Search

Supplementary Data from Phase I Pharmacokinetic and Pharmacodynamic Study of Carboplatin and Topotecan Administered Intravenously Every 28 Days to Patients with Malignant Solid Tumors

Purpose: Preclinical studies have shown that the combination of topotecan and carboplatin is synergistic. To evaluate the schedule dependency of this interaction, the following phase I trial was designed to determine the safety and maximum tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of carboplatin and topotecan in patients with malignant solid tumors.Experimental Design: In part 1, patients received carboplatin on day 1 and topotecan on days 1, 2, and 3 (C→T schedule). In part 2, topotecan was administered on days 1, 2, and 3, followed by carboplatin on day 3 (T→C schedule). Pharmacokinetics were determined in plasma and DNA topoisomerase I catalytic activity and Pt-DNA adducts in WBC and tumor tissue.Results: Forty-one patients were included. Dose-limiting toxicities during the C→T schedule were grade 4 thrombocytopenia and febrile neutropenia (MTD: carboplatin target area under the free carboplatin plasma concentration versus time curve, 4 min mg/mL; topotecan, 0.5 mg/m2/d). Dose-limiting toxicities during the T→C schedule included grade 4 neutropenia, thrombocytopenia, neutropenic fever, and grade 4 nausea and vomiting (MTD: carboplatin target area under the free carboplatin plasma concentration versus time curve, 6 min mg/mL; topotecan, 0.9 mg/m2/d). One complete response and five partial responses were observed. The clearance of and exposure to carboplatin and topotecan did not depend on the sequence of drug administration. No schedule-dependent effects were seen in Pt-DNA levels and DNA topoisomerase I catalytic activity in WBC and tumor tissue. However, myelotoxicity was clearly more evident in the C→T schedule.Conclusion: The T→C schedule was better tolerated because both hematologic and nonhematologic toxicities were milder. Other pharmacodynamic factors than the ones investigated must explain the schedule-dependent differences in toxicities.

Purpose To evaluate the safety, maximum tolerated dose (MTD), and pharmacokinetics of patupilone administered once every 3 weeks with proactive standardized diarrhea management in patients with resistant or refractory ovarian, fallopian, or peritoneal cancer. Patients and Methods Patients received patupilone (6.5 to 11.0 mg/m2) every 3 weeks via 20-minute infusion. Adverse events, dose-limiting toxicities (DLT), MTD, and tumor response were determined. The tumor response was measured by Response Evaluation Criteria in Solid Tumors (RECIST) and cancer antigen 125 levels. Results Forty-five patients were enrolled. Adverse events were mild to moderate in intensity, and grade 3 diarrhea (13%) was the most commonly reported serious adverse event. Grade 3 peripheral neuropathy was noted in two patients (4%). Diarrhea, peripheral neuropathy, and fatigue were the most common DLTs; however, these were uncommon in the first cycle and the MTD was therefore not reached in this study. Overall response (OR; complete and partial responses; median cycles, 8) per RECIST in patients with measurable disease (n = 36) was 19.5%. Median duration of disease stabilization (complete and partial responses and stable disease) was 15.8 months. These results appear improved from a previous study in a similar patient population using a weekly schedule (2.5 mg/m2/week; N = 53; OR, 5.7%). Conclusion Patupilone once every 3 weeks was well-tolerated at doses up to 11.0 mg/m2. Patupilone demonstrated promising antitumor activity in patients with drug-resistant/refractory disease. An ongoing phase III study in this patient population is testing the 10.0 mg/m2 dose.

There is growing concern that some cytotoxic regimens for cancer affect cognitive functioning. This study examined the prevalence of cognitive complaints and deficits in testicular cancer (TC) patients treated with the worldwide standard BEP (bleomycin, etoposide and cisplatin) chemotherapy.Seventy TC patients treated with BEP chemotherapy after surgery (S + CT) were examined with interviews and neuropsychological tests. These patients were compared with 57 TC patients treated with radiotherapy after surgery (S + RT) and with 55 TC patients that received surgery only (S). Patients were examined a median of 3 years after completion of treatment.Thirty two percent of the S + CT patients reported cognitive complaints compared with 32% of the S + RT patients and 27% of the S patients (p = 0.85). No differences in mean cognitive test performance were observed between the groups. On individual impairment scores, more S + CT patients showed cognitive dysfunction compared with S patients, but not compared with S + RT patients (S + CT versus S [p = 0.038, OR = 4.6, CI = 1.1-19.7], S + CT versus S + RT [p = 0.70, OR = 0.8, CI = 0.3-2.4] and S + RT versus S [p = 0.070, OR = 3.7, CI = 0.8-15.7). Cognitive complaints were not related to cognitive test performance, but to emotional distress and fatigue.Cognitive complaints are common among TC patients, independent of treatment modality. These complaints are related to emotional distress and fatigue and not to formal cognitive deficits. The finding of a small group of TC patients treated with chemotherapy exhibiting cognitive deficits should be confirmed in a prospective study before we can decide on its cause and relevance.

