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Clinical Trials |
1 Department of Internal Medicine, and 2 Department of Pharmacology and Clinical Pharmacology Unit, Seoul National University College of Medicine, Seoul, Korea, and 3 Samyang Research Corporation, Salt Lake City, Utah
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Experimental Design: Twenty-one patients were entered into the study. Genexol-PM was i.v. administered over 3 h every 3 weeks without premedication. The Genexol-PM dose was escalated from 135 mg/m2 to 390 mg/m2.
Results: All of the patients were evaluable for toxicity and response. Acute hypersensitivity reactions were not observed. Neuropathy and myalgia were the most common toxicities. During cycle 1, grade 3 myalgia occurred in 1 patient at 230 and 300 mg/m2, respectively. At 390 mg/m2, 2 of 3 patients developed grade 4 neutropenia or grade 3 polyneuropathy. Therefore, the maximum tolerated dosage was determined to be 390 mg/m2. There were 3 partial responses (14%) among the 21 patients. Of the 3 responders, 2 were refractory to prior taxane therapy. The paclitaxel area under the curve from time 0 to infinity and peak or maximum paclitaxel concentration seemed to increase with escalating dose, except at 230 mg/m2, which suggests that Genexol-PM has linear pharmacokinetics.
Conclusion: The main dose-limiting toxicities were neuropathy, myalgia, and neutropenia, and the recommended dosage for a phase II study is 300 mg/m2. Genexol-PM is believed to be superior to conventional paclitaxel in terms of the obviation of premedication and the delivery of higher paclitaxel doses without additional toxicity.
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Therefore, to circumvent these unfavorable effects resulting from the addition of CrEL, efforts have been made to develop new taxane formulations that do not require CrEL as a solubilizer. Several drug delivery systems using emulsion, micelles, water-soluble prodrugs, and conjugates are currently under clinical investigation (14, 15, 16, 17, 18, 19)
. For example, ABI-007, which is a CrEL-free, protein stabilized, nanoparticle paclitaxel formulation, was safely administered without HSRs up to 300 mg/m2 (20)
. A new polymer-conjugated derivative of paclitaxel, PNU166945, displayed linear pharmacokinetic behavior for the bound fraction as well as for released paclitaxel (21)
. Among the various alternatives for CrEL, the polymeric micelles have a great potential in terms of water solubility, in vivo stability, and the nanoscopic size of the micellar structure. Moreover, this novel delivery system has been shown to be effective in targeting the therapeutics to their site of action (22, 23, 24, 25)
. The polymeric micelles are composed of hundreds of amphiphilic diblock copolymers and have a diameter of 20–50 nm. Block copolymers include poly-(ethylene glycol), which is useful for nonimmunogenic carriers, and biodegradable core-forming poly-(D,L-lactic acid) required for the solubilization of the hydrophobic drug. Samyang Corporation (Seoul, Korea) has developed a novel taxane formulation, Genexol-PM, which is a polymeric micelle loaded paclitaxel without CrEL (Fig. 1)
. Genexol-PM was found to have a three-times higher maximum-tolerated dose (MTD) in nude mice, and the biodistribution of Genexol-PM showed 2–3-folds higher levels in various tissues including, liver, spleen, kidney, and lung, and more importantly in tumors. The in vivo antitumor efficacy of Genexol-PM was also significantly greater that that of Taxol (26)
. On the basis of these promising results, we performed a phase I study to determine the MTD, DLTs, and the pharmacokinetic profile of Genexol-PM in patients with advanced, refractory malignancies.
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PATIENTS AND METHODS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Study Design.
This study was an open-label phase I, dose-escalation study. Samyang Corporation supplied the Genexol-PM. One vial of Genexol-PM contains 30 mg of paclitaxel (Genexol) and 150 mg of methoxy polyethylene glycol-poly (D,L-lactide) as a solubilizer (26)
. Five-ml saline solution for injection was aseptically transferred to the vial containing Genexol-PM. Each 1 ml of diluted solution contained 6 mg of paclitaxel and 30 mg of methoxy polyethylene glycol-poly (D,L-lactide). After brief stirring, clear colorless solution was additionally diluted in 500 ml of 5% dextrose at final concentrations of 0.6–3.0 mg/ml and considered to be stable for at least 12 h at room temperature. Because there is neither the leaching of the plasticizer from polyvinyl chloride equipment nor the precipitation of paclitaxel crystal, it can be safely administered using conventional polyvinyl chloride infusion set without in-line filtration. The Genexol-PM was administered i.v. in an outpatient setting into a peripheral vein for 3 h once every 3 weeks. All of the treatments were administered without premedication.
