Oral Taxane Research Articles

641 POSTER Effecacy and prediction of response to the new oral taxane DJ-927 in anthacycline pre-treated advanced breast cancer (ABC)

641 POSTER Effecacy and prediction of response to the new oral taxane DJ-927 in anthacycline pre-treated advanced breast cancer (ABC)

644 POSTER The novel oral taxane BMS275183 has a favorable activity and toxicity profile in a twice weekly schedule; Preliminary findings from an extended phase I trial

644 POSTER The novel oral taxane BMS275183 has a favorable activity and toxicity profile in a twice weekly schedule; Preliminary findings from an extended phase I trial

A phase II pilot trial of low dose, continuous infusion, or “metronomic”, paclitaxel and oral celecoxib in patients with metastatic melanoma

8010 Background: In patients (pts) with metastatic melanoma (MM), tumor angiogenesis has been associated with tumor progression and survival (Ugurel et al, JCO 19:577). Microtubule and cyclooxygenase (COX)-2 inhibitors, both alone and in combination, have been shown to have inhibitory effects on endothelial cells and tumor angiogenesis both in vitro and in vivo (Merchan et al, Int J Ca 113:490. Jones et al, Nat Med 5:1418). We tested the safety and efficacy of a regimen involving low dose, continuous infusion (CIV) paclitaxel and oral celecoxib in pts with MM. Methods: Pts received paclitaxel 10mg/m2 for 96 hours weekly by CIV and Celecoxib 400 mg po/bid. Systemic tumor response was assessed at 6 wk intervals (1 cycle (C)). Pts without unacceptable toxicity or clinically significant disease progression (PD) received additional cycles. Pts exhibiting PD after C 2 relative to end of C 1 were removed from study. Pts on anticoagulants, with recent MI or untreated brain metastases were ineligible. Results: 20 pts (12 M/ 8 F), median age 55 (range 44–65), ECOG PS 0/1/2 (5/13/2), M1a/M1b/M1c: 1/1/18 (90%), and prior systemic therapy regimens 0/1/2/3+: 1/7/5/7 were enrolled in the protocol. Sites of systemic disease included: lung (13 pts), LN (14), soft tissue (13), liver (9), bone (4), brain (6), other (11). 3 pts came of study prior to treatment with rapid disease progression. Treatment related grade 3–4 toxicities included line related (LR) bacteremia (3 pts), LR DVT (3 pts), LR PE (3). There were no grade 3–4 toxicities attributed to paclitaxel or celecoxib. No pt exhibited a major tumor response; 6/20 (30%) pts had stable disease for 17, 18, 18, 18+, 30+, 60 wks. Median TTP was 6 wks (range 3- 60); median overall survival was 6 months (range 1–29). Conclusions: Low-dose, CIV paclitaxel and oral celecoxib leads to disease stabilization in a significant portion of previously treated pts with MM. This suggests a role for combination anti-angiogenic therapy in MM. The incidence of LR toxicities indicates that alternative microtubule inhibitors, such as oral taxanes, should be considered in combination with COX-2 inhibitors for future studies. Results of biomarker studies will be presented at the meeting. Supported by Pfizer Inc. and NIH R21 CA097730. [Table: see text]

Phase I Trial with BMS-275183, a Novel Oral Taxane with Promising Antitumor Activity

BMS-275183 is an orally administered C-4 methyl carbonate analogue of paclitaxel. We did a dose-escalating phase I study to investigate its safety, tolerability, pharmacokinetics, and possible antitumor activity. A cycle consisted of four weekly doses of BMS-275183. The starting dose was 5 mg, which was increased by 100% increments (i.e., 5, 10, 20 mg/m2, etc.) in each new cohort consisting of one patient. Cohorts were expanded when toxicity was encountered, and 20 patients were treated at the maximum tolerated dose (MTD). Plasma pharmacokinetics were done on days 1 and 15. A total of 48 patients were enrolled in this trial. Dose-limiting toxicities consisted of neuropathy, fatigue, diarrhea, and neutropenia. First cycle severe neuropathy was reported in four patients treated at 320 (n = 1), 240 (n = 2), and 160 mg/m2 (n = 1), whereas eight patients treated at dose levels ranging from 160 to 320 mg/m2 experienced grade 2 neuropathy in cycle one. The MTD was 200 mg/m2, as 3 of 20 patients experienced grade 3 or 4 toxicity in cycle one [fatigue (n = 2), and neutropenia/diarrhea (n = 1)]. BMS-275183 was rapidly absorbed with a mean plasma half-life of 22 hours. We observed a significant correlation between drug-exposure and toxicity. Tumor responses were observed in 9 of 38 evaluable patients with non-small cell lung cancer, prostate carcinoma, and other tumor types. BMS-275183 is generally well tolerated on a weekly schedule. The main toxicity is peripheral neuropathy, and the MTD is 200 mg/m2. Promising activity was observed in several tumor types, and a phase II trial in non-small cell lung cancer has been initiated.