Purpose To evaluate the long-term risk of cardiovascular disease (CVD) in survivors of testicular cancer (TC). Patients and Methods We compared CVD incidence in 2,512 5-year survivors of TC, who were treated between 1965 and 1995, with general population rates. Treatment effects on CVD risk were quantified in multivariate Cox regression analysis. Results After a median follow-up of 18.4 years, 694 cardiovascular events occurred, including 141 acute myocardial infarctions (MIs). The standardized incidence ratio (SIR) for coronary heart disease was 1.17 (95% CI, 1.04 to 1.31), with 14 excess cases per 10,000 person-years. The SIR for MI was significantly increased in nonseminoma survivors with attained ages of less than 45 (SIR = 2.06) and 45 to 54 years (SIR = 1.86) but significantly decreased for survivors with attained ages of 55 years or older (SIR = 0.53). In Cox analysis, mediastinal irradiation was associated with a 3.7-fold (95% CI, 2.2- to 6.2-fold) increased MI risk compared with surgery alone, whereas infradiaphragmatic irradiation was not associated with an increased MI risk. Cisplatin, vinblastine, and bleomycin (PVB) chemotherapy (CT) was associated with a 1.9-fold (95% CI, 1.7- to 2.0-fold) increased MI risk, and bleomycin, etoposide, and cisplatin (BEP) CT was associated with a 1.5-fold (95% CI, 1.0- to 2.2-fold) increased CVD risk and was not associated with increased MI risk (hazard ratio = 1.2; 95% CI, 0.7 to 2.1). Recent smoking was associated with a 2.6-fold (95% CI, 1.8- to 3.9-fold) increased MI risk. Conclusion Nonseminomatous TC survivors experience a moderately increased MI risk at young ages. Physicians should be aware of excess CVD risk associated with mediastinal radiotherapy, PVB CT, and recent smoking. Intervention in modifiable cardiovascular risk factors is especially important in TC survivors. Whether BEP treatment increases CVD risk should be evaluated after more prolonged follow-up.

A phase I study was conducted with oral irinotecan given daily for 14 days every 3 weeks in 45 patients with solid tumours to establish the maximum tolerated dose (MTD), toxicity, preliminary antitumour response and pharmacokinetics. Irinotecan was administered orally as a powder-filled capsule at doses ranging from 7.5 to 40 mg/m2 per day. Tumours were predominantly colorectal (30) together with 10 other gastrointestinal, 2 breast, 2 small cell lung and 1 ovarian. All but three patients had received prior chemotherapy. The median number of administered cycles was 3 (range 1-19). Gastrointestinal toxicities (grade 3 nausea, grade 3/4 vomiting and diarrhoea) and one incidence of grade 3 asthenia were dose limiting. There were no grade 3/4 haematological toxicities. The MTD was 30 mg/m2 per day. There were two documented partial responses, one in a patient with cancer of the small intestine and the other in a patient with colon cancer. Stable disease was seen in 16 patients (35.5%). Peak concentrations of irinotecan and metabolite SN-38 were reached within 2.0-2.4 h. The metabolic ratio of SN-38 AUC to irinotecan AUC was 0.17+/-0.10 (mean+/-SD). The dose recommended for phase II studies is 30 mg/m2 per day administered daily for 14 days every 3 weeks.

Purpose: To investigate dose escalation of bi-daily (b.i.d.) oral paclitaxel in combination with cyclosporin A in order to improve and prolong the systemic exposure to paclitaxel and to explore the maximum tolerated dose and dose limiting toxicity (DLT) of this combination. Patients and methods: A total of 15 patients received during course 1 two doses of oral paclitaxel (2×60, 2×90, 2×120, or 2×160 mg/m2) 7 h apart in combination with 15 mg/kg of cyclosporin A, co-administered to enhance the absorption of paclitaxel. During subsequent courses, patients received 3-weekly intravenous paclitaxel at a dose of 175 mg/m2 as a 3-h infusion. Results: Toxicities observed following b.i.d. dosing of oral paclitaxel were generally mild and included toxicities common to paclitaxel administration and mild gastrointestinal toxicities such as nausea, vomiting, and diarrhea, which occurred more often at the higher dose levels. Dose escalation of b.i.d. oral paclitaxel from 2×60 to 2×160 mg/m2 did not result in a significant increase in the area under the plasma concentration-time curve (AUC) of paclitaxel. The AUC after doses of 2×60, 90, 120, and 160 mg/m2 were 3.77±2.70, 4.57±2.43, 3.62±1.58, and 8.58±7.87 µM.h, respectively. The AUC achieved after intravenous administration of paclitaxel 175 mg/m2 was 17.95±3.94 µM.h. Conclusion: Dose increment of paclitaxel did not result in a significant additional increase in the AUC values of the drug. Dose escalation of the b.i.d. dosing regimen was therefore not continued up to DLT. As b.i.d. dosing appeared to result in higher AUC values compared with single-dose administration (data which we have published previously), we recommend b.i.d. dosing of oral paclitaxel for future studies. Although pharmacokinetic data are difficult to interpret, due to the limited number of patients at each dose level and the large interpatient variability, we recommend the dose level of 2×90 mg/m2 for further investigation, as this dose level showed the highest systemic exposure to paclitaxel combined with good safety.

PURPOSE: Oral bioavailability of docetaxel is very low, which is, at least in part, due to its affinity for the intestinal drug efflux pump P-glycoprotein (P-gp). In addition, metabolism of docetaxel by cytochrome P450 (CYP) 3A4 in gut and liver may also contribute. The purpose of this study was to enhance the systemic exposure to oral docetaxel on coadministration of cyclosporine (CsA), an efficacious inhibitor of P-gp and substrate for CYP 3A4. PATIENTS AND METHODS: A proof-of-concept study was carried out in 14 patients with solid tumors. Patients received one course of oral docetaxel 75 mg/m2 with or without a single oral dose of CsA 15 mg/kg. CsA preceded oral docetaxel by 30 minutes. During subsequent courses, patients received intravenous (IV) docetaxel 100 mg/m2. RESULTS: The mean (± SD) area under the concentration-time curve (AUC) in patients who received oral docetaxel 75 mg/m2 without CsA was 0.37 ± 0.33 mg·h/L and 2.71 ± 1.81 mg·h/L for the same oral docetaxel dose with CsA. The mean AUC of IV docetaxel 100 mg/m2 was 4.41 ± 2.10 mg·h/L. The absolute bioavailability of oral docetaxel was 8% ± 6% without and 90% ± 44% with CsA. The oral combination of docetaxel and CsA was well tolerated. CONCLUSION: Coadministration of oral CsA strongly enhanced the oral bioavailability of docetaxel. Interpatient variability in the systemic exposure after oral drug administration was of the same order as after IV administration. These data are promising and form the basis for the further development of a clinically useful oral formulation of docetaxel.