Toxicity was graded according to the National Cancer Research Institute Common Toxicity Criteria. The DLT was defined as a National Cancer Research Institute Common Toxicity Criteria grade 3 or 4 nonhematologic toxicity (except for nausea, vomiting, and alopecia), grade 4 neutropenia, or grade 4 thrombocytopenia that occurred during the first cycle of treatment. Dose escalation followed the standard "3 + 3" rule. Cohorts of 3 patients were treated with increasing Genexol-PM doses, which were started at 135 mg/m2, which was equivalent to one tenth of the LD10 in mice (1302 mg/m2; Ref. 26 ). The dose was increased in 30% increments in a group of 3 patients, provided that none of these patients experienced DLT. If 1 of these 3 patients experienced DLT, 3 additional patients were entered at that dose level. If no DLT was observed in this second group of 3, the dose was escalated to next higher dose level. When 2 or more of the first 3 patients experienced DLT, a total of 6 patients should be treated at the one dose level below. The MTD was defined as one dose level higher at which none or 1 of 6 patients develops DLT or as current dose level at which 2 or more of 6 patients develop DLT.
An evaluation of the treatment efficacy was performed at the end of treatment, and responses were assessed using WHO response criteria. Treatment efficacy was defined as the best tumor response during treatment. Treatment was stopped either if the disease progressed, if grade 4 toxicity occurred, if the performance status of the patients was Eastern Cooperative Oncology Group 4, or if a patient refused additional treatment.
Pharmacokinetic Study.
At least 2 patients per dose level underwent blood sampling during the administration of the first Genexol-PM cycle. The drug was administered by continuous infusion over 3 h. Blood samples (5 ml) were collected in heparinized tubes before infusion and at 1.5 h into infusion, and 0, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 24, 34, and 48 h after infusion. Plasma was separated immediately by centrifugation (1500 x g, 10 min), and stored at –20°C until analysis. The paclitaxel concentrations in plasma were determined by reverse-phase high-performance liquid chromatography with a UV detector. Samples were extracted with ethyl acetate and mixed with acetonitrile as a mobile phase for high-performance liquid chromatography analysis. The pharmacokinetic parameters of the paclitaxel after Genexol-PM administration were estimated by using the noncompartmental open model and the WinNonlin program (version 3.1; Pharaight Corp., Mountain View, CA). The peak or maximum paclitaxel concentration (Cmax) and the corresponding peak time were the values observed. The elimination half-life (T1/2) was determined by ln (2)
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z derived from the linear regression analysis of the terminal phase. The area under the curve (AUC) from time 0 to infinity (AUCinf) was obtained by summing AUClast and AUCext. The dose area relationship (total dose divided by AUCinf) was used to determine total body clearance. The volume of the distribution was determined based on the terminal phase. Descriptive statistics were computed for pharmacokinetic assessment. Regression analysis of AUCinf versus dose was performed to gain an appreciation of pharmacokinetic linearity, if evident, for the dose range evaluated in this trial. Differences between the Cmax and AUCinf means, according to dose level or the presence of neuromuscular toxicity, were analyzed for significance using the ANOVA t test.
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RESULTS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. The median patient age was 52 years (range, 27–63). Fifteen patients were male and 6 female. Eight patients had lung cancer, 2 colorectal cancer, 2 renal cell cancer, and 9 cancers, including ovarian and breast cancer. All of the patients received prior chemotherapy, and 12 received 3 or more types of chemotherapeutic regimens. Nine patients had received prior taxane therapy, and 6 of these showed tumor progression within 6 months of the last taxane. A total of 81 cycles of Genexol-PM was administered with a median of 3.9 cycles per patient (range, 1–5).