The effect of food on the pharmacokinetics of BMS-275183, a novel oral taxane, in patients with advanced solid malignancies

2053 Background: BMS-275183 is a novel oral taxane with promising activity against NSCLC and other tumor types. The effect of food on absorption of BMS-275183 is not known. In this study, the effect of food on the pharmacokinetics (PK) of BMS-275183 was assessed in patients with advanced solid tumors refractory to standard therapy. The inter-patient PK variability after a fixed dose was also compared to that after a dose based on body surface area. Methods: Thirty-two patients were randomized to receive weekly 200 mg doses of BMS-275183 on each of three occasions: after a fast of 10 hours, 30 minutes after a standard low-fat meal, or 30 minutes after a standard high-fat meal. Patients were subsequently treated at the 200 mg/m2 Phase II dose on a continuous, weekly schedule under fasted conditions. Blood samples for BMS-275183 PK were collected predose and over 72 hours from the start of dosing on Days 1, 8, 15, and 22. BMS-275183 plasma concentrations were measured using a validated LC/MS/MS assay. Determination of food effect was based on bio-equivalence criteria Cmax and AUC. Results: BMS-275183 PK data are summarized for the 24 patients fully evaluable for PK assessment in the following table. Analysis of provisional data showed diminished Cmax and delayed Tmax, but no effect on AUC of BMS-275183 when given with food compared to the fasted state. The inter-patient variability of BMS-275183 AUC after a 200 mg dose was 84% and that after a 200 mg/m2 dose was 66%. BMS-275183 was generally well tolerated. Conclusions: Food affected the Cmax, but not the AUC of BMS-275183 and could moderate Cmax-related toxicities. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb

A phase I trial investigating a twice weekly administration of the oral taxane BMS-275183 in patients with advanced solid tumors

2040 Background: BMS-275183, a novel oral taxane, had peripheral neuropathy as the main side effect on a weekly regimen with the recommended phase II dose being 200 mg/m2. Considerable anti-tumor a...

Therapeutic Synergy of Oral Taxane BMS-275183 and Cetuximab versus Human Tumor Xenografts

Combination therapy consisting of an oral taxane, BMS-275183, and the anti-epidermal growth factor receptor monoclonal antibody, cetuximab, was assessed for enhanced therapeutic benefit in preclinical tumor models. Mice bearing human tumor xenografts, either L2987 lung or GEO colon carcinoma, were administered the aforementioned treatments singly or in combination regimens. Delays in tumor growth and tumor-free status were evaluated and combination treatments were assessed relative to optimal solo treatments. Combination therapies with the oral taxane plus cetuximab were tolerated and therapeutic synergistic outcomes obtained. The therapeutic enhancements were >1 log cell kill greater than the antitumor effect caused by either solo agent applied optimally. For example, at the maximum-tolerated dose of BMS-275183, 60 mg/kg/administration, given p.o. once every 3 days for a total of six administrations (q3dx6), 1.0 gross log cell kill was achieved in mice bearing well established (100 to 200 mg) s.c. implanted L2987 tumors. Cetuximab, at an optimal dose of 1 mg/mouse, given i.p. q3dx6, produced 1.3 log cell kill. When cetuximab, 1 mg/mouse, i.p., plus BMS-275183, 25 mg/kg/administration, p.o., were both given q3dx6, the result was 2.6 log cell kill with three of eight mice cured (P < 0.01). Similar efficacy benefits were obtained in the GEO tumor model. The combination of oral taxane BMS-275183 plus cetuximab provided therapeutically synergistic antitumor activity in two different human tumor xenograft models. Clinical evaluation of this combination is recommended.