Purpose: Carboplatin doses are often determined by using modified Calvert formulas. It has been observed that the area under the concentration versus time curve (AUC) for free carboplatin is lower than expected when modified formulas are used for carboplatin/paclitaxel chemotherapy combination regimens. By using limited-sampling models, the carboplatin AUC actually reached can easily be verified, and the dose adjusted accordingly. Methods: In this report, we describe the development and validation of a limited-sampling model for carboplatin from 77 pharmacokinetic curves, when carboplatin is used in combination with paclitaxel. Results: The following single-point model was selected as optimal: AUC carboplatin (min mg−1 ml−1) = 418 · c2.5 h(mg/ml) + 0.43 (min mg−1 ml−1), where c2.5 h is the concentration (mg/ml) of carboplatin 2.5 h after the start of a 30-min infusion. This model proved to be unbiased (mean prediction error = 3.4 ± 1.6%) and precise (root mean square error = 10.1 ± 1.5%). Conclusions: The proposed model can be very useful for ongoing and future carboplatin/paclitaxel studies aimed to optimise and individualise treatment.

In the past years, alternative administration routes and pharmaceutical formulations of anticancer agents have been investigated in order to improve conventional chemotherapy treatment. The impact of these adjustments on the pharmacokinetics and pharmacodynamics is discussed. A review of the literature shows many examples of alternative administration forms of anticancer agents with improved pharmacokinetics. Local administration routes have been investigated in order to reduce the systemic toxicity and to enhance the local efficacy of conventional chemotherapy. Oral administration of anticancer agents is preferred by patients for its convenience and its potential for outpatient treatment. In addition, oral administration facilitates a prolonged exposure to the cytotoxic agent. However, poor bioavailability and substantial interpatient variability are noted as limitations for oral chemotherapy. Increased tumour selectivity can also be achieved by the use of specific pharmaceutical formulations, such as liposomes and macromolecular drug conjugates. The composition of these formulations often determine the pharmacokinetic behaviour of the formulated drug. In conclusion, several alternative administration forms of anticancer agents have been designed in the past years, with the potential for improvement of conventional chemotherapy, however, more extensive clinical evaluation of these novel strategies is warranted to prove their real clinical value.

To evaluate the pharmacokinetics of paclitaxel and cisplatin administered in combination with bleomycin and etoposide and Granulocyte Colony-Stimulating Factor (G-CSF) in patients with advanced solid tumours.Patients were recruited to a phase I trial where escalating doses of paclitaxel (125 to 200 mg/m(2)) were administered in combination with etoposide 100 or 120 mg/m(2), and fixed dose of cisplatin 20 mg/m(2) and bleomycin 30 mg, with the concomitant use of G-CSF. Paclitaxel (3-h infusion) was followed by 1-h etoposide, 4-h cisplatin and 30-min bleomycin infusions, respectively. Pharmacokinetics sampling for paclitaxel analysis was performed in ten patients from dose levels II-V.The mean paclitaxel area under the plasma concentration-versus-time curves (AUC) for the 125-mg/m(2) dose level (II) was 7.0 +/- 3.6 h micromol(-1) l(-1), for the 175-mg/m(2) dose level (III) 10.6 +/- 2. 8 h micromol(-1) l(-1), for the 200-mg/m(2) dose level (IV) it was 16.0 +/- 5.0 h micromol(-1) l(-1), and for the 175-mg/m(2) dose level (V) it was 12.5 +/- 6.1 h micromol(-1) l(-1). The mean peak plasma concentration (C(max)) values for dose levels II-V were 1.9 +/- 1.1 micromol/l, 3.4 +/- 1.2 micromol/l, 4.3 +/- 1.0 micromol/l and 3.8 +/- 1.2 h micromol/l, respectively.In this study, relevant pharmacokinetic parameters of paclitaxel like AUC, C(max) and the paclitaxel plasma concentration above the pharmacologically relevant 0.1-micromol/l threshold concentration (t0.1 microM) when administered in combination with cisplatin, etoposide and bleomycin (PEB) were not statistically different from paclitaxel data of historical controls. However, given the trial design, pharmacokinetic interactions between the agents cannot be excluded.

Objective. Paclitaxel is an antineoplastic agent with significant activity against several tumour types. The major portion of the drug disposition (80-90%) in volves metabolism and biliary excretion. The purpose of this study was to investigate the relationships between the mean urinary paclitaxel excretion frac tion and the administered dose, creatinine clearance, or the measured paclitaxel area under the plasma concentration versus time curve. Design. The design used was a retrospective convenience sample study. Setting. The setting for this study was a hospi talised care center. Patients. A total of 103 24-hour urine collections from 60 patients treated with paclitaxel were used to investigate these relationships. Results. In this large series study, the paclitaxel urinary fraction was 5 ± 3% (mean ± SD) as a fraction of the administered paclitaxel dose. No correlations were found between the paclitaxel urinary excretion fraction and the administered dose, creatinine clear ance, and plasma concentration-time curve. In addi tion, the paclitaxel metabolites 6α-hydroxypaclitaxel, 3'- p-hydroxypaclitaxel and some unidentified com pounds were detected in the 24-hour urine samples of two patients, of whom one had a mild impaired renal function. Conclusions. Considering the low urinary ex cretion of paclitaxel, it is anticipated that patients with renal dysfunction require no dose adjustments. Metabolites were found in the urine.

