen patients had clinical benefit. Five patients had partial response (PR) (21%), nine (38%) had stable disease at 16 weeks and seven patients (29%) had PD. Of the five patients with PR, two patients had head and neck squamous cell carcinomas, two had lung carcinomas and one had nasopharyngeal carcinoma. Five of 11 patients who had received taxane-based treatment previously also achieved clinical benefit. pharmacokinetics Complete plasma pharmacokinetic profiles were obtained from 23 patients. Two patients had extremely high values of Cmax
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and AUC0–N. The Cmax of each patient was 75 986.7 and 231 448.8 ng/ml, respectively, which were 27- and 81-fold greater than the median Cmax of the rest of the patients, respectively. The AUC0–N of these two patients were 49 528.6 ngh/ml and 157 194.8 ngh/ml, which were 9- and 30-fold greater than the median AUC0–N of the rest of the patients, respectively. These two patients were considered outliers and excluded from further pharmacokinetic analysis. Table 6 shows a summary of the pharmacokinetic parameters by dose levels in 21 patients. Figure 1 depicts the mean plasma concentration–time profiles of Genexol-PM in patients treated at different dose levels. The maximum concentration was reached at the end of the infusion and the decline in concentration during the terminal elimination phase was similar at the various dose levels after 8 h. At 24 h,
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80 (n = 3) 1/2 3
original article
Annals of Oncology
Genexol-PM concentrations were <10% of Cmax, with a median terminal half-life (t½) of 8 h. The interpatient variability [as measured by the percent coefficient of variation (CV)] for Cmax and AUC0–N values were 54% and 45%, respectively. The pharmacokinetics of Genexol-PM displayed doseproportionality, with both Cmax and AUC0–N values increasing by approximately four- and threefold as the dose of GenexolPM was increased from 80 to 200 mg/m2 with no significant change in clearance (Figure 2A–C). The median total-body clearance of Genexol-PM for all patients was 43.9 l/h. The apparent volume of distribution (Vd) was >500 l, indicative of paclitaxel’s extensive tissue binding.
discussion
Table 5. Best overall response Clinical characteristics
Partial response
Primary sites Breast Head and neck 2 Lung 2 Nasopharyngeal 1 Others Previous taxane exposure No 3 Yes 2 Dose level (actual dose, mg/m2) 1 (80) 2 (100) 1 3 (120) 4 (140) 2 5 (160) 1 6 (180) 7 (200) 1
Stable disease
Progressive disease
Not evaluable
2
1 1 1 4
1
6 3
3 4
1 2
1 1 2
2 1 1 1 1
2 4 1
1 2 2
1
2
1 2
Table 6. Pharmacokinetic parameters of Genexol-PM at different dose levels in Asian cancer patients (N = 21) Dose level (mg/m2)
No. of patients
Median (range) Cmax (ng/ml)
AUC0–N (ngh/ml)
t½ (h)
Vd (l)
CL (l/h)
80 100 120 140 160 180 200
3 3 3 2 3 3 4
1187.5 1857.7 2584.2 2775.6 3017.6 4675.8 4704.6
2249.8 2925.3 4867.1 5062.6 5212.1 7470.2 7610.2
10.9 11.3 7.5 8.1 7.2 7.8 7.6
760.6 698.3 435.2 485.7 527.6 362.5 491.8
49.7 42.9 40.4 41.9 48.8 37.6 43.7
(976.8–1644.6) (1244.0–2691.1) (1938.2–4209.1) (2575.1–2976.2) (2716.1–7882.4) (2405.5–6167.5) (4183.2–5000.5)
(2058.8–2673.2) (2890.7–4917.7) (4747.9–6013.1) (4734.8–5390.4) (4134.6–7863.3) (5523.6–11011.8) (7003.4–11008.6)
(7.95–14.1) (6.0–18.6) (7.5–9.1) (7.8–8.3) (7.2–9.5) (6.7–8.3) (6.2–8.7)
(569.8–1434.2) (248.8–1512.6) (306.9–578.0) (445.2–526.1) (271.5–665.7) (259.5–634.9) (293.2–595.0)
(48.3–70.7) (28.6–56.4) (28.3–43.9) (37.1–46.7) (26.1–51.0) (21.6–56.1) (32.7–50.0)
t½, half-life; Vd, volume of distribution.