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. All of the treatments were administered without premedicating hydrocortisone and histamine blocker. No hypersensitivity reaction was observed in any patient. Because grade 3 or greater toxicity did not developed at dose level 1 (135 mg/m2) or 2 (175 mg/m2), the escalation proceeded to dose level 3. At dose level 3 (230 mg/m2), 1 of the first 3 patients developed grade 3 myalgia. Three more patients were accrued at this dose level with no additional instances of grade 3 or 4 toxicity. At dose level 4 (300 mg/m2), 1 of the first 3 patients also experienced grade 3 myalgia. An additional 3 patients were accrued at level 4, and no DLT was observed in these patients. At dose level 5 (390 mg/m2), 2 of the first 3 patients developed grade 3 sensory and motor neuropathy, and grade 4 neutropenia, respectively. Because 2 of the first 3 patients experienced DLTs at dose level 5, and 1 of 6 patients developed DLT at dose level 4, dose level 5 was defined as the MTD. Thus, the MTD of Genexol-PM administered as a 3-h infusion every 3 weeks was 390 mg/m2. The DLTs were myalgia, sensory and motor neuropathy, and neutropenia.
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summarizes the drug-related hematological toxicities observed during the study. Grade 3 neutropenia occurred in 1 patient at dose levels 3 and 4, respectively. Grade 4 neutropenia was observed at dose level 5 in a patient who had refractory small cell lung cancer and had been previously heavily pretreated with etoposide, cisplatin, topotecan, gemcitabine, and carboplatin. However, no patient with grade 3 or 4 neutropenia experienced any related complications such as fever. Because the neutrophil count recovered by day 21, treatment delay or growth factor support due to neutropenia was never required.
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and 5
summarize the drug-related nonhematological toxicities observed during the treatments. The most common nonhematological effects of Genexol-PM were neuromuscular toxicities. Almost all of the patients developed sensory neurotoxicity, characterized by stocking/glove distribution, numbness, and pain at the extremities. Every patient had a past history of cisplatin administration and complained of mild paresthesia after the first cycle of Genexol-PM. At dose level 5, 1 patient who had non-small cell lung cancer complained of severe sensory polyneuropathy after the second cycle of chemotherapy. The patient also developed motor weakness of the lower extremities. Nerve conduction studies and electromusculography were shown to be consistent with polyneuropathy. Because of grade 4 toxicity, the patient was taken off treatment, and thereafter, his neurological symptoms improved. All of the patients at dose levels 3 and 4 developed grade 3 myalgia. Muscle ache developed during the first week after the treatment. Because of pain, the patients required analgesics, and their daily activities were disrupted. The onset of myalgia, which typically involved both upper and lower extremities, occurred 3–5 days after infusion, but symptomatic improvement was always observed between days 8 and 21 in most patients. The myalgia was controlled by nonsteroidal anti-inflammatory drugs from the second cycle. Other minor toxicities included alopecia, skin changes, and nausea. Alopecia was universal. Skin toxicity including pruritus and urticaria was also mild. Gastrointestinal complication such as nausea, anorexia, and diarrhea were also mild and transient.
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Pharmacokinetics.