Paclitaxel (Taxol(R)) is an active agent in platinum-refractory ovarian cancer. Since the available pharmacokinetic data of 135 mg m-2 paclitaxel administered by 3-h infusion are scarce and fragmented, we now describe a comprehensive pharmacologic study in a group of 13 patients who were pretreated with platinum for advanced ovarian cancer. The mean paclitaxel AUC was 10.3+/-2.4 h micromol l-1 (range 6.8-13.9 h micromol l-1). Quantification of the two major paclitaxel metabolites, 6alpha-hydroxypaclitaxel and 3'-p-hydroxypaclitaxel yielded AUCs of 0.44+/-0.30 h micromol l-1 and 0.31+/-0.20 h micromol l-1, respectively. The AUC of 3'-p-hydroxypaclitaxel was significantly different from that of patients with an altered hepatic function. The administration of 135 mg m-2 single-paclitaxel was safe, and the toxicities observed at higher doses in earlier studies were absent in this study. This is important, because the schedule and paclitaxel dose of 135 mg m-2 given by a 3-h infusion is expected to be used more frequently in combination with other cytotoxic agents with the aim of improving efficacy.

Paclitaxel and docetaxel are taxane derivatives with a significant antitumour activity. For both drugs, a high incidence of hypersensitivity reactions (HSRs) has been observed during the initial clinical development. However, current pretreatment regimens, consisting of corticosteroids and antihistamines, have led to a substantial decrease in major HSRs. In this study, we describe a case series of 9 out of a total of 415 patients from eight different taxane studies who received either paclitaxel or docetaxel and experienced severe HSRs, despite the use of premedication. Five of these 9 patients had allergies or atopy. We observed an increase in blood pressure during the HSR in 5 patients, whereas a decrease was anticipated. Retreatments, with additional corticosteroids, antihistamines and in some cases a lower infusion rate, were performed successfully in 7 patients. One of these patients was given, after two courses with HSR symptoms, sodium cromoglycate as prophylaxis, after which she received four successive courses without symptoms of HSR.

BACKGROUND Changes in serum CA 125 from baseline do not reflect response to paclitaxel in relapsed ovarian carcinoma patients. Our study aimed to determine whether CA 125 changes relate to tumor response and overall survival during paclitaxel salvage treatment. METHODS Response data and CA 125 values of 77 platinum pretreated ovarian carcinoma patients were included in the study. Patients received 496 courses of paclitaxel in total (median 6; range: 2–18 courses). RESULTS Response group numbers on the basis of World Health Organization (WHO) criteria were: 7 partial response, 22 stable disease, and 48 progressive disease. CA 125 values at the moment of clinical response allocation, the median survival duration, and the 3-year survival rate did not differ among WHO defined response groups. For both the stable disease group and the responders, the slopes of the exponential CA 125 regression curves during paclitaxel treatment were negative. Response groups, as defined by CA 125 changes, i.e., halving or doubling of baseline values, after 4 courses were concordant with WHO defined response groups in only 27%, but predicted survival far better. CONCLUSIONS This study confirms that CA 125 changes in patients receiving paclitaxel treatment do not correlate with response allocations according to WHO criteria. In particular, patients with clinically and radiologically defined progression will often not show an increase in CA 125 concentrations from baseline. Those patients who do show doubling of CA 125 values, however, have a very poor prognosis. The CA 125 ratio, as determined after 4 courses of paclitaxel treatment, may be a better indicator of response than WHO defined response status. Cancer 1996;78:118-27.

Purpose: Preclinical studies have shown that the combination of topotecan and carboplatin is synergistic. To evaluate the schedule dependency of this interaction, the following phase I trial was designed to determine the safety and maximum tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of carboplatin and topotecan in patients with malignant solid tumors. Experimental Design: In part 1, patients received carboplatin on day 1 and topotecan on days 1, 2, and 3 (C→T schedule). In part 2, topotecan was administered on days 1, 2, and 3, followed by carboplatin on day 3 (T→C schedule). Pharmacokinetics were determined in plasma and DNA topoisomerase I catalytic activity and Pt-DNA adducts in WBC and tumor tissue. Results: Forty-one patients were included. Dose-limiting toxicities during the C→T schedule were grade 4 thrombocytopenia and febrile neutropenia (MTD: carboplatin target area under the free carboplatin plasma concentration versus time curve, 4 min mg/mL; topotecan, 0.5 mg/m2/d). Dose-limiting toxicities during the T→C schedule included grade 4 neutropenia, thrombocytopenia, neutropenic fever, and grade 4 nausea and vomiting (MTD: carboplatin target area under the free carboplatin plasma concentration versus time curve, 6 min mg/mL; topotecan, 0.9 mg/m2/d). One complete response and five partial responses were observed. The clearance of and exposure to carboplatin and topotecan did not depend on the sequence of drug administration. No schedule-dependent effects were seen in Pt-DNA levels and DNA topoisomerase I catalytic activity in WBC and tumor tissue. However, myelotoxicity was clearly more evident in the C→T schedule. Conclusion: The T→C schedule was better tolerated because both hematologic and nonhematologic toxicities were milder. Other pharmacodynamic factors than the ones investigated must explain the schedule-dependent differences in toxicities.

