Pgtxl And Pgcpt From The Laboratory To The Clinic 1041 Pgtxl

Taxanes are a class of the widely used and clinically active cytotoxic agents that exert their action by promoting tubulin polymerization and microtubule assembly.43 Because of its poor aqueous solubility, use of TXL requires Cremophor and ethanol mixture as a vehicle, and it must be infused over 3-24 h. The conjugate PG-TXL where TXL is attached to PG via ester bonds has demonstrated significantly enhanced anti-tumor efficacy and improved safety when compared with TXL in preclinical studies.44

The release of TXL from PG-TXL and the metabolism of PG-TXL in both in vitro and in vivo models have been investigated.45 These studies showed that when PG-TXL was incubated in buffered saline or plasma (mouse or human) for 24 h at 37°C, less than 14% of the bound TXL was released, suggesting that PG-TXL is relatively resistant to plasma esterase.

Tumor uptake of TXL and PG-TXL was compared using [3H]TXL and PG-[3H]TXL.46 When free [3H]TXL was incubated with MDA-MB453 cells, [3H]TXL was taken up rapidly by the cells and was followed by a rapid drug efflux process. In contrast, when the tumor cells were incubated with PG-[3H]TXL, a slower uptake and more persistent retention of radioactivity was observed. These data suggest that a fraction of PG-[3H]TXL was taken up by tumor cells, possibly through pinocytosis, and that [3H]TXL was more readily pumped out of the cells than were the more hydrophilic PG-[3H]TXL and its degradation products. A recent report confirmed monoglu-tamyl-2'-TXL and diglutamyl-20-TXL as the major intracellular metabolites of PG-TXL.47 Hydrolysis of these metabolites led to release of free TXL. Specific enzyme inhibitors such as CA-074 methyl ester, a cell-permeable irreversible inhibitor of cathepsin B, and EST, a cell-permeable irreversible inhibitor of cysteine protease, decreased the formation of monoglutamate TXL and free TXL in a tumor cell line that had been incubated with PG-TXL. All of these findings are consistent with the results of proteolysis of the PG backbone through the action of cellular dipeptidases. Another experiment showed that the metabolism of PG-TXL in non tumor-bearing cathepsin B homozygous knockout mice is reduced, but not eliminated; this seems to confirm that in addition to cathepsin B, other cysteine proteases on the surface of tumor cells play important roles in the release of TXL from PG-TXL.47

PG-TXL's anti-tumor activity was first assessed in a variety of syngeneic and xenogeneic tumor models. For example, the maximum tolerated dose of PG-TXL after a single intravenous injection in rats and mice was 60 and 160 mg/kg, respectively.44 In comparison, the maximum tolerated dose of TXL in rats and mice was 20 and 60 mg/kg, respectively. Therefore, PG-TXL's use represented a twofold and threefold improvement in toxicity in rats and mice, respectively. To determine if PG-TXL has a broad spectrum of anti-tumor activity, its therapeutic activity was evaluated against four syngeneic murine tumor cell lines (MCa-4 breast carcinoma, MCa-35 breast carcinoma, HCa-1 hepatocarcinoma, and FSa-II sarcoma) intramuscularly inoculated into C3Hf/ Kam mice.48 The anti-tumor and antimetastatic activities of PG-TXL were investigated using intraperitoneal injection of the SKOV3ip1 human ovarian tumor cell line in nude mice49 and human MDA-MB-435-Lung2 breast tumors grown in the mammary fat pads of nude mice.48 Treatment with PG-TXL exhibited significantly better anti-tumor activity than did treatment with TXL alone in all of the tumor models.

The pharmacokinetic profile and tissue distribution of PG-TXL were examined to verify the enhanced permeability and retention effect of macromolecules.45 It was found that PG-[3H]TXL has a much longer half-life in plasma (317 min) than [3H]TXL does (29 min). Consequently, the area under the tissue-concentration-time curve (AUC) in tumors was five times greater when mice were injected with PG-TXL than when they were injected with TXL. Therefore, enhanced tumor uptake and sustained release of TXL from PG-TXL in tumor tissue seem to be among one of the major factors contributing to PG-TXL's markedly improved anti-tumor activity in vivo.