Pharmacokinetic evaluations were performed in 13 patients over the 135–390 mg/m2 dose range. The profiles of 2 patients were not included in the analysis because the data showed unexpectedly low paclitaxel concentrations. Fig. 2
shows the concentration versus time curves of paclitaxel at each Genexol-PM dose level. Plasma concentrations peaked between 1.5 and 3.32 h of the infusion, and the decline from Cmax was biphasic. The pharmacokinetic parameters of the total paclitaxel after Genexol-PM administration are summarized in Table 6
. Both the AUCinf and Cmax for total paclitaxel increased proportionally with increasing dose, except at dose level 3 (Fig. 3)
. The pharmacokinetics of Genexol-PM administered for 3 h appeared to be nonlinear across the whole dose range. Calculations from the data in Fig. 3
revealed a 5-fold increase in the AUCinf and a 4-fold increase in Cmax over a 3-fold increase in dose from 135 mg/m2 to 390 mg/m2. The coefficients of AUCinf and Cmax variation were <0%, except at 230 mg/m2. However, excluding 230 mg/m2, the pharmacokinetics of Genexol-PM appeared to be linear (Fig. 4)
. The AUCinf and Cmax of Genexol-PM revealed lower values than equivalent doses of Taxol (data not shown). The terminal plasma T1/2 of total paclitaxel after Genexol-PM administration (135–300 mg/m2) ranged from 11.0 to 12.7-h and did not show any significant dose-dependent changes except in the 390 mg/m2 group. The T1/2 of Genexol-PM is relatively short, compared with the 20.1 h of Taxol (Table 6
; Ref. 27
). It has been reported that CrEL inhibits the metabolism of paclitaxel in the rat. Thus, the metabolism of CrEL-free Genexol-PM may be augmented compared with Taxol, and this would result in lower values of AUCinf and T1/2. Fig. 5
is a plot that depicts the relationship between AUCinf and Cmax versus the neuromuscular toxicities for each group of patients who experienced grade 3–4 toxicity and who did not. The development of grade 3–4 neuropathy or myalgia seemed to be correlated with pharmacokinetic parameters but did not show statistically significant different AUCinf (P = 0.2281) and Cmax (P = 0.3363) values between two groups of patients.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Over the past few years, significant progress has been made in the development of alternative formulation of paclitaxel. The approaches used thus far include cosolvents, cyclodextrins, liposomes, and various conjugates such as polymer, docosahexanoic acid, polyglutamate, and albumin. Among these, the development of cosolvents or cyclodextrin-based formulations of paclitaxel has been hampered by paclitaxel precipitation and/or vehicle-related toxicities (14 , 19) . Similarly, a clinical development of PNU166945, a polymer-conjugated prodrug of paclitaxel, was prematurely discontinued due to its severe neurotoxicity (21) . On the contrary, liposomes and some conjugate systems have shown encouraging preclinical and clinical results to replace the CrEL-based vehicle for paclitaxel delivery. Liposomal paclitaxel (34, 35, 36) , docosahexanoic acid-paclitaxel (37 , 38) and polyglutamate-paclitaxel conjugates (CT-2103; Refs. 39 , 40 ) have common features of favorable toxicity profiles and targeted drug delivery to tumor sites. ABI-007, a human albumin-conjugated paclitaxel, was also well tolerated and showed some tumor responses in patients who had prior paclitaxel therapy (20) . Compared with conventional paclitaxel, ABI-007 has been reported to be more effective in terms of antitumor activity in metastatic breast cancer (41) . In addition to aforementioned formulations, the polymeric micelles delivery system has also been considered to be an attractive formulation because of its nanoscopic size and preferential tumor distribution (22, 23, 24, 25) . Compared with the current paclitaxel, preclinical studies demonstrated that the polymeric micelle-formulated paclitaxel displayed a 3-fold increase in the MTD and a significantly increased antitumor efficacy (26) . In the present phase I study, a novel taxane formulation without CrEL, Genexol-PM, was found to be nontoxic at dosages up to 300 mg/m2. However, at the MTD of 390 mg/m2, a variety of DLTs were observed, which included neuropathy, myalgia, and neutropenia. Because Genexol-PM is not formulated with CrEL, it is anticipated that both prophylaxis for HSR and in-line filtration would not be required. In the present study, the drug was safely administered in the outpatient setting over 3 h without prophylactic medication and without in-line filtration, as was expected. There was no HSR in any patient, although 1 patient at the dose level 2 experienced facial flushing shortly after starting infusion. Therefore, Genexol-PM appears to offer practical advantages in terms of safety and convenience due to no premedication and the avoidance of a specialized infusion device.