From 1979 to 1983 the EORTC GU Group treated 239 patients with disseminated non-seminomatous testicular cancer with combination chemotherapy comprising cisplatin, vinblastine and bleomycin in a prospectively controlled trial. The protocol required complete resection of residual masses after induction chemotherapy, provided that serum tumour markers were normal. 102 patients were operated on. 27 patients had mature teratoma (teratoma differentiated) in the resected specimens and 23 had viable cancer. Follow-up data were available for 26 and 22 of these patients, respectively. 23 of 26 patients (88%) with mature teratoma are alive and disease free after a follow-up of 53-110 months (median 92 months). 3 patients developed progressive disease; 1 died. A peculiar case of growing mature teratoma on the forearm is described. 13 of 22 patients (59%) with residual carcinoma are alive and disease free after a follow-up of 74-112 months (median 95 months). The prognosis of patients with carcinoma is shown to be correlated with the completeness of surgery, which in turn is correlated with the initial tumour mass before chemotherapy.

Topotecan stabilizes the topoisomerase I (Topo I) cleavable complex. We measured Topo I levels in white blood cells of patients with ovarian cancer treated with topotecan. Topotecan was given i.v. daily x 5 q 3 weeks in combination with paclitaxel (1 day before topotecan) and cisplatin (just prior topotecan). Our aim was to correlate Topo I levels to pharmacokinetics and toxicity. Topo I levels were determined using Western blotting and were expressed relative to the Topo I level present in 10 microg cell lysate of the human IGROV1 ovarian cancer cell line. We found no correlation between Topo I levels and (non-)hematological toxicity. Topo I levels after the fifth topotecan infusion were significantly negatively correlated with the AUC of topotecan (R = -0.64, p = 0.026), in contrast with Topo I levels prior to (R = -0.25, p = 0.4) and after (R = -0.30, p = 0.3) the first topotecan infusion. Topo I levels after the fifth topotecan infusion (48 +/- 27%, mean +/- SD) were higher than Topo I levels prior to and after the first topotecan infusion (3.0 +/- 4.7 and 2.7 +/- 3.6%, respectively) (p = 0.001). In conclusion, we detected a significant inverse correlation between Topo I level and topotecan AUC at day 5, and we found increasing Topo I levels during a daily x 5 schedule of treatment with topotecan.

Purpose: To investigate the safety and pharmacokinetics of a new liposomal formulation of cisplatin, SPI-77, in patients with advanced malignancies. Patients and methods: Patients with histologically proven malignancies not amenable to other treatment were eligible for this study. The starting dose of SPI-77 (cisplatin in Stealth liposomes) was 40 mg/m2 administered every 4 weeks in a 2-h infusion, and doses were escalated up to 420 mg/m2. Pharmacokinetic monitoring was performed in all patients and samples were analysed for platinum content by atomic absorption spectroscopy. Platinum-DNA (Pt-DNA) adduct levels in leucocytes (white blood cells, WBC) and tumour tissue were quantified using a sensitive 32P-postlabelling assay. Results: A total of 27 patients were accrued. The main toxicities observed were infusion-related reactions, which could be prevented by lowering the initial infusion rate, and anaemia. The pharmacokinetics of SPI-77-derived platinum were strikingly different from standard cisplatin. Free platinum levels in plasma ultrafiltrate samples were undetectable at the lowest dose levels (40 and 80 mg/m2), and low but highly variable at higher doses of SPI-77. Plasma pharmacokinetics of total platinum were linear with small interpatient variability. The total body clearance of SPI-77 varied from 14 to 30 ml/h and was significantly lower than reported clearance values for cisplatin of 20 l/m2 per h, due to the slow release of cisplatin from the liposomes. Pt-DNA adduct levels in WBC ranged from 0.02 to 4.13 fmol/µg DNA for intrastrand Pt-GG (guanine-guanine) adducts and from 0.02 to 1.27 fmol/µg DNA for intrastrand Pt-AG (adenosine-guanine) adducts, which is more than tenfold lower than after administration of a comparable dose of non-liposomal cisplatin. In tumour samples obtained from two patients treated at the highest dose-levels, relatively low levels of Pt-DNA adducts were observed. Conclusions: The results of this phase I trial show that the pharmacokinetic behaviour of cisplatin is significantly altered by its encapsulation in Stealth liposomes. The pharmacokinetics of SPI-77 are mainly dominated by the liposomal properties, resulting in high cholesterol concentrations and relatively low concentrations of (free) platinum in plasma, WBC and tumour tissue, which may explain the observed differences between the toxicity profiles of SPI-77 and cisplatin.

