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Byline: Jaffer A. Ajani (1,2), Yixing Jiang (1,2,3), Josephine Faust (1,2), Baochong B. Chang (1,2), Linus Ho (1,2), James C. Yao (1,2), Steven Rousey (1,2), Shaker Dakhil (1,2), Richard C. Cherny (1,2), Catherine Craig (1,2), Archie Bleyer (1,2) Keywords: Bryostatin-1; Protein Kinase C; gastric or gastroesophageal adenocarcinoma Abstract: Purpose: Protein Kinase C (PKC), involved in transmembrane signaling of cell surface receptors, promotes carcinogenesis and tumor progression. Bryostatin-1 competes with PKC for phorbol esters (tumor promoters), thus inhibiting tumor progression. Bryostatin-1 also increases cytotoxicity of paclitaxel in a sequential fashion. We studied sequential paclitaxel and bryostatin-1 in patients with untreated, advanced gastric adenocarcinoma. Methods: Patients with histologic proof of gastric or gastroesophageal junction adenocarcinoma with advanced, measurable cancers were eligible. Patients were required to have near normal organ function and ECOG performance status of 0 or 1. All patients gave an informed consent. Patients received paclitaxel 80 mg/m.sup.2 in 2 h intravenously on day 1 and bryostatin-1 40 mcg/m.sup.2 in 1 h intravenously on day 2 each week for 3 consecutive weeks out of 4. Primary objective was to assess the objective response rate. Results: In a multi-center setting, 37 patients were enrolled and 35 were assessable for response. A confirmed partial response rate was 29%. The median time-to-progression was 4.25 months and the median survival time was 8 months. Grade 3 cumulative myalgias occurred in 55% of patients. Twelve patients discontinued therapy due to myalgias, including 6 patients who had not progressed after achieving a partial response. Other toxic effects were uncommon. Conclusions: Sequential paclitaxel plus bryostatin-1 resulted in a superior response rate than would be expected of paclitaxel alone in patients with untreated, advanced gastric or gastroesophageal junction adenocarcinoma. Further development of this combination is warranted once an effective method to ameliorate or prevent myalgias can be established. Author Affiliation: (1) Department of GI Medical Oncology, University of Texas, M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030 (2) UT M. D. Anderson Community Clinical Oncology Program (CCOP), Houston, TX (3) Milton S. Hershey Medical Center, Hershey, PA Article History: Registration Date: 01/01/2006 Online Date: 05/04/2006 Article note: Supported in part by the NCI phase II contract no. N01-CM-1703 and CCOP contract no. 5 U10 CA 045809-15

Byline: Heleen A. Bardelmeijer (1), MariA< Keywords: absorption; drug transport; pharmacokinetics; P-glycoprotein; paclitaxel Abstract: P-glycoprotein inhibitors can increase the oral bioavailability of paclitaxel. We have now explored the mechanisms that determine the efficacy of several novel P-glycoprotein inhibitors to increase the absorption of paclitaxel from the gut lumen of mice in both in vivo and in vitro experiments. The inhibitors studied were cyclosporin A, PSC 833, GF120918, LY335979 and R101933. Mass balance studies showed that GF120918 was the most effective inhibitor, resulting in almost complete uptake of paclitaxel. PSC 833 was slightly less effective, whereas cyclosporin A and LY335979 were moderately effective. R101933 had only marginal effects. These findings were in line with in vitro transport experiments using LLC-mdr1a cells. By studying the intra-intestinal kinetics of the agents we found that cyclosporin A, PSC 833 and GF120918 rapidly passed the stomach and traveled concurrently with paclitaxel through the intestines, whereas LY335979 and R101933 delayed stomach emptying. Moreover, these latter compounds appear to be more readily absorbed when released into the intestines thus reducing local intestinal concentrations. Due to their combined effects on absorption and metabolic elimination of paclitaxel, cyclosporin A and PSC 833 resulted in the highest paclitaxel levels in plasma. In conclusion, our models provide insight into the factors that determine the suitability of P-glycoprotein inhibitors to enable oral paclitaxel therapy and will be useful in selecting candidate inhibitors for clinical testing. Author Affiliation: (1) Department of Clinical Chemistry, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands Article History: Registration Date: 21/10/2004