In the XYOTAX formulation used in clinical studies, the median molecular weight of PG-TXL is 48,000 Da, and the content of TXL is about 37% by weight, equivalent to approximately one TXL molecule for every 11 glutamic acid units in each PG polymer chain.47 This formulation eliminated the use of Cremophor and alcohol, and it allows infusion of TXL over 30 min. In initial clinical trials in the United Kingdom, the investigators gave PG-TXL (CT-2103) to cancer patients in a 30-min infusion every three weeks at doses ranging from 30 to 720 mg/m2.50 They detected CT-2103 in all the patients' plasma and observed a long plasma half-life of up to 185 h. Importantly, the peak plasma concentration of released free TXL was less than 0.1 mM 24 h after administration of CT-2103 at doses up to 480 mg/m2 (176 mg/m2 TXL equivalent). As shown in Figure 10.1, the plasma concentrations of PG-TXL biphasically declined. The distribution phase was prolonged, and the apparent monoexponential terminal phase associated with drug elimination appeared approximately 48 h after administration of PG-TXL. The plasma concentration of PG-TXL in the terminal phase declined slowly, and the drug could be detected in plasma three weeks after administration at a dose of 200 mg/m2. In comparison, the plasma concentration of free TXL paralleled with the PG-TXL concentration. Importantly, this study found that the AUC of free TXL was about 1-2% of the AUC of PG-TXL that supported the in vivo stability of PG-TXL in the plasma and the slow, prolonged release of the active moiety.51 The steady-state volume of distribution ranged from 1.3 to 5.9 l/m2 and was low that suggested that the distribution of PG-TXL was restricted mainly to the plasma and other extracellular body fluids.47

More than 400 patients have received PG-TXL in phase I and II trials.52,53 Drug-related events that were reported in 10-20% of the patients included thrombocytopenia, diarrhea, leukopenia, myalgia, arthralgia, and anemia. Compared with conventional TXL-based treatment, PG-TXL showed three safety-related advantages. First, alopecia was rare, and complete hair loss was not observed. Second, nausea and vomiting were uncommon. Third, hypersensitivity reactions were rarely observed, and those that did occur were usually mild to moderate; therefore, routinely used prophylactic premedications were not required. The incidence of significant hypersensitivity reactions was less than 1% with no grade 4 hypersensitivity reactions.

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Average dose 496 mg

Average dose 496 mg

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FIGURE 10.1 Plasma pharmacokinetics of PG-TXL and free TXL in cancer patients. The data are from four phase I dose-escalation studies using 1-, 2-, and 3-week schedules. In all of the studies, PG-TXL was administrated in a short intravenous infusion. (From Singer, J. W., Shaffer, S., and Baker, B., Anti-cancer Drugs, 16, 243-254, 2005. With permission.)

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FIGURE 10.1 Plasma pharmacokinetics of PG-TXL and free TXL in cancer patients. The data are from four phase I dose-escalation studies using 1-, 2-, and 3-week schedules. In all of the studies, PG-TXL was administrated in a short intravenous infusion. (From Singer, J. W., Shaffer, S., and Baker, B., Anti-cancer Drugs, 16, 243-254, 2005. With permission.)