Purpose. The objectives of the study were to determine the pharmacokinetics and routes of excretion of topotecan following intravenous or oral administration to patients with refractory solid tumours. Methods. Patients were randomized to receive either oral (2.3 mg/m2) or intravenous (1.5 mg/m2) topotecan once daily for 5 days in course 1. Patients who received in course 1 oral topotecan received in course 2 intravenous topotecan on day 1 followed by oral topotecan on days 2 to 5. Patients who received in course 1 intravenous topotecan received in course 2 oral topotecan once daily for 5 days. Plasma pharmacokinetics were performed on day 1 of course 1 (all patients) and course 2 (only patients receiving intravenous topotecan on that day). In course 1, urine and feces were collected for up to 9 days after the first dosage. The amounts of topotecan and N-desmethyl topotecan in plasma, urine and feces were determined by validated high-performance liquid chromatographic assays. Results. A total of 11 patients were enrolled in the study. Nine patients were evaluable for pharmacokinetics. Plasma pharmacokinetics were similar to those previously reported. The principal route of excretion was the urine, with approximately 49% of the intravenously administered topotecan dose and 20% of the oral dose collected in the urine as parent drug. Approximately 18% and 33% of the intravenous and oral dose, respectively, were recovered unchanged in the feces. Only small amounts of N-desmethyl topotecan were found in the excreta. Conclusions. Fecal and urinary excretion of unchanged topotecan were the major routes of topotecan elimination. Approximately 28% of the intravenous dose and 43% of the oral dose of topotecan were unaccounted for and eliminated through other routes.

Intravenous administration of paclitaxel is hindered by poor water solubility of the drug. Currently, paclitaxel is dissolved in a mixture of ethanol and Cremophor EL; however, this formulation (Taxol) is associated with significant side effects, which are considered to be related to the pharmaceutical vehicle. A new polymer-conjugated derivative of paclitaxel, PNU166945, was investigated in a dose-finding phase I study to document toxicity and pharmacokinetics. A clinical phase I study was initiated in patients with refractory solid tumors. PNU16645 was administered as a 1-h infusion every 3 weeks at a starting dose of 80 mg/m(2), as paclitaxel equivalents. Pharmacokinetics of polymer-bound and released paclitaxel were determined during the first course. Twelve patients in total were enrolled in the study. The highest dose level was 196 mg/m(2), at which we did not observe any dose-limiting toxicities. Hematologic toxicity of PNU166945 was mild and dose independent. One patient developed a grade 3 neurotoxicity. A partial response was observed in one patient with advanced breast cancer. PNU166945 displayed a linear pharmacokinetic behavior for the bound fraction as well as for released paclitaxel. The study was discontinued prematurely due to severe neurotoxicity observed in additional rat studies. The presented phase I study with PNU166945, a water-soluble polymeric drug conjugate of paclitaxel, shows an alteration in pharmacokinetic behavior when paclitaxel is administered as a polymer-bound drug. Consequently, the safety profile may differ significantly from standard paclitaxel.

PURPOSE: To evaluate the feasibility of administering irinotecan as a continuous intravenous infusion for 14 to 21 days. PATIENTS AND METHODS: Patients with solid tumors refractory to standard therapy received continuous infusions of irinotecan by means of an ambulatory infusion pump. The starting dosage was 12.5 mg/m2/d for 14 days every 3 weeks. After identification of the maximum-tolerated dose for the 14-day infusion schedule, the protocol was amended to prolong the infusion duration to 17 and 21 days. Pharmacokinetics of irinotecan and SN-38 and its glucuronide were determined using high-performance liquid chromatography and noncompartmental modeling. RESULTS: Thirty-three patients received 85+ courses. At the first dose level (12.5 mg/m2/d), cumulative grade 3 or 4 diarrhea and grade 3 or 4 neutropenia occurred in three of five patients. At a dosage of 10 mg/m2/d, 14-day administration resulted in grade 4 diarrhea in two of six patients and one episode of grade 4 vomiting occurred, whereas with 17-day administration, one episode of grade 3 nausea and two episodes of grade 3 or 4 diarrhea were observed in six patients. Increasing the number of days of infusion to 21 days was not feasible because of cumulative diarrhea. Hematologic toxicity was rare. The mean metabolic SN-38 area under the curve/irinotecan area under the curve ratio was 16% ± 6% compared with 3% to 5% after short infusion schedules involving therapeutic dosages. Partial responses were observed in two patients with extraovarian and colorectal cancer. CONCLUSION: The recommended dosage is 10 mg/m2/d for 14 days, repeated every 3 weeks. Enhanced metabolism of irinotecan to SN-38 may explain in part the low recommended dose for this schedule.

Aim: To investigate the pharmacokinetics of paclitaxel (Paxene TM ) administered to patients with advanced breast or ovarian cancer and to document safety and anti-tumour activity in this study population. Patients and methods: Patients with advanced breast or ovarian cancer were accrued to two clinical studies. Paclitaxel (Paxene TM ) was administered as a 3-h 175 mg m −2 or as a 96-h 140 mg m −2 (105 mg m −2 in the presence of liver metastases) infusion. Patients not responding to the 3-h schedule were permitted to cross-over to the 96-h schedule. The data were compared to those of five patients who were previously treated with paclitaxel administered as Taxol ® (140 mg m −2 96-h infusion) at our Institute. Results: Fourteen patients with breast cancer and five ovarian cancer patients were entered into this study. Seven patients received the 3-h regimen, and 12 were assigned to the 96-h schedule. Five patients originally treated with the 3-h schedule, crossed over to the 96-h arm. For the 3-h 175 mg m −2 dose, the area under the plasma concentration vs time curve (AUC) was (mean±SD) 16.9±4.8 h·μmol·l −1 , whereas the AUCs were 5.5±1.2 and 4.3±0.9 h·μmol·l −1 for the 96-h 140 mg m −2 and 105 mg m −2 doses, respectively. The clearance of paclitaxel was independent of the dose in the 96-h group, indicating linear pharmacokinetics. Pharmacokinetics of Paxene TM (96-h 140 mg m −2 ) were not significantly different from the kinetics after Taxol ® (96-h 140 mg m −2 ) administration.