571 Bioavailability and pharmacokinetic study of the novel oral C-seco taxane derivative IDN 5390 in mice

571 Bioavailability and pharmacokinetic study of the novel oral C-seco taxane derivative IDN 5390 in mice

522 Oral taxane BMS-275183 demonstrates therapeutic synergy in human tumor xenografts when combined with cetuximab

Although the taxanes paclitaxel and docetaxel are among the most active agents for the treatment of a wide range of cancers, tumours often develop resistance to these treatments. Cabazitaxel is a novel taxane active in both preclinical models of chemotherapy-sensitive and -resistant human tumours and patients with advanced prostate cancer that progressed following docetaxel treatment.To establish the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of cabazitaxel.Cabazitaxel was administered every 3 weeks to patients with advanced solid tumours. The design allowed intrapatient dose escalation. The primary objective was to determine the MTD. Secondary objectives were to describe the safety profile, establish an appropriate dose, determine the pharmacokinetic (PK) profile of cabazitaxel, and assess antitumour activity.Twenty-one patients were recruited. The MTD was reached at 30 mg/m2, at which three of five patients experienced haematologic DLTs during the first cycle. DLTs during subsequent cycles were mainly haematologic and reported at 25 and 30 mg/m2 dosing levels. Nail disorders and severe alopecia were not reported, and neurotoxicity, fluid retention and hypersensitivity were mild and infrequent. Cabazitaxel demonstrated linear PK, a triphasic elimination profile, with a long half-life and high clearance. Of the 19 patients evaluable for response, one unconfirmed partial response and six occurrences of stable disease were reported.The 25 mg/m2 dose of cabazitaxel was recommended for use in future clinical studies. In this study, cabazitaxel had an acceptable tolerability profile and activity in cervical, colorectal, endometrial and lung cancers.

A phase I trial of the novel oral taxane BMS-275183 in patients with advanced solid tumors

2029 Background: BMS-275183, a novel orally administered taxane, has been studied in this phase I trial to assess its safety, tolerability, pharmacokinetics (PK) and possible anti-tumor activity. Methods: BMS-275183 was given in a continuous, weekly schedule to adult patients (pts) with advanced solid tumors refractory to standard therapy. Plasma samples were collected on weeks 1 and 3 for 48 h after drug administration and analyzed using a LC/MS/MS assay. Results: To date, 31 pts have been treated at escalating dose levels of 5 mg (n=1) and 5 (n=2), 10 (n=1), 20 (n=1), 40 (n=1), 80 (n=1), 160 (n=1) and 320 mg/m2 (n=6), and at subsequent intermediate dose levels of 240 (n=2) and 200 mg/m2(n=15). Most common and dose limiting toxicity (DLT) consists of peripheral neuropathy, which was severe (CTC grade 3) in 1/6 pts at 320 and 2/2 pts at 240 mg/m2, and developed rapidly after the first dose but generally recovered to gr 1 after dose reduction or discontinuation. Severe hematological toxicity was infrequent with gr 3 - 4 neutropenia in 4/31 pts, all treated at doses ≥ 200 mg/m2. At the 200 mg/m2dose level (n=15), 5 DLTs were observed consisting of 3 cases of delayed recovery (> 1 week) from gr 2 neuropathy, 1 gr 4 malaise and 1 gr 3 diarrhea / gr 4 neutropenia. Other side effects included gr 1 - 2 arthralgia, myalgia, anemia, alopecia, gastrointestinal symptoms, fatigue, fever, epistaxis, skin rash and nail changes. PK analysis at the 200 mg/m2dose level (n=15) revealed a rapid uptake with a median Tmax of 1 h and a mean T½ of 20.3 h. The mean AUC is 4595 ng.h/mL with an interpatient variability of 56%. Interestingly, a correlation between the AUC and the severity of the side effects was observed, as most patients with a DLT or dose reduction, had an AUC > 5600 ng.h/mL following the first dose. Seven confirmed partial responses were observed in 23 evaluable pts, all treated at a dose ≥ 160 mg/m2: 4/8 evaluable NSCLC pts (duration 26, 28, 20 and 26+ weeks), 1/3 NSCLC pts with non-measurable disease (16 weeks), 1/1 sarcoma pt (50 weeks) and 1/1 prostate/NSCLC pt (19 weeks). Conclusions: BMS-275183 is a novel oral taxane with promising activity in NSCLC. The recommended dose for future phase II trials currently is 200 mg/m2. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb

A phase I trial of the novel oral taxane BMS-275183 in patients with advanced solid tumors