Byline: Albert J. ten Tije (1), Timothy W. Synold (2), Darcy Spicer (3), Jaap Verweij (1), James H. Doroshow (2), Alex Sparreboom (4) Keywords: valspodar; paclitaxel; disposition; P-glycoprotein; resistance Abstract: The aim of this multicenter study was to determine whether valspodar (Amdray[TM] code designation, SDZ PSC 833), a potent P-glycoprotein (P-gp) inhibitor, affects the pharmacokinetics of unbound paclitaxel (C .sub.u). Data were obtained from 31 patients with advanced breast cancer. Thirteen patients were treated with paclitaxel alone (3-h infusion at 175mg/m.sup.2) and another 18 received paclitaxel (3-h infusion at 70mg/m.sup.2) in combination with a 21-day cycle of oral valspodar (5mg/kg given four times a day) starting 1 day before administration of paclitaxel. Serial blood samples were taken in the first course and C .sub.u in plasma determined using equilibrium dialysis with a [G- 3.sup.H]paclitaxel tracer. The apparent clearance of C .sub.u was not significantly different between the two groups, with mean +- standard deviation (+-SD) values of 230 +- 56.0 and 202 +- 49.9L/h/m.sup.2 in the absence and presence of valspodar, respectively (P = 0.17). The volume of C .sub.u distribution was slightly larger in the presence of valspodar (1160 +- 474 vs. 1620 +- 552L/m.sup.2 P = 0.025), which contributed to a minor difference in the terminal disposition half-life (6.12 +- 3.42 vs. 8.50 +- 2.06h P = 0.028). These data indicate that (i) valspodar lacks the significant interaction with paclitaxel observed previously with other P-gp modulators, (ii) the majority of the increased toxicity of the combination does not appear to be attributable to increased levels of C .sub.u, and (iii) provide further evidence of the conjecture that the plasma concentration of paclitaxel may not be an appropriate measure to monitor the impact of P-gp inhibition. Author Affiliation: (1) Erasmus MC -- Daniel den Hoed Cancer Center, Department of Medical Oncology, Rotterdam, The Netherlands (2) City of Hope Cancer Center, Duarte, CA (3) USC/Norris Comprehensive Cancer Center, Los Angeles, CA (4) Erasmus, Department of Medical Oncology, MC -- Daniel den Hoed Cancer Center, Rotterdam, The Netherlands (5) National Cancer Institute, Bethesda, MD, 20892 Article History: Registration Date: 06/10/2004

Byline: Michael J. Kelner (1), Trevor C. McMorris (2), Rafael J. Rojas (1), Nicole A. Trani (1), Tami R. Velasco (1), Leita A. Estes (1), Pharnuk Suthipinijtham (1) Keywords: irofulven; taxol; taxotere; vinblastine; vincristine; vinorelbine Abstract: The aim of this study was to determine theantitumor activity of irofulven whenadministered in combination with a varietyof antimitotic agents. Irofulven incombination with either paclitaxel ordocetaxel demonstrated synergistic activityin both the in vitro and invivo studies. The majority of xenograftbearing animals that received suboptimal (&lt MTD) doses of irofulven and a taxanedemonstrated complete cures. In contrast,in vitro studies produced either anadditive or an antagonistic effect whenirofulven was combined with otherantimitotic agents such as vinca alkaloids,rhizoxin, s-trityl cysteine, orallocolchicine. Xenograft studies ofirofulven and vinca alkaloids reflectedin vitro results, as the tumorresponse in combination treated animals wasless than the response in irofulven(monotherapy) treated animals. Theseresults indicate that the therapeuticactivity of irofulven is enhanced whencombined with taxanes, and warrant furtherevaluation of these combinations. Author Affiliation: (1) Department of Pathology, University of California, San Diego, USA (2) Department of Chemistry, University of San Diego, CA, USA Article History: Registration Date: 10/10/2004

