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Clinical Cancer Research Vol. 11, 3806-3813, May 15, 2005
© 2005 American Association for Cancer Research

Cancer Therapy: Clinical

Phase I and Pharmacokinetic Study of the Dolastatin 10 Analogue TZT-1027, Given on Days 1 and 8 of a 3-Week Cycle in Patients with Advanced Solid Tumors

Maja J.A. de Jonge1, Ate van der Gaast1, André S.T. Planting1, Leny van Doorn1, Aletta Lems1, Inge Boot1, Jantien Wanders2, Masahiko Satomi3 and Jaap Verweij1

Authors' Affiliations: 1 Erasmus University Medical Center/Daniel den Hoed Cancer Center, Rotterdam, the Netherlands; 2 Daiichi Pharmaceuticals UK, Ltd., London, United Kingdom; and 3 Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan

Requests for reprints: Maja J.A. de Jonge, Department of Medical Oncology,Erasmus University Medical Center/Daniel den Hoed Cancer Center, Groene Hilledijk 301, 3075 EA Rotterdam, the Netherlands. Phone: 31-10-4391760; Fax: 31-10-4391003; E-mail: m.dejonge{at}erasmusc.nl.


   Abstract
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 Abstract
Materials and Methods
 Results
 Discussion
 References
 
Purpose: TZT-1027 {N2-(N,N-dimethyl-L-valyl)-N-[(1S,2R)-2-methoxy-4-[(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-oxo-3-[(2-phenylethyl)]amino]propyl]-1-pyrrolidinyl]-1-[(S)-1-methylpropyl]-4-oxobutyl]-N-methyl-L-valinamide} is a cytotoxic dolastatin 10 derivative inhibiting microtubule assembly through the binding to tubulins. The objectives of this phase I study was to assess the dose-limiting toxicities (DLT), to determine the maximum tolerated dose, and to study the pharmacokinetics of TZT-1027 when given i.v. over 60 minutes on days 1 and 8 every 3 weeks to patients with advanced solid tumors.

Experimental Design: Patients were treated with escalating doses of TZT-1027 at doses ranging from 1.35 to 2.7 mg/m2. For pharmacokinetic analysis, plasma sampling was done during the first and second course and assayed using a validated high-performance liquid chromatographic assay with mass spectrometric detection.

Results: Seventeen patients received a total of >70 courses. The stopping dose was reached at 2.7 mg/m2, with neutropenia and infusion arm pain as DLT. Neutropenia was not complicated by fever. Over all dose levels, eight patients experienced pain in the infusion arm 1 to 2 days after administration of the drug, which seemed ameliorated by adding additional flushing after drug administration. Other side effects included nausea, vomiting, diarrhea, and fatigue. One partial response lasting >54 weeks was observed in an extensively pretreated patient with metastatic liposarcoma. The pharmacokinetics of TZT-1027 suggested linearity over the dose ranges. No correlation between body surface area and absolute CL of TZT-1027 was established, vindicating that a flat dosing regimen might be used in the future. A correlation was observed between the percentage decrease in neutrophil count and the AUC of TZT-1027.

Conclusions: In this study, the DLT of TZT-1027 was neutropenia and infusion arm pain. The recommended dose for phase II studies of TZT-1027 is 2.4 mg/m2 given i.v. over 60 minutes, on days 1 and 8 every 21 days. Phase II studies have recently started.

Key Words: TZT-1027 • Dolastatin 10 analog • Phase I • Solid tumors

Dolastatins were isolated in 1987 from Dolabella auricularia, a mollusk from the West Indian Ocean, in the course of identifying novel anticancer agents in marine organisms (1–3). TZT-1027 {N2-(N,N-dimethyl-L-valyl)-N-[(1S,2R)-2-methoxy-4-[(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-oxo-3-[(2-phenylethyl)]amino]propyl]-1-pyrrolidinyl]-1-[(S)-1-methylpropyl]-4-oxobutyl]-N-methyl-L-valinamide; Fig. 1} is a cytotoxic dolastatin 10 derivative inhibiting microtubule assembly through the binding to tubulins (4, 5). TZT-1027 interacts with tubulin in the same domain as the Vinca alkaloid–binding region. Although TZT-1027 and vinblastine affect each other in the binding to tubulins, it is considered that their binding sites are not completely identical. Like dolastatin 10, TZT-1027 also seems to have a unique antitumoral vascular activity resulting in the collapse of the tumor vasculature after exposure to the drug that might potentate the direct antitumor effect due to the antimicrotubule activity of the drug (6–8).