The antitumor activity of zeniplatin, a third-generation, water-soluble platinum compound that has shown broad preclinical antitumor activity and no significant nephrotoxicity in phase I trials, was tested in patients with advanced malignant melanoma and advanced renal cancer. Patients who had not previously been treated, except with local limb perfusion and immunotherapy, were given zeniplatin as bolus injections at 125 mg/m2 every 3 weeks. The main hematological toxicity was leukopenia (7/30 patients, WHO grade > or = 3) and the main nonhematological toxicity was nausea and vomiting (21/30 patients, WHO grade > or = 2). Serious nephrotoxicity was observed early in the renal cancer study and, later, also in the melanoma study. Hyperhydration did not prevent the nephrotoxicity, and the studies were stopped after 6 renal cancer patients and 24 malignant melanoma patients had been included. Zeniplatin gave objective responses in 3 of the 21 evaluable malignant melanoma patients [2 complete responses (CRs) in patients with lymph-node metastases lasted 5 and 14 months, respectively; 1 partial response (PR) in a patient with lymph-node and liver metastases lasted 6 months]. In the renal cancer study, only four patients were evaluable for response and none responded. The results show that zeniplatin has some activity (14%) in patients with advanced malignant melanoma, but no conclusion can be drawn regarding the activity of zeniplatin in renal cancer as the number of patients was too low. The main toxicities were leukopenia and nausea and vomiting. Unexpected and serious nephrotoxicity was observed, and for this reason the studies were terminated before the planned number of patients had been included. A possible explanation for the nephrotoxicity may be drug interactions, but no firm conclusion can yet be drawn.

Topotecan (Hycamtin), a semisynthetic water-soluble derivative of camptothecin, is a potent inhibitor of DNA topoisomerase I in vitro and has demonstrated encouraging antitumour activity in a wide variety of tumours, including ovarian cancer and small cell lung cancer. Now approved in the US, topotecan has completed single-agent phase I testing; phase II/III trials are ongoing. Under physiological conditions the lactone moiety of topotecan undergoes a rapid and reversible pH-dependent conversion to a carboxylated open-ring form, which lacks topoisomerase I inhibiting activity. At equilibrium at pH 7.4 the open-ring form predominates. Topotecan is stable in infusion fluids in the presence of tartaric acid (pH < 4.0), but is unstable in plasma, requiring immediate deproteinisation with cold methanol after blood sampling and storage of the extract at -30 degrees C to preserve the lactone form. Topotecan has been administered in phase I trials in several infusion schedules ranging from 30 minutes to 21 days. The plasma decay of topotecan concentrations usually fits a 2-compartment model. Rapid hydrolysis of topotecan lactone results in plasma carboxylate levels exceeding lactone levels as early as 45 minutes after the start of a 30-minute infusion. The peak plasma concentrations and the area under the plasma concentration-versus-time curves (AUC) show linear relationship with increasing dosages. No evidence of drug accumulation is seen with daily 30-minute infusions for 5 consecutive days. Topotecan lactone is widely distributed into the peripheral space, with a mean volume of distribution (Vd) at steady-state of 75 L/m2. The mean total body clearance of the lactone form is 30 L/h/m2, with a mean elimination half-life (t1/2 beta) of 3 hours; renal clearance accounts for approximately 40% of the administered dose with a large interindividual variability. The oral bioavailablity of topotecan is approximately 35%. The low bioavailability may be caused by hydrolysis of topotecan lactone in the gut, yielding substantial amounts of the open-ring form, which is poorly absorbed. Renal dysfunction may decrease topotecan plasma clearance. Creatinine clearance is significantly, but poorly, correlated with topotecan clearance. Hepatic impairment does not influence topotecan disposition. Indices of systemic exposure (steady-state concentrations and AUC) are correlated with the extent of myelotoxicity. Sigmoidal functions adequately describe the relationships between systemic exposure and the percentage decrease in neutrophils.

OBJECTIVE: To report a hypersensitivity reaction to etoposide occurring in a patient after 2 months of drug therapy. CASE SUMMARY: a 20-year-old man with a diagnosis of testicular carcinoma was treated with bleomycin, etoposide, and cisplatin (BEP regimen). After dose 20 of etoposide, an exanthema was noted, which was attributed to etoposide. The patient had received 19 doses of etoposide during the previous 2 months without any sign of an allergic reaction. Rechallenging the patient with etoposide from another batch resulted in recurrence of the exanthema. DISCUSSION: Both etoposide and its excipient (polysorbate 80) are suspected of causing hypersensitivity reactions. Although the exact mechanism of the hypersensitivity reaction is not known, it is believed to be of nonimmunogenic origin. CONCLUSIONS: With a lower rate of infusion of etoposide and/or by premedication with antihistamines and/or corticosteroids, hypersensitivity reactions to etoposide might be prevented in patients with a history of hypersensitivity to this drug.

Anaxirone, a rationally synthesised triepoxide derivative, was given to 46 patients with metastatic colorectal cancer. Good risk patients received 800 mg/m(2) as a rapid intravenous injection every 4 weeks, whereas poor risk patients received 650 mg/m(2). Of 46 patients, 45 were evaulable for toxicity and 42 for efficacy analysis. There were 37/45 patients with poor risk, showing no difference in toxicity as compared to good risk patients. The major toxic effect was myelosuppression with 34% of all patients experiencing grade 3 or 4 leucopenia; thrombocytopenia was less frequent. Locoregional phlebitis occurred in 66% of the patients. There was no objective tumour response to anaxirone in 42 evaluable patients. Only 4 patients achieved stabilisation of the disease lasting maximally up to 248 days. Anaxirone is inactive in metastatic colorectal cancer.