2029 Background: BMS-275183, a novel orally administered taxane, has been studied in this phase I trial to assess its safety, tolerability, pharmacokinetics (PK) and possible anti-tumor activity. Methods: BMS-275183 was given in a continuous, weekly schedule to adult patients (pts) with advanced solid tumors refractory to standard therapy. Plasma samples were collected on weeks 1 and 3 for 48 h after drug administration and analyzed using a LC/MS/MS assay. Results: To date, 31 pts have been treated at escalating dose levels of 5 mg (n=1) and 5 (n=2), 10 (n=1), 20 (n=1), 40 (n=1), 80 (n=1), 160 (n=1) and 320 mg/m2 (n=6), and at subsequent intermediate dose levels of 240 (n=2) and 200 mg/m2(n=15). Most common and dose limiting toxicity (DLT) consists of peripheral neuropathy, which was severe (CTC grade 3) in 1/6 pts at 320 and 2/2 pts at 240 mg/m2, and developed rapidly after the first dose but generally recovered to gr 1 after dose reduction or discontinuation. Severe hematological toxicity was infrequent with gr 3 - 4 neutropenia in 4/31 pts, all treated at doses ≥ 200 mg/m2. At the 200 mg/m2dose level (n=15), 5 DLTs were observed consisting of 3 cases of delayed recovery (> 1 week) from gr 2 neuropathy, 1 gr 4 malaise and 1 gr 3 diarrhea / gr 4 neutropenia. Other side effects included gr 1 - 2 arthralgia, myalgia, anemia, alopecia, gastrointestinal symptoms, fatigue, fever, epistaxis, skin rash and nail changes. PK analysis at the 200 mg/m2dose level (n=15) revealed a rapid uptake with a median Tmax of 1 h and a mean T½ of 20.3 h. The mean AUC is 4595 ng.h/mL with an interpatient variability of 56%. Interestingly, a correlation between the AUC and the severity of the side effects was observed, as most patients with a DLT or dose reduction, had an AUC > 5600 ng.h/mL following the first dose. Seven confirmed partial responses were observed in 23 evaluable pts, all treated at a dose ≥ 160 mg/m2: 4/8 evaluable NSCLC pts (duration 26, 28, 20 and 26+ weeks), 1/3 NSCLC pts with non-measurable disease (16 weeks), 1/1 sarcoma pt (50 weeks) and 1/1 prostate/NSCLC pt (19 weeks). Conclusions: BMS-275183 is a novel oral taxane with promising activity in NSCLC. The recommended dose for future phase II trials currently is 200 mg/m2. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb

Phase I and Pharmacokinetics (PK) of DJ-927, an oral taxane, in patients (Pts) with advanced cancers

2028 Background: DJ-927, a novel semi-synthetic taxane and a poor substrate of P-glycoprotein (Pgp), is orally bioavailable and possesses potent anti-tumor activity against Pgp expressing human cancers. Preclinically, DJ-927 is more potent than both paclitaxel and docetaxel. Methods:This first-in-human study assessed the maximum tolerated dose [MTD], dose limiting toxicities [DLT] and PK of DJ-927 administered as a single oral 3-weekly dose. Pts were stratified based on prior therapy into minimally (MP) and heavily (HP) pretreated cohorts. The starting dose of DJ-927, 1.5 mg/m2, was increased in 100% increments until grade 2 toxicities occurred during course 1 and by 50% thereafter, until consistent DLT were observed. Results: To date, 40 pts have received 109 courses [median-2; range 1–8] at the following doses: 1.5 mg/m2 [3], 3 mg/m2 [3], 6 mg/m2 [3], 12 mg/m2 [3], 18 mg/m2 [4], 27 mg/m2 [8], 35 mg/m2 [8] and 40 mg/m2 [8]. Demographics: 23 male / 17 female; median [range] age- 57 [31–81]; PS 0 [7], PS 1...

Phase I and Pharmacokinetics (PK) of DJ-927, an oral taxane, in patients (Pts) with advanced cancers