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  		Fig. 1. Chemical structure of TZT-1027.

 
In vitro, TZT-1027 exerted a time-dependent antitumor activity against a variety of murine and human tumor cell lines including rapidly proliferating murine leukemias and human colon, breast, stomach, and prostatic carcinoma cell lines (9). In vivo, TZT-1027 was highly active (>75% tumor growth inhibition) against human stomach, colon, breast, and lung cancer xenografts (10, 11). This spectrum of antitumor activity differs from the antitumor activity of vincristine. TZT-1027 was also active against vincristine-resistant, cisplatin-resistant, and 5-fluorouracil–resistant murine P388 leukemia.

In animals, TZT-1027 predominantly induced bone marrow and gastrointestinal toxicity. In addition, when doses were increased, myocardial degeneration and focal necrosis of the myocardium were observed in rats and monkeys. In addition, transient elevation of liver transaminases and creatine phosphokinase occurred. No peripheral neurotoxicity was observed in mice, rats, or rabbits (12). The LD10 of a single administration of TZT-1027 to mice was 3.4 mg/kg (equivalent to 10 mg/m2).

The pharmacokinetics of TZT-1027 have been studied in several animal species (data on file Investigator's brochure TZT-1027, 21 February 2003, European Edition No. 2). After single i.v. administration, the unchanged drug was the major component in plasma. Plasma half-life varied from 5 to 8 hours. Repeated daily, i.v. doses did not result in accumulation of TZT-1027 in plasma. In plasma, TZT-1027 was bound to protein, predominantly {alpha}1-acid glycoprotein, between 50% and 85%.

The major route of metabolism constituted conversion by CYP3A4. In all species, the main route of elimination of TZT-1027 was fecal. Biliary recirculation of TZT-1027 was not apparent.

In humans, two previous phase I studies have been done in Japan and one phase I study in Hungary. In Japan, a single administration phase I study was conducted with doses up to 1.35 mg/m2 (13). The predominant toxicity was neutropenia. Before determination of dose-limiting toxicity (DLT) and maximum tolerated dose, the schedule was amended to administration of TZT-1027 on days 1, 8, and 15 for only one cycle. DLT was reached at the 2.1 mg/m2 dose level and constituted of neutropenia. The recommended dose for phase II studies with the latter schedule is 1.8 mg/m2 (14). In the recent phase I study, TZT-1027 was given in patients with non–small cell lung cancer on day 1 of a 3- to 4-weekly cycle (15). Doses up to 5.6 mg/m2 have been studied. The observed toxicities were neutropenia, nausea, vomiting, constipation, alopecia, and pain at the injection site. In all these studies, pharmacokinetics of TZT-1027 suggested linearity over the dose levels studied. Plasma protein binding is ~95% with {alpha}1-acid glycoprotein being the major plasma protein that binds with TZT-1027. In all studies, several patients showed tumor reduction and disease stabilization.

The purposes of the present phase I study were to determine the maximum tolerated dose of TZT-1027 given i.v. on days 1 and 8 every 21 days, to establish the dose limiting and other toxic effects, to describe the pharmacokinetics of TZT-1027 with respect to interpatient and intrapatient variation, to document any antitumor effects, and to establish a dose suitable for further phase II evaluation of the compound.