Regarding toxicities, the main side-effects of Genexol-PM were neutropenia and neuromuscular toxicity, in common with paclitaxel (1 , 2) . However, a lower incidence of myelosuppression was observed than that anticipated for an equivalent dose of paclitaxel. Grades 3–4 neutropenia were observed between dose levels 3 and 5 (230 and 390 mg/m2), but these were of short duration and normalized before the next cycle. In the case of Taxol, neutropenia is more common for 24-h infusion than for 3-h infusion, because CrEL clearance is increased according to time, and, thus CrEL decreases the plasma paclitaxel concentration for the 3-h infusion, showing that paclitaxel-induced neutropenia is dependent on the presence of CrEL as well as the paclitaxel dosage (1 , 2) . Thus, the lower myelosuppressive effect of Genexol-PM can be explained in part by the absence of CrEL. On the other hand, the neuromuscular toxicity of Genexol-PM seemed to be similar to CrEL-formulated paclitaxel. In particular, significant neurotoxicities were observed between 230 and 390 mg/m2, and higher AUC and Cmax in those groups showed a tendency to be associated with the development of severe neurotoxicity, indicating that Genexol-PM-induced neuropathy is more likely to be caused by the paclitaxel itself (13 , 30) . Similar to our findings, less myelosuppression and similar neuromuscular toxicity were observed in CrEL-free ABI-007 (20) . However, a case of superficial keratopathy, which is a unique toxicity of ABI-007, was not observed for Genexol-PM.
In general, CrEL-free taxane formulations permit the administration of higher paclitaxel doses than conventional paclitaxel (20 , 21 , 42) . The MTD of Genexol-PM was determined to be 390 mg/m2 in the present study, and that of ABI-007 is 300 mg/m2 (20) . The achievement of a higher dose in the case of CrEL-free paclitaxel may be explained by the absence of the CrEL-mediated modulation of the pharmacokinetics of paclitaxel. The pharmacokinetics of Genexol-PM displays a tendency to be linear, except at a dose of 230 mg/m2. It has been suggested that polymeric micelle nanoparticle drug carriers preferentially target tumor tissues, resulting in prolonged tumor exposure (24 , 25 , 43) As compared with conventional paclitaxel, Genexol-PM shows lower AUC and a shorter plasma half-life, suggesting the enhanced partitioning of Genexol-PM into the tissues and possibly more into the tumor beds. This observation is supported by the finding that the highest paclitaxel concentration was found in the tumor in a preclinical study of Genexol-PM (26) . Accordingly, CrEL-free paclitaxel is expected to have significant advantages over conventional paclitaxel in terms of permitting the delivery of much higher doses and of having an enhanced tumor distribution. In the present study, the response rate of Genexol-PM was 14% (3 of 21), and disease stabilization was observed in 42% of patients refractory to conventional chemotherapy. Of 3 responders, 1 patient received regular dose of Genexol-PM (175 mg/m2), whereas the remaining 2 received higher doses (230 and 300 mg/m2). Note that 2 patients treated at 175 or 230 mg/m2 were taxane-failure. Therefore, it is conceivable that Genexol-PM is able to overcome taxane resistance either by the delivery of higher doses of paclitaxel or by an enhanced targeting to tumor tissues.
In conclusion, a novel taxane formulation, Genexol-PM, which is a CrEL-free paclitaxel formulated with a polymeric micelle, was safely administered without HSRs and showed a favorable toxicity profile. The major DLTs were neuromuscular toxicity and myelosuppression, and the recommended phase II dosage for Genexol-PM was determined to be 300 mg/m2 for 3 h once every 3 weeks. Genexol-PM displayed the pharmacokinetics characteristic of CrEL-free paclitaxel. Of note, Genexol-PM permits the delivery of a higher paclitaxel dose. The achievement of higher paclitaxel dose without additional toxicity may suggest that this CrEL-free novel taxane formulation is likely to replace the current paclitaxel formulation. Phase II studies with Genexol-PM are currently underway for patients with advanced breast and non-small cell lung cancers.
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FOOTNOTES |
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Note: This paper was first presented in part at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31, 2003.
Requests for reprints: Tae-You Kim, Department of Internal Medicine, Seoul National University College of Medicine, 28, Yongon-dong, Chongno-gu, Seoul, 110-744, Korea. Phone: 82-2-760-2390; Fax: 82-2-762-9662; E-mail: bangyj{at}plaza.snu.ac.kr
Received 11/28/03; revised 2/17/04; accepted 2/25/04.
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REFERENCES |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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