Byline: Elisabeth I. Heath (1), Susan Urba (2), John Marshall (3), Steven Piantadosi (1), Arlene A. Forastiere (1) Keywords: cancer of the esophagus; chemotherapy; docetaxel; paclitaxel Abstract: Background: Chemotherapy remains theprimary mode of treatment for metastaticcarcinoma of the esophagus. The efficacyof various chemotherapeutic regimens hasbeen studied predominantly in patients withsquamous cell carcinoma of the esophagus. In light of the increasing incidence ofadenocarcinoma of the esophagus, studiesevaluating newer chemotherapy agents, suchas docetaxel, in this patient populationare necessary. The objective of this trialwas to determine the complete and partialresponse rate of docetaxel in patients withincurable adenocarcinoma of theesophagus. Patients and methods: Eligiblepatients had histologically confirmedmetastatic adenocarcinoma of the esophagusor locally extensive disease not curablewith surgery or radiation therapy. Patients were either chemotherapy naive orpreviously treated with chemotherapy(including paclitaxel). Docetaxel wasadministered at a dose of 75 [mg/m.sup.2]every three weeks intravenously.Appropriate imaging studies/examinationswere obtained after every two cycles toevaluate response. Results: A total of 22 patients wereenrolled in the trial. Chemotherapy-naivepatients achieved a response rate of 18%(95% CI = 2.3 to 51.8) while patients whoreceived prior chemotherapy achieved a 0%response rate (95% CI = 0 to 25). Therewere no complete responses. The overallmedian survival time is 3.4 months and theone-year survival rate is 21%. Thetoxicities included febrile neutropenia(32%) as well as grade 3 and 4 fatigue(14%) and anorexia (9%). Conclusions: Although chemotherapy naivepatients achieved an 18% response rate andno responses were seen in previouslytreated patients, the limitations of thistrial does not allow for any definitiveconclusions to be made about the efficacyof single agent docetaxel chemotherapy inpatients with incurable esophagealcancer. Author Affiliation: (1) Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MP, USA (2) Department of Oncology, University of Michigan, Ann Arbor, MI, USA (3) Department of Oncology, Georgetown University Hospital, Washington, DC, USA Article History: Registration Date: 10/10/2004

Byline: Suzanne Jones (1), John Hainsworth (1), Howard A. Burris (1), Dana Thompson (1), Eric Raefsky (1), Valerie Johnson (1), Sharon Calvert (1), Cecile Bulanhagui (2), David Lebwohl (2), F. Anthony Greco (1) Keywords: JM-216; paclitaxel; phase I trial Abstract: This phase I study wasconducted to determine the dose limitingtoxicity, maximum tolerated doses, andrecommended phase II doses of thecombination of JM-216 and paclitaxel. Patients received paclitaxel intravenouslyover one hour on day 1 of each cycle. OralJM-216 was administered on days 1--5starting after the paclitaxel infusion. Cycles were repeated every 21 days. Patients were accrued at nine differentdosing combinations. JM-216 doses rangedfrom 10--80 mg/m.sup.2/day and werecombined with paclitaxel doses of 150, 175,or 200 mg/m.sup.2. Forty-three patientswere treated with 146 cycles of therapy. Dose-limiting toxicity, consisting offebrile neutropenia and grade 3thrombocytopenia, was encountered in 2patients at the seventh dose level (JM-21680 mg/m.sup.2/day + paclitaxel175 mg/m.sup.2). Two intermediate doselevels were explored. The first level(JM-216 70 mg/m.sup.2/day + paclitaxel175 mg/m.sup.2) produced dose-limitingthrombocytopenia in 1 of 6 patients. However, two additional patients alsodemonstrated delayed recovery fromthrombocytopenia following treatment. As aresult, a second intermediate dose level(JM-216 60 mg/m.sup.2/day + paclitaxel200 mg/m.sup.2) was filled with sixpatients. No dose-limiting toxicities werereported in any patients at this doselevel. The combination of oral JM-216 andpaclitaxel is well-tolerated with minimalnon-hematologic and reversible hematologictoxicity. The recommended dose for phaseII study is JM-216 60 mg/m.sup.2/day for 5days and paclitaxel 200 mg/m.sup.2 on day 1repeated every 21 days. Higher doses ofJM-216 are associated with more severethrombocytopenia and delayed hematologicrecovery resulting in subsequent dosingdelays. Author Affiliation: (1) The Sarah Cannon Cancer Center and Tennessee Oncology, Nashville, TN, USA (2) Bristol-Myers Squibb Pharmaceutical Research Institute Wallingford, CT, USA Article History: Registration Date: 10/10/2004