   Materials and Methods
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 Materials and Methods
Results
 Discussion
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Patient selection. Patients with a cytologically or histologically confirmed diagnosis of a malignant solid tumor refractory to standard forms of therapy were eligible for this study provided that they met the following criteria: age, ≥18 years; Eastern Cooperative Oncology Group performance status, ≤2; estimated life expectancy, ≥2 months; no previous anticancer therapy for at least 4 weeks (6 weeks for nitrosoureas, carboplatin, or mitomycin C); no previous wide field radiotherapy to >25% of the bone marrow within the previous 4 weeks or radiotherapy to limited portals within the previous 2 weeks; and adequate hematopoietic (hemoglobin ≥ 5.2 mmol/L, absolute peripheral granulocyte count ≥ 1.5 x 109/L, and platelet count ≥ 100 x 109/L), hepatic (bilirubin ≤ 25.6 µmol/L and serum aspartate aminotransferase and alanine aminotransferase ≤2.5 times the upper normal limit), and renal (serum creatinine concentration ≤ 176.8 µmol/L) functions. The left ventricular ejection fraction (LVEF), measured by MUGA scan, had to be within the limits of normal. Patients with symptomatic brain or leptomeningeal metastases, or known extensive bone marrow involvement were excluded. All patients gave written informed consent before study entry. The study was approved by the Institutional Medical Ethics Committee.

Treatment and dose escalation. TZT-1027 was supplied by Daiichi Pharmaceutical Co., Ltd. (Tokyo, Japan) as an aqueous solution for injection in glass vials, containing 0.2 mg/mL of active drug and sodium chloride and lactic acid as excipients. The vials were stored at room temperature (15-25°C) and were protected from light. The content of the vial was added to a polyvinylchloride bag with saline to a total volume of 250 mL. The solution was kept at room temperature protected from light until administration. TZT-1027 was given i.v. over 60 minutes within 24 hours from drug preparation. With the exception of the first and second course, during which patients were hospitalized for pharmacokinetic sampling, patients were treated on an outpatient basis.

The starting dose of TZT-1027 was 1.35 mg/m2 based on the data of previous and ongoing phase I studies and was given on days 1 and 8 of a 3-week cycle. Dose escalations were based on the prior dose level toxicity allowing a dose escalation of 12.5% to 33% (which was determined by the worst significant toxicity). At least three patients were entered at each dose level. The stopping dose was defined as the dose level that induced DLT during course 1 in ≥2 of 3 or ≥2 of 6 patients. DLTs were defined as grade 4 granulocytopenia for >5 days, grade 4 neutropenia complicated by fever at ≥38.5°C, platelets < 25.0 x 109/L, and/or nonhematologic toxicity ≥ grade 3. Nausea and vomiting subsequently responding to antiemetic therapy was not considered as a DLT. Inability to administer the second drug administration on day 8 of the first course or to start a second course after a 1-week delay because ongoing toxicity was also considered as a DLT. The treatment was resumed when the ANC count had recovered to ≥1.5 x 109/L and the platelet count to ≥100 x 109/L and nonhematologic toxicity had recovered to baseline value. In case the toxicity had not recovered within 2 weeks of the planned retreatment time, the patient went off study.

Toxicities were evaluated according to the National Cancer Institute Common Toxicity Criteria, version 2.0.

Treatment assessment. Before treatment, a complete medical history was recorded and a physical examination done. A CBC, including WBC differential, and serum biochemistry, which involved sodium, potassium, calcium, urea, creatinine, total protein, albumin, total bilirubin, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, glucose, creatinine phosphokinase, and {alpha}1-acid glycoprotein, were done, as were urinalysis, pregnancy test, relevant tumor markers, electrocardiogram, LVEF, and a chest X-ray. Weekly evaluations included history, physical examination, toxicity assessment according to the CTC criteria version 2.0, and serum chemistries. CBC was determined twice weekly. During the first two cycles, a 12-lead ECG was done before drug administration, at the end of drug administration, and after 24 hours. From the third cycle onwards, a 12-lead ECG was only done before drug administration. Evaluation of the LVEF with MUGA scan was done every two courses. Tumor evaluation was done after every two courses according to the Response Evaluation Criteria in Solid Tumors (16). Patients were taken off protocol at the onset of disease progression or when unacceptable toxicity occurred.

Sample collection and drug analysis. For pharmacokinetic analysis, 20 blood samples (~5 mL each) were obtained from an indwelling i.v. cannula from a vein in the arm opposite to that used for drug infusion and collected in vials containing lithium heparin as anticoagulant. The samples were taken immediately before dosing, 30 minutes after start of the infusion, at the end of the infusion, and at 30 minutes, and 1, 2, 4, 6, 8, and 24 hours after administration of the drug on day 1 of the first and second course.