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Microtubule stabilizers such as paclitaxel and docetaxel, either alone or in combination, represent an important class of drugs in the treatment of various cancers. The major limitation associated with the use of paclitaxel concerns the hypersensitivity reactions commonly encountered during treatment which is mainly due to the presence of Cr-EL in the
formulation. The Cr-EL is also responsible for alterations in the pharmacokinetics of paclitaxel and limits the administration of higher doses that may be therapeutically advantageous. The shortcomings associated with the conventional formulation of paclitaxel has seen the development of several novel formulations of paclitaxel that are either free of Cr-EL such as ABI-007 (nanoparticle formulation of paclitaxel) and GenexolPM or are formulated with smaller amounts of Cr-EL to improve safety and feasibility of shorter administration schedules such as BMS-184476. The safety profile of a 3-weekly schedule of Genexol-PM in a phase I setting has been reported previously [22] and found to be tolerable with neuropathy, myalgia and neutropenia being the main DLTs. The recommended phase II dose of the 3-weekly regimen of Genexol-PM was 300 mg/m2. This 3-weekly dose of Genexol-PM has been safely combined with cisplatin 60 mg/m2 as first-line chemotherapy in non-small-cell lung cancer [26]. Patients were initially started at 230 mg/m2 of Genexol-PM and this was successfully dose escalated to 300 mg/m2 in cycle 2 in 46% of patients. There was no excess toxicity seen with this combination and the response rates were promising. Further promise was seen in a phase II study of advanced pancreatic cancer that attempted monotherapy dosing of patients at 435 mg/m2 every 3 weeks [27]. This was not well tolerated in the first 11 patients and a permanent dose reduction to 300–350 mg/m2 was required for the subsequent 45 patients. The overall clinical benefit rate was 60% and the median progression-free survival is at least comparable to historical controls of single-agent gemcitabine. The weekly regimen of Genexol-PM has not been previously reported. The present phase I and pharmacokinetic study investigating the weekly regimen of Genexol-PM demonstrated that doses exceeding 180 mg/m2 were associated with increased incidence of hematologic and non-hematologic toxic effects in patients with advanced malignancies. Therefore, the weekly regimen of Genexol-PM 180 mg/m2 is the recommended phase II dose. The severity of neutropenia varied with the dose of GenexolPM, with grade 3 neutropenia being more common between dose levels 3 and 6 (120 and 180 mg/m2) and grade 4 neutropenia occurring more frequently at dose level 7 (200 mg/m2). These variations in the hematologic pharmacodynamics of Genexol-PM mirrored similar variations in the exposure levels of Genexol-PM at the different dose levels. Both Cmax and AUC0–N fluctuated minimally between
original article
Annals of Oncology
dose levels 3 and 5 (120 and 160 mg/m2) but increased 30% at dose levels 6 and 7 (180 and 200 mg/m2). The clearance of Genexol-PM, however, remained constant throughout the different dose levels and may partly account for the noncumulative hematologic toxicity observed at the different dose levels. Significant thrombocytopenia and anemia were uncommon. The incidence of non-hematologic toxicity was mild and manageable and mostly limited to grade 1 or 2. Fatigue, myalgia and peripheral neuropathy were the most common non-hematologic toxic effects observed with a trend of increased frequency and severity observed at dose levels exceeding 160 mg/m2. Although the incidence of neutropenia was similar to that observed in the study by Kim et al. [22], the non-hematologic toxic effects were less severe in the present study utilizing the weekly regimen of Genexol-PM. This improvement in the toxicity profile may be attributed to the lower exposure levels of paclitaxel associated with the weekly regimen as compared with the 3-weekly regimen [22]. While response was not a primary end point, the response rate in this heavily pretreated population was 21% with an additional 38% of patients achieving disease stabilization of at least 12 weeks. Furthermore, discernible clinical benefit was observed in 5 of 11 patients who had prior exposure to taxanes. These findings indicate that the weekly regimen of Genexol-PM should be explored further in formal phase II studies. Sixteen patients had received previous radiation therapy either as primary treatment or as palliation. The single patient who suffered radiation recall was a patient who had recent thoracic radiation for palliation of hemoptysis. The skin erythema and desquamation corresponded exactly to the radiation port. As radiation recall is known to recur on repeat exposure, no further drug challenge was attempted. This is a rare phenomenon albeit more common with taxanes and adriamycin [28] and should not restrict the use of this drug in future studies. In conclusion, the weekly regimen of Genexol-PM was found to be safe at a MTD of 180 mg/m2 with predictable pharmacokinetic characteristics. Preliminary clinical benefits were observed in patients with head and neck, lung and nasopharyngeal cancers as well as in patients in whom prior
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Figure 1. Mean plasma concentration–time profiles of Genexol-PM in Asian cancer patients (N = 21) treated at different dose levels.
Figure 2. Box Whisker Plots of Genexol-PM. (A) Cmax, (B) AUC0–N and (C) clearance at various dose levels in Asian cancer patients.
taxane-based chemotherapy had failed. Future phase II studies should be conducted to validate these findings.
funding Singapore Cancer Syndicate Grant (SCS-PS0023).
doi:10.1093/annonc/mdp315 | 387
original article disclosures The authors declare absence of conflict of interest as well as financial interest in the conduct of this study.
references
388 | Lim et al.
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Annals of Oncology