Phase II trials CT-2103, including the multicenter open-label studies (CTI-1071 and CTI-1069), have been completed.47,53 The former study aimed to determine the rate of response and time to disease progression in a heterogeneous population of patients with advanced epithelial ovarian cancer who received CT-2103. 7 Ninety-nine patients registered in this trial received PG-TXL at a dose of 175 mg/m2 every three weeks. The toxic effects were mild in this heavily pretreated population and consisted of the following: grade 3 neuropathy (n = 15), grade 3 neutropenia (n = 10), and grade 4 neutropenia (n = 4). Of 18 patients who received one or two prior chemotherapy regimens and had CDDP-sensitive disease, five (28%) had a response, and six (33%) had stable disease (SD). The cancer was difficult to treat in 21 patients with platinum-resistant disease who underwent pretreatment, yet the investigators observed responses in two patients (10%) and SD in four patients (19%). In CTI-1069,47 the researchers aimed to evaluate the efficacy and tolerability of PG-TXL in patients with nonsmall cell lung cancer who were 70 years of age or older and had an Eastern Cooperative Oncology Group (ECOG) performance status of 2 (PS2). Thirty patients were registered in this trial, and they received PG-TXL at a dose of 175 mg/m2 (n = 28) or 235 mg/m2 (n = 2) every three weeks. Two patients had a partial response, whereas 16 patients had SD lasting at least 10 weeks. Among the 28 patients who received PG-TXL at 175 mg/ m2, the median survival duration was 8.1 months in those with an ECOG performance status of 0 (PS0) or 1 (PS1) and 5.4 months in PS2 patients. Both of the patients who received PG-TXL at 235 mg/m2 died within 30 days after treatment; one died of neutropenia, whereas the other died of septic shock and renal failure.

More than 700 patients with lung cancer have participated in phase III trials PG-TXL(XYOTAX) that include two phase III trials of XYOTAX as first-line treatment in PS2 patients (STELLAR 3 and STELLAR 4) and one phase III trial of XYOTAX as second-line treatment in PS0, PS1, and PS2 patients (STELLAR 2).47 The total number of patients in the STELLAR 2, STELLAR 3, and STELLAR 4 trials was 850, 400, and 477, respectively. Cell Therapeutics Inc. (CTI) announced the results of these trials in March and May 2005. Although none of the three trials met their primary end points, they did demonstrate similar efficacy, reduced side effects, and more convenient administration of XYOTAX when compared with the control drugs (TXL, docetaxel, gemcitabine, and vinorelbine).

In addition, clinical data from a pooled analysis of CTI's STELLAR 3 and 4 trials showed that in the 198 women treated on those trials, superior survival was observed in those who received XYOTAX (p = 0.03). The most notable impact was among women less than 55 years old and presumably pre-menopausal who were treated with XYOTAX compared to standard chemotherapy (median survival 10.0 vs. 5.3 months, hazard ratio = 0.51, log rank p = 0.038) while a survival trend (p = 0.134) was observed in women 55 years of age and older (post-menopausal) (http:// www.ctiseattle.com). The favorable anti-tumor activity among women less than 55 years of age stimulated the initiation of the PIONEER 1 clinical trial where about 600 PS2 chemotherapy-naive women with advanced stage NSCLC will be recruited. Each study arm of approximately 300 patients will be randomized to receive either XYOTAX at 175 mg/m2 or TXL at 175 mg/m2 once every three weeks. The primary endpoint is superior overall survival with several secondary endpoints including disease control, response rate in patients with measurable disease, time to disease progression, and disease-related symptoms.

CTI also reported the preliminary results of a phase II study of XYOTAX in combination with carboplatin for first-line induction and single-agent maintenance therapy for advanced-stage III/IV ovarian cancer in May 2005. Among the 82 patients in this study, 98% had a major tumor response, 85% had a complete response, and 12% had a partial response during induction of the therapy. At a dose of 175 mg/m2, XYOTAX and carboplatin (AUC = 6) had grade 3/4 side effects, including thrombocytopenia (55%), neuropathy (23%), febrile neutropenia (19%), nausea (15%), anemia (11%), and vomiting (7%). The investigators found no grade 4 neuropathy, and only 4% patients needed dose delay because of neutropenia. CTI and the Gynecologic Oncology Group are collaborating on phase III studies for which they expect to enroll about 1550 patients to receive treatment with carboplatin and TXL initially followed by XYOTAX for consolidation in half of the patients.

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