All samples were centrifuged immediately after sampling at 1,200 x g for 15 minutes at 4°C and the plasma was stored at –80°C in polypropylene tubes in the dark until analysis. A total of three urine samples were also collected over a 24-hour period: preinfusion, 0-6 hours, and 6-24 hours. Of the total amount collected, a measured quantity of 10 mL was drawn off and stored at –80°C until analysis. Concentrations of TZT-1027 in plasma were determined according to a validated liquid chromatography/mass spectrometry (17–19). The lower limit of quantitation was 0.25 ng/mL.

Pharmacokinetic and pharmacodynamic data analysis. The terminal elimination half-life (T1/2) of TZT-1027 was calculated as ln2 / k, where k is the terminal elimination rate constant (expressed in h–1). The peak plasma concentrations (Cmax) and the time to peak plasma concentration (Tmax) were determined graphically from the experimental values. The area under the plasma concentration-time curve (AUC) of TZT-1027 were estimated using the experimental values (linear trapezoidal method) with extrapolation to infinity (AUC0-{infty}) using the terminal elimination rate constant, defined as the slope of final three to four data points of the log-linear concentration-time plot. The total body clearance (CL) was calculated as the ratio between the given dose and the AUC0-{infty}. Pharmacokinetics data analysis was carried out using a noncompartmental analysis approach with the aid of a validated software (PhAST2.3).

Pharmacokinetic/pharmacodynamic relationships between TZT-1027 kinetic variables and hematologic toxicity associated with drug administration were explored using a nonlinear regression model. Because in previous studies a correlation existed between plasma {alpha}1-acid glycoprotein and the unbound fraction of TZT-1027, relationship between plasma {alpha}1-acid glycoprotein and hematologic toxicity was also studied. Within individual patients, myelosuppression was described as the continuous variable, consisting of percentage decrease in WBC, ANC, and platelet count. The relative hematologic toxicity was defined as % decrease = (pretreatment value – nadir value) / (pretreatment value) x 100. Data from each patient derived during course 1 were taken into consideration. The relationship between the hematologic toxicity and the pharmacokinetic variables AUCinf, Cmax, and {alpha}1-acid glycoprotein were evaluated by linear regression, maximum effect (Emax), and sigmoidal maximum effect (Emax) model fitting. The "goodness of fitting" was based on the minimization of the values of the AKAIKE information criterion test and on the reduction of the estimated coefficient of variation for fitted variables. The model that best fitted the data was found to be the sigmoidal Emax model which is based on the modified Hill equation, as follows: E = Emax x [(PK{gamma}) / (PK{gamma} + PK50{gamma})]. In this equation, Emax is the maximum response, PK is the pharmacokinetic variable of interest, PK50 the value of the pharmacokinetic variable predicted to result in half of the maximum response, and {gamma} is the Hill constant describing the sigmoidicity of the curve.

Descriptive statistics. All pharmacokinetic data are presented as mean values and coefficient variations (%).


   Results
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 Materials and Methods
 Results
Discussion
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Between December 2001 and November 2002, 17 patients, whose main characteristics are listed in Table 1, were enrolled in the study. All patients were eligible. One patient, treated at the 2.4 mg/m2 dose level, was taken off study before the day 8 administration of TZT-1027 due to deterioration of his condition not considered related to the administration of TZT-1027. This patient was considered not evaluable for toxicity and was replaced. The majority of the patients were either asymptomatic or had only mild symptoms at study entry. Most patients were pretreated with two prior chemotherapy regimens (range, 1-4). The total number of assessable courses was >70. The median number of courses per patient was 2 (range, 1 to >16). Dose levels studied were 1.35, 1.8, 2.4, and 2.7 mg/m2 given i.v. on days 1 and 8 over 1 hour, with courses repeated once every 21 days. Drug-related toxicity did not necessitate dose reductions or treatment cessation. In the absence of DLT, the dose of TZT-1027 was escalated in four steps from 1.35 to 2.7 mg/m2. At the 2.7 mg/m2 dose level, DLT was encountered in three of four patients consisting of neutropenia grade 4 lasting >5 days (two patients) and neutropenia grade 2 on day 8 preventing the administration of TZT-1027 on day 8 of the first course (one patient). In none of the patients, neutropenia was complicated by fever or infection. At this point, the previous dose level 2.4 mg/m2 was expanded to six patients. One of the additional patients experienced DLT consisting of grade 3 drug-related pain in the infusion arm without evidence of extravasation of the drug.