Byline: Mirte M. Malingre (1,2), Jos H. Beijnen (1,2,3), Jan H.M. Schellens (1,3) Keywords: paclitaxel; docetaxel; oral administration; bioavailability; P-glycoprotein; cytochrome P450 Abstract: Oral treatment with cytotoxic agents is tobe preferred as this administration routeis convenient to patients, reducesadministration costs and facilitates theuse of more chronic treatment regimens. Forthe taxanes paclitaxel and docetaxel,however, low oral bioavailability haslimited development of treatment by theoral route. Preclinical studies with mdr1aP-glycoprotein knock-out mice, which lackfunctional P-glycoprotein activity in thegut, have shown significant bioavailabilityof orally administered paclitaxel.Additional studies in wild-type micerevealed good bioavailability after oraladministration when paclitaxel was combinedwith P-glycoprotein blockers such ascyclosporin A or the structurally relatedcompound SDZ PSC 833. Based on theextensive preclinical research, thefeasibility of oral administration ofpaclitaxel and docetaxel in cancer patientswas recently demonstrated in our Institute.Co-administration of cyclosporin A stronglyenhanced the oral bioavailability of bothpaclitaxel and docetaxel. For docetaxel incombination with cyclosporin A an oralbioavailability of 90% was achieved withan interpatient variability similar to thatafter intravenous drug administration forpaclitaxel the oral bioavailability isestimated at approximately 50%. The safety of the oralroute for both taxanes is good. A phase IIstudy of weekly oral docetaxel incombination with cyclosporin A is currentlyongoing. Author Affiliation: (1) Department of Medical Oncology, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, The Netherlands (2) Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, Amsterdam, The Netherlands (3) Division of Drug Toxicology, Faculty of Pharmacy, Utrecht University, Utrecht, The Netherlands Article History: Registration Date: 11/10/2004

Byline: Seong H. Jang (1), M. Guillaume Wientjes (1), Jessie L.-S. Au (1) Keywords: paclitaxel; uptake; efflux; penetration; apoptosis; solid tumor histoculture Abstract: This report addresses the determinants ofthe rate and extent of paclitaxelaccumulation in tumors. In a 2-dimensionalsystem such as monolayers where the drug isdirectly in contact with tumor cells, drugaccumulation is determined by theextracellular-to-intracellularconcentration gradient, the drug binding toextracellular and intracellularmacromolecules, the presence of the mdr1p-glycoprotein (Pgp), and thetime-dependent and drugconcentration-dependent changes in tubulinsand cell density. Intracellularpharmacokinetic models were developed todepict the effects of these parameters.Computer simulation results indicate thatat the clinically relevant concentrationrange of 1 to 1,000 nM, (a) the bindingaffinity and the number of intracellularsaturable drug binding sites are importantfor drug accumulation at low and highextracellular concentrations, respectively,(b) saturation in the drug binding to thehigh affinity intracellular binding sites(e.g., tubulin/microtubule) occurs atextracellular drug concentration above 100nM, (c) treatment with 1,000 nM paclitaxelfor aY=4 hr results in increased levels oftubulin/microtubule and consequentlyincreased intracellular drug accumulation,whereas the continued cell proliferationafter treatment with low drugconcentrations results in reducedintracellular accumulation, and (d)saturation of Pgp in mdr1-transfectedcells occurs at the high end of theclinically relevant concentration range. Ina 3-dimensional system such as the solidtumor histocultures, which contain tumorcells as well as stromal cells, the drugaccumulation into the inner cell layers isdetermined by the unique properties ofsolid tumors, including tumor cell densityand spatial arrangement of tumor andstromal tissues. Most interestingly, drugpenetration is modulated by thedrug-induced apoptosis the reduced celldensity due to apoptosis results in anenhancement of the rate of drug penetrationinto the inner cell layers of solid tumors.In conclusion, the uptake, accumulation,and retention of paclitaxel in solid tumorsare determined by (a) factors that areindependent of biological changes in tumorcells induced by paclitaxel, i.e., ratio ofextracellular and intracellularconcentrations, and drug binding toextracellular and intracellularmacromolecules, and (b) factors that aredependent on the time- and drugconcentration-dependent biological changesinduced by paclitaxel, i.e., induction ofapoptosis, enhancement oftubulin/microtubule production, andinduction of Pgp expression. Author Affiliation: (1) College of Pharmacy, The Ohio State University, Columbus, OH, USA Article History: Registration Date: 11/10/2004