2028 Background: DJ-927, a novel semi-synthetic taxane and a poor substrate of P-glycoprotein (Pgp), is orally bioavailable and possesses potent anti-tumor activity against Pgp expressing human cancers. Preclinically, DJ-927 is more potent than both paclitaxel and docetaxel. Methods:This first-in-human study assessed the maximum tolerated dose [MTD], dose limiting toxicities [DLT] and PK of DJ-927 administered as a single oral 3-weekly dose. Pts were stratified based on prior therapy into minimally (MP) and heavily (HP) pretreated cohorts. The starting dose of DJ-927, 1.5 mg/m2, was increased in 100% increments until grade 2 toxicities occurred during course 1 and by 50% thereafter, until consistent DLT were observed. Results: To date, 40 pts have received 109 courses [median-2; range 1–8] at the following doses: 1.5 mg/m2 [3], 3 mg/m2 [3], 6 mg/m2 [3], 12 mg/m2 [3], 18 mg/m2 [4], 27 mg/m2 [8], 35 mg/m2 [8] and 40 mg/m2 [8]. Demographics: 23 male / 17 female; median [range] age- 57 [31–81]; PS 0 [7], PS 1 [31], and PS 2 [2]. Primary tumors are colorectal [15], breast [4], pancreas [5], renal cell [3], soft tissue sarcoma [3] and others [10]. Minimal drug-related toxicities were observed at doses 5 days duration [7] and grade 3 thrombocytopenia [4] were the predominant hematological toxicities observed at 40 and 35 mg/m2 doses. Non-hematological toxicities included: transient grade 3 peripheral sensory neuropathy after 3 cycles [1] at 27 mg/m2, grade 3 diarrhea and grade 3 mucositis [1] at 40mg/m2. Minor responses were seen in taxane-refractory breast carcinoma [1] and transitional cell carcinoma of the bladder [1]. Disease stabilization for >3 months was noted in 8 pts. Plasma PK of DJ- 927 were dose proportional over the dose range explored. The Cmax, mean (CV%) 58.83 (70.2) μg/L, AUC (inf) 1792.7 (36.4) h*μg/L), clearance/F 45.93 (48.6) L/h, and terminal half-life 175.5 (38.2) h were seen at 40 mg/m2 dose (8). Conclusions: DJ-927 generates predictable systemic drug exposures and has been well tolerated when orally administered. Dose escalation ceased due to DLT in 2/3 MP + 2/5 HP at 40 mg/m2 and 2/6 MP + 2/2 HP at 35 mg/m2. MTD has been defined as 27 mg/m2 for MP and HP patients. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Daiichi Pharmaceutical Corp.; MDS Pharma Daiichi Pharmaceutical Corp.; Daiichi, USA; MDS Pharma Daiichi Pharmaceutical Corp.; MDS Pharma Daiichi Pharmaceutical Corp. Daiichi Corp.

IDN 5390: an oral taxane candidate for protracted treatment schedules.

The recognition of the antiangiogenic properties of taxanes provides a basis for novel therapeutic approaches. A prolonged exposure to low drug concentrations has been proposed to be the most suitable approach to exploit the antiangiogenic potential of cytotoxic agents. Such schedule is required to target preferentially slowly dividing endothelial cells. The protracted use of taxanes could benefit from the availability of a taxane endowed with a favourable tolerability profile. Among compounds of a novel series of C-seco taxanes, IDN 5390 was originally selected on the basis of its potent antimotility activity and poor cytotoxicity on endothelial cells. The aim of the study was to investigate the preclinical pharmacologic profile of IDN 5390 in a variety of human tumour xenografts, including ovarian and colon carcinoma and a glioblastoma. IDN 5390, delivered by s.c. injection, daily for 5 days per week, exhibited a high activity against all tumours investigated (tumour growth inhibition was always >85%) in the range of well-tolerated doses. The maximum tolerated dose/injection (MTD), with no signs of systemic or local vesicant toxicity, was 120 mg kg−1. In contrast, paclitaxel, delivered according to the same schedule, exhibited a variable antitumour efficacy associated with a substantial local toxicity (MTD=10 mg kg−1). Considering the remarkable efficacy of IDN 5390 delivered s.c. by protracted treatment schedule, the oral route of administration was further investigated, as the most suitable for daily treatment. Indeed, a good bioavailability of oral IDN 5390 was found. Oral IDN 5390 maintained a substantial efficacy against human tumour xenografts, including paclitaxel-resistant tumours, without loss of potency with respect to s.c. administration. In conclusion, the therapeutic advantages of IDN 5390, over paclitaxel, in protracted daily treatment schedules are represented by the oral efficacy and the high tolerability, which are favourable features to exploit the antiangiogenic potential and to design combinations with other effective agents.

Protein kinase A as target for novel integrated strategies of cancer therapy.