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  		Table 1. Patient characteristics

 
Based on these results, the recommended dose of TZT-1027 for further studies is 2.4 mg/m2 given on days 1 and 8 every 3 weeks.

Tolerability. Neutropenia was the principal DLT observed at the 2.7 mg/m2 dose level. Overall, the hematologic toxicity was mild (Tables 2 and 3). The median time to neutrophil nadir was 15 days (range, 8-21 days), followed by a spontaneous recovery to neutrophil values of ≥1.5 x 109/L allowing patients retreatment on time. Even if grade 3 or 4 neutropenia was encountered, it was not complicated by fever. In the three patients, who received six or more cycles, there was no evidence of a cumulative effect of TZT-1027 on the hematologic toxicity. In one patient, grade 1 thrombocytopenia was observed. In nine patients, grade 1 anemia was encountered; in three patients, grade 2 anemia was observed. Anemia did not seem dose related.


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  		Table 2. Toxicity in the first cycle according to NCI-CTC, version 2.0

 

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  		Table 3. Worst toxicity per patient for all cycles according to NCI-CTC, version 2.0

 
Pain in the infusion arm was the one DLT observed at 2.4 mg/m2. Other nonhematologic toxicity was mild and mostly limited to grade 1 to 2. The most common nonhematologic effects of TZT-1027 were fatigue, nausea, vomiting, and diarrhea (Tables 2 and 3). Patients treated did not routinely receive antiemetic premedication with their first dose. When they experienced nausea or vomiting, they tended to respond to metoclopramide. For subsequent cycles, the prophylactic use of antiemetics was introduced. Diarrhea was self-limiting in most patients; however, three patients needed treatment with loperamide. The median day of onset was day 5 (range, 1-18 days) with a median duration of 1 day (range, 1-6 days). Neurologic toxicity was observed in five patients and was limited to grade 1 peripheral sensory polyneuropathy in all but one patient. Four of these patients had preexisting neurotoxicity as a consequence of prior treatment with platinum containing chemotherapy regimens. Only in one patient treated at the highest dose level did this preexisting peripheral sensory polyneuropathy aggravate to grade 2 in the fourth treatment cycle. In all other patients, neurologic symptoms remained stable compared with baseline. One patient also treated at the highest dose level, who was previously treated with oxaliplatin, experienced perioral paresthesias grade 1 during her first and second cycle, which recovered within 3 to 6 days. Over all dose levels, 10 patients experienced pain in the infusion arm usually 1 to 2 days after the administration of the drug. The pain was diffuse; in some patients, in combination with a localized pain over the vein in which the drug was given. Only in one patient was this associated with a phlebitis. In one patient treated at the 2.4 mg/m2 dose level, this grade 3 event was even considered to be dose limiting. Several patients received subsequent courses with additional flushing consisting of 500 mL normal saline over 1 hour following the administration of TZT-1027, which seemed to ameliorate the severity of this side effect. Alopecia was observed in nine patients (5 grade 1 patients and 4 grade 2 patients).

In one patient, the administration of TZT-1027 was complicated by an extravasation of several milliliters of the drug. Local ice therapy was applied intermittently for 24 hours. The local reaction was limited to discoloration of the skin and did not result in ulceration nor desquamation.

The cardiac function was assessed in all patients before the start of treatment. In 65% of the patients, the LVEF was evaluated during treatment, mainly at the end of the second cycle. No decline in LVEF ≥20% or below the lower normal limit was noted. In addition, there were no clinical signs of impaired cardiac function in any of the treated patients. Neither any changes in cardiac conduction velocities were observed.

Antitumor activity. One partial response was observed in an extensively pretreated patient with a metastatic liposarcoma, which lasted >54 weeks. Eight patients experienced stabilization of their disease (leiomyosarcoma, ACUP, non–small cell lung cancer, colon, urothelial, esophageal, pancreatic, and head and neck cancer; one patient each) for a median duration of 13 weeks (range, 6-27 weeks).