Byline: Danny Rischin (1), Lorraine K. Webster (2), Michael J. Millward (1), Guy C. Toner (1), Sumith Nawaratne (3), Vinod Ganju (1), Prudence Francis (1), James F. Bishop (1) Keywords: taxanes; anthracyclines; pharmacology Abstract: The objectives of this phase I trial were to determine the maximally tolerated doses of the combination of epirubicin and paclitaxel with and without G-CSF (granulocyte colony stimulating factor) support and to investigate whether epirubicin pharmacokinetics are altered by paclitaxel. Patients with advanced cancer, performance status 0--2, and a normal left ventricular ejection fraction who had received up to 1 prior chemotherapy regimen were treated with epirubicin followed by a 3-hour infusion of paclitaxel repeated every 3 weeks. Dose levels studied were (paclitaxel/epirubicin) 155/75, 175/75, 175/90, 200/90 mg/m.sup.2 without G-CSF and 175/90 mg/m.sup.2 with G-CSF. Thirty-five patients were entered and all were assessable for toxicity. The dose-limiting dose level was 175 mg/m.sup.2 paclitaxel and 90 mg/m.sup.2 epirubicin with limiting toxicities of febrile neutropenia, diarrhea and esophagitis. The addition of G-CSF did not allow escalation of epirubicin. No significant cardiac toxicity was observed. Epirubicin pharmacokinetics were studied during the first 2 cycles in 6 patients, who were randomized to receive 1 cycle with no interval between the completion of the epirubicin and the commencement of the paclitaxel infusion and the other cycle with a 72-hour interval between the drugs. There was no substantial effect of paclitaxel on epirubicin or epirubicinol pharmacokinetics, although there was a marginal increase in glucoronidation. In conclusion, paclitaxel 175 mg/m.sup.2 and epirubicin 75 mg/m.sup.2 is recommended for phase II and III studies. Author Affiliation: (1) Division of Haematology and Medical Oncology, USA (2) Trescowthick Research Laboratories, Peter MacCallum Cancer Institute, Australia (3) Victorian College of Pharmacy, Monash University, Melbourne, Australia Article History: Registration Date: 14/10/2004

Byline: T.A. Dunn (1), H.J. Schmoll (2), V. Gruunwald (1), J. Casper (3), C. Bokemeyer (4) Keywords: human germ cell cancer; cytotoxic drugs; taxol; drug resistance Abstract: Taxol (Paclitaxel) is a novel anti-cancer drug which has shown excellent clinical activity in a variety of solid tumors, particularly in metastatic breast and ovarian cancer. 70-80% of patients with metastatic non-seminomatous germ cell tumor (NSGCT) attain disease free status with standard cisplatin-based combination chemotherapy but the emergence of drug resistance still prevents a small proportion of these patients from achieving long-term remission. Here we report the results of pre-clinical studies investigating whether taxol exhibits cross-resistance to cisplatin or ifosfamide in human NSGCT cell lines and in a cisplatin refractory xenograft model of human NSGCT. Following 96h drug exposure in a 5-day sulphohodamine B (SRB) in vitro assay, taxol demonstrated potent cytotoxicity in cell lines which were cisplatin sensitive (577 LM, H32, H12.1 mean IC50s 1.5-3.0 nM) or those with acquired or intrinsic cisplatin resistance (H12DDP, H23 mean IC50s 2.5 nM). Compared to the drug sensitive cell line, H12.1, the IC50 values of taxol were increased in cell line 1777NRp Cl-A with intermediate level resistance to cisplatin and ifosfamide (4.7 nM p &gt 0.05) and significantly elevated in cell line 1411HP, with a high level of cisplatin resistance (6.9 nM p &gt 0.01). The latter 2 cell lines may represent models corresponding to patients relapsing after high-dose platinum-based chemotherapy who seem to be resistant to taxol therapy. The IC50s of taxol in H32 and H12DDP were approximately 100 fold lower following drug exposure times exceeding 24 hours compared with short exposure times (1-6h). Dose dependent anti-tumor activity was observed with taxol in a cisplatin-refractory xenograft model of NSGCT (H23), with significant anti-tumor activity observed at a dose of 15 mg/kg/d injected intra-venously on days 1 through 5. The results of this study are in accordance with the most recent clinical data which showed that taxol is a useful drug in relapsed or cisplatin-refractory testicular germ cell cancer, with significant anti-tumor activity being observed in 25% of patients, but poor activity in patients previously treated with high-dose therapy. Further pre-clinical research, especially using models such as 1411HP and 1777NRp Cl-A, on the combinations of taxol with other regimens are required to enable successful treatment of the most drug resistant relapsed germ cell tumors. Author Affiliation: (1) Department of Hematology and Oncology, Hannover Medical University, Konstanty-Gutschow Strasse 8, 30623 (2) Department of Hematology and Oncology, Martin-Luther University of Halle-Wittenberg, Ernst-Grube Strasse 40, 06120, Halle/Saale, Germany (3) Department of Hematology and Oncology, University of Rostock, 18055, Rostock (4) Department of Hematology and Oncology, Eberhard-Karls-Universitat, Otfried-Muller Strasse 10, 72076, Tubingen Article History: Registration Date: 29/09/2004