We have studied the role of protein kinase A (PKA) in neoplastic transformation, apoptosis, and angiogenesis and its relationship with other signaling molecules, as a basis for developing novel therapeutic strategies. We demonstrated the involvement of PKA type I (PKA-I) in the transduction of mitogenic signals from different sources and demonstrated functional and structural interactions between PKA-I and the activated epidermal growth factor receptor (EGFR). We contributed to the identification and development of several selective inhibitors of PKA-I, such as 8-Cl-cAMP and a hybrid DNA/RNA antisense oligonucleotide of a novel class (AS-PKA-I) and of EGFR, including mAbC225 and ZD1839 (Iressa). All these agents have been investigated in cancer patients. We demonstrated the therapeutic potential of the combined blockade of PKA-I and EGFR, reporting a synergistic antitumor effect when their inhibitors are used in combination. We have also shown that PKA-I and EGFR inhibitors are able to cooperate with selected class of cytotoxic drugs and with ionizing radiation, causing a synergistic inhibition of tumor growth in vitro and in vivo, accompanied by inhibition of expression of growth and angiogenic factors and by suppression of vessel production. Moreover, PKA-I is implicated in a bcl-2-dependent apoptotic pathway, and we have recently reported a cooperative antitumor and proapoptotic effect of AS-PKA-I in combination with an AS-bcl-2. Finally, we have shown that AS-PKA-I also has antitumor and antiangiogenic effects following oral administration and that they can be greatly enhanced in combination with oral ZD1839 and oral taxanes.

High-performance liquid chromatography/tandem mass spectrometry for the quantitative analysis of a novel taxane derivative (BAY59-8862) in biological samples and characterisation of its metabolic profile in rat bile samples.

A sensitive, specific, accurate and reproducible high-performance liquid chromatography (HPLC) analytical method was developed and validated for the quantification of the novel oral taxane analogue BAY59-8862 in mouse plasma and tissue samples. A fully automated solid-phase extraction procedure was applied to the plasma after internal standard (IS) addition, with only 0.2 mL volume of the sample loaded on a CN-Sep-pak cartridge. In the case of the tissues a very simple acetonitrile extraction was used to recover BAY59-8862 and its internal standard from liver. The procedure for the quantification of BAY59-8862 and its IS (IDN5127) is based on high-performance liquid chromatography/ion spray-tandem mass spectrometry, operating in selected ion monitoring mode. The retention times of BAY and IS were 7.21 and 10.36 min, respectively. In both plasma and tissue specimens the assay was linear in the range 50-5000 ng/mL (ng/g). The overall precision and accuracy were assessed on three different days. The results for plasma were within 6.1% (precision) and between 99 and 112% (accuracy), and for the liver samples within 7.3% and between 104 and 118%, respectively. The LOD was 5 ng/mL and 20 ng/g in the plasma and liver, respectively. In addition, the biliary excretion of the compound in rats was studied. The study showed that an oxidative chemical reaction was the preferred metabolic pathway for biliary excretion, and two sets of mono- and dihydroxylated metabolites were detected by LC/ISP-MS/MS experiments. With this method, BAY59-8862 pharmacokinetic was determined in mice. The combined results demonstrate that the methodology can be considered a valid approach to conduct pharmacokinetic and metabolic studies during preclinical and clinical investigations.

Dose Scheduling – Herceptin®

Preclinical and phase I/II studies of Herceptin^® demonstrated a dose-related, non-linear pharmacokinetic profile. The results of a dose-finding study supported a regimen comprising an initial intravenous (i.v.) dose of 4 mg/kg with subsequent weekly doses of 2 mg/kg. However, pharmacokinetic and safety data suggested that increased dose and reduced frequency of Herceptin administration are feasible. In addition, evidence shows that Herceptin plus paclitaxel has additive antitumor efficacy in vitro, and this regimen produces significant clinical benefits. These observations form the rationale for conducting a phase I/II trial of Herceptin (8 mg/kg initial dose, 6 mg/kg maintenance dose) plus paclitaxel, both given 3-weekly. Preliminary results are promising, with serum trough Herceptin concentrations being similar and AUC being greater than those observed with weekly Herceptin plus 3-weekly paclitaxel. Two further trials are proposed: 3-weekly Herceptin as first-line monotherapy of metastatic breast cancer; and 3-weekly Herceptin with the oral 5-fluorouracil derivative, Xeloda^® (capecitabine). Subcutaneous (s.c.) administration of Herceptin would further simplify administration and studies are also underway to clinically evaluate s.c. administration of Herceptin in combination with paclitaxel. With the recent development of oral taxanes, it is predicted that combinations including an oral taxane, Xeloda and either 3-weekly or possibly s.c. Herceptin may become future therapies for breast cancer patients.