Pharmacokinetics and pharmacodynamics. Complete plasma sampling was done in 17 (17 in course 1 and 15 in course 2) patients for pharmacokinetic analysis of TZT-1027. After i.v. administration, the plasma concentration-time profiles of TZT-1027 were similar for all patients studied and showed a polyexponential decline. A mean plasma concentration time profile for patients treated at 2.4 mg/m2 is shown in Fig. 2.



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  		Fig. 2. Mean plasma TZT-1027 concentrations, course 1(n = 7) and course 2 (n = 6). Dose: 2.4 mg/m2 (semi log plot).

 
The total plasma clearance, estimated terminal elimination half-life, mean residence time, and volume of distribution (Vss) of TZT-1027 were not significantly different (P = 0.44, 0.72, 0.17, and 0.065 for CL, T1/2, mean residence time, and Vss, respectively) between courses 1 and 2 at various dose levels suggesting a time-independent pharmacokinetic behavior. The mean pharmacokinetic variables determined using a noncompartmental analysis are listed in Table 4. Maximum plasma levels of TZT-1027 were reached ~1 hour after the start of the administration of TZT-1027 (usually observed at the end of the TZT-1027 infusion). Only 1% to 8% of the given dose of TZT-1027 was excreted unchanged in urine mainly in the first 6 hours after drug administration. No correlation between total body clearance of TZT-1027 and body surface area was observed (Fig. 3).


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  		Table 4. Summary of the pharmacokinetics of TZT-1027 during the first treatment cycle

 


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  		Fig. 3. Correlation between total body clearance of TZT-1027 and body surface area.

 
Sigmoidal maximum effect modeling of pharmacokinetic and hematologic toxicity data (maximum percentage decrements in neutrophils during the first treatment course versus pretreatment value) revealed that both the AUC and Cmax (Fig. 4) of TZT-1027 correlated with the percentage decrease in neutrophil count. No observed correlation between {alpha}1-acid glycoprotein and hematologic toxicity could be discerned. However, clearance of TZT-1027 was significantly related to lower levels of {alpha}1-acid glycoprotein in plasma (R2 = 0.628).



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  		Fig. 4. Scatter plots of the individual relationships between percentage decrements in neutrophils during course 1 and AUC of TZT-1027. Solid lines, fits of sigmoidal Emax models to the data.

 

   Discussion
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 Materials and Methods
 Results
 Discussion
References
 
Over the past decade, several new experimental anticancer agents derived from marine sources have entered preclinical and clinical trials. This field has expanded significantly as a result of improvements in the technology of deep-sea collection, extraction, and large-scale production. Of the marine-derived compounds, which have entered phase I and II trials as antitumor agents, the dolastatins are derived from the sea hare, D. auricularia. Dolastatins 10 and 15 are small peptides inhibiting microtubule assembly and tubulin polymerization, both displaying significant antitumor activity in preclinical models. Although dolastatin 10 is well tolerated clinically with hematologic toxicity being the main side effect, in recent phase II clinical trials as a single agent, it lacked significant activity (20–23). TZT-1027 is a derivative of dolastatin 10 with superior preclinical activity. In vivo, TZT-1027 showed notable antitumor activity against a broad range of human malignancies, including those resistant to conventional chemotherapeutic agents. In preclinical studies, the antitumor activity of TZT-1027 was schedule dependent (data on file Investigator's brochure TZT-1027, 21 February 2003, European Edition No. 2). The antitumor activity was enhanced as the dosing schedule progressed from a single administration to consecutive daily administration to intermittent administration. During the previous phase I study done in Japan, studying the days 1, 8, and 15 administration of TZT-1027, several patients were not able to receive the day 15 administration of the drug due to neutropenia. Based on this knowledge, this phase I and pharmacologic study was designed to evaluate the feasibility of administering TZT-1027 as a 60-minute i.v. infusion on days 1 and 8 every 3 weeks, and this schedule will be taken forward in the further evaluation of the drug.

The principal DLT of TZT-1027 on this administration schedule was neutropenia either grade 4 or ongoing neutropenia resulting in omitting the administration of TZT-1027 on day 8 and grade 3 pain in the infusion arm. Neutropenia was dose related, reversible, and noncumulative. At the dose recommended for further studies (2.4 mg/m2), only in 2 of >39 cycles grade 3 neutropenia was observed. Neutropenia also was the dose limiting toxicity for dolastatin 10, the parent compound of TZT-1027. In the phase I study, evaluating the once every 3 weeks administration of TZT-1027 neutropenia constituted also a DLT. The neutropenia was generally short lasting.

Over all dose levels, seven patients experienced a diffuse pain in the infusion arm usually 1 to 2 days after the administration of TZT-1027, which seemed ameliorated by additional fluid after drug administration. Only in one case was this diffuse pain associated with inflammation along the course of the peripheral vein used for drug administration. These episodes were not accompanied by an increase in creatine phosphokinase. The pathogenetic mechanism related to the observed pain in the infusion arm is presently not clear. Especially, it is not known whether it is related to the antivascular effects of TZT-1027. Interestingly, although in preclinical studies TZT-1027 exerted a potent antivascular effect, patients in our phase I study did not experience the tumor pain associated with the infusion of combretastatin (24). This side effect was only observed in one patient during the phase I study with the administration of TZT-1027 once every 3 weeks. Of note is that in this study most patients received the drug through central venous lines via port catheters in contrast to our patients who received the drug through peripheral vein infusions (19).

Drugs that inhibit microtubule polymerization are known to be associated with neurotoxicity. TZT-1027 was evaluated preclinically in rats, mice, and rabbits. When exposed to various doses and schedules, no abnormalities suggesting peripheral neurotoxicity, oto-ocular, or ocular toxicity were observed (12). In this phase I study, only in one patient worsening of preexisting neuropathy was observed after treatment with TZT-1027 after four cycles at the highest dose level. Only one patient previously treated with oxaliplatin, experienced perioral paresthesias during her first course at the 2.4 mg/m2 dose level. This is in contrast with observations in a phase I study on TZT-1027 studying the 3-week administration (19). In this study, several patients experienced a short-lasting reversible neurotoxic syndrome of mandibular cramps, paresthesias, insomnia, and agitation preventing further dose escalation over 2.7 mg/m2.

A possible explanation might be the difference in pretreatment of the patients on study, because 11 of 21 patients in the aforementioned study suffered from colorectal cancer and received prior treatment with oxaliplatin. Because of the occurrence of neurotoxicity in this study, the recommended dose for further study (2.7 mg/m2 given once every 3 weeks) is ~50% of the dose defined in the presently reported study. However, the cumulative neurotoxic effect of TZT-1027 has not been sufficiently evaluated yet. Only four patients in the present study received more than four courses of TZT-1027.

Considering the fact that in preclinical studies cardiac toxicity was observed, all patients were evaluated for cardiac toxicity. No electrocardial abnormalities nor changes in the LVEF were noted. In addition, no clinical signs of impaired cardiac function were observed in any of the treated patients.

The objective response that occurred in this trial was in a patient with refractory liposarcoma with extensive hepatic metastases. The activity of this agent against this refractory malignancy has prompted the initiation of phase II trials of TZT-1027 in anthracyclin-refractory soft tissue sarcoma.

Over the dose levels studied, AUC and Cmax of TZT-1027 were seen to increase proportionally with the dose given although substantial interpatient variability was shown in these exposure variables. However, this interpatient variability in clearance lies in the range observed for commonly used agents like for instance cisplatin, epirubicin, and docetaxel and more important the toxicity encountered was rather predictable (25–27). Population pharmacokinetic models might identify means of reducing the interpatient variability in the future. As for many other chemotherapeutic agents, it was interesting to note that there was no correlation between body surface area and absolute CL, vindicating that a flat dosing regimen might be used in the future.

In summary, this study defined a recommended dose of 2.4 mg/m2 of TZT-1027 given on days 1 and 8 every 3 weeks that was well tolerated.


   Footnotes
 
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.

Received 9/21/04; revised 12/16/04; accepted 1/13/05.


   References
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 Abstract
 Materials and Methods
 Results
 Discussion
 References
 

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