OBJECTIVE: A case in which a possible cisplatin interference with lithium pharmacokinetics is evaluated. DATA SYNTHESIS: A 36–year-old woman with disseminated cervical cancer and multiple metastatic lesions in both kidneys was being treated with five courses of bleomycin, vindesine, mitomycin C, and cisplatin. The patient had also been taking lithium carbonate for the management of a manic-depressive disorder. Serum and urinary lithium concentrations were measured daily during the first course of chemotherapy and on a periodic basis during and between the consecutive courses. Lithium concentrations remained within the therapeutic range during the first course and increased later in association with deterioration of the patient's renal function secondary to progressive disease in both kidneys. This required dose adjustments of lithium. CONCLUSIONS: Lithium therapy should be guided by serial serum concentrations in such patients.

Spiroplatin was investigated in a multicentre phase I study. 67 patients with advanced solid tumours received 151 cycles either by short-term or prolonged infusion, repeated every 3 weeks, at 2.5–40 mg/m 2 . Myelosuppression and renal toxicity were dose-limiting. Proteinuria, which was dose- and schedule-dependent, indicated glomerular and tubular damage. The maximum tolerated doses (MTD) for poor-risk and good-risk patients were 35 and 40 mg/m 2 , respectively. The area under the curve (AUC) at the MTD did not correspond with the AUC at the LD 10 in mice with ratios of 0.3 for free platinum and 2.6 for total platinum; these were not suitable for predicting the MTD. 1 complete response was observed in a patient with breast cancer and lung metastases and 1 partial response in a patient with adenocarcinoma of the lung. The recommended dose for phase II studies was 30 mg/m 2 by 4 h infusion every 3 weeks.

In a phase I study mitozolomide was given on a once daily for 5 days schedule to 18 patients with a variety of malignancies. Non-hematological toxicity was negligible. Significant myelosuppression occurred at a total dose as low as 62.5 mg/m2 per course. In particular, thrombocytopenia, which was unpredictable, precluded dose increments beyond 15 mg/m2 per day (or a total of 75 mg/m2). Antitumor effects were not observed. The 5-day schedule of mitozolomide appears to have no advantage over administration once every 3–4 weeks, and may even be more dangerous than the latter schedule.

Objective. Extravasations of anticancer agents may give serious complications and specific therapy might be needed. Topotecan is a new cytotoxic drug and is used in many clinical studies. In our clinic two extravasations of topotecan occurred, and the clinical consequences are discussed. Clinical Features. The extravasations oc curred in two patients who were receiving topo tecan intravenously because of ovarian carcinoma stage III. The patients experienced some discom fort caused by the expansion of soft tissue. How ever, no serious complications were observed. Case Progress and Outcome. Both patients received all further courses of topotecan without any negative effects. Conclusion. In conclusion, besides stopping the injection, trying to aspirate the fluid, keeping the arm high, and cooling the swelling, we advise no specific measures to be taken after extravasa tion of topotecan.

5102 Background: Patients (pts) with newly diagnosed advanced ovarian cancer generally receive a taxane in combination with a platinum agent. However, pts refractory to this therapy have few treatm...

PURPOSE: To determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLT), and pharmacokinetics of 9-aminocamptothecin (9-AC) in a colloidal dispersion (CD) formulation administered as a 30-minute intravenous (IV) infusion over 5 consecutive days every 3 weeks. PATIENTS AND METHODS: Patients with solid tumors refractory to standard therapy were entered onto the study. The starting dose was 0.4 mg/m2/d. The MTD was assessed on the first cycle and was defined as the dose at which ≥ two of three patients or ≥ two of six patients experience DLT. Pharmacokinetic measurements were performed on days 1 and 5 of the first cycle and on day 4 of subsequent cycles using high-performance liquid chromatography. RESULTS: Thirty-one patients received 104+ treatment courses at seven dose levels. The DLT was hematologic. At a dose of 1.3 mg/m2/d, three of six patients experienced grade 3 thrombocytopenia. Grade 4 neutropenia that lasted less than 7 days was observed in four patients. At a dose of 1.1 mg/m2/d, four of nine patients had grade 4 neutropenia of brief duration, which was not dose limiting. Nonhematologic toxicities were relatively mild and included nausea/vomiting, diarrhea, obstipation, mucositis, fatigue, and alopecia. Maximal plasma concentrations and area under the concentration-time curve (AUC) increased linearly with dose, but interpatient variation was wide. Lactone concentrations exceeded 10 nmol/L, the threshold for activity in preclinical tumor models, at all dose levels. Sigmoidal Emax models could be fit to the relationship between AUC and the degree of hematologic toxicity. A partial response was observed in small-cell lung cancer. CONCLUSION: 9-AC CD administered as a 30-minute IV infusion daily times 5 every three weeks is safe and feasible. The recommended phase II dose is 1.1 mg/m2/d.

PURPOSE: To evaluate the feasibility of administering topotecan in combination with paclitaxel and cisplatin without and with granulocyte colony-stimulating factor (G-CSF) support as first-line chemotherapy in women with incompletely resected stage III and stage IV ovarian carcinoma. PATIENTS AND METHODS: Starting doses were paclitaxel 110 mg/m2 administered over 24 hours (day 1), followed by cisplatin 50 mg/m2 over 3 hours (day 2) and topotecan 0.3 mg/m2/d over 30 minutes for 5 consecutive days (days 2 to 6). Treatment was repeated every 3 weeks. After encountering dose-limiting toxicities (DLTs) without G-CSF support, the maximum-tolerated dose was defined as 5 μg/kg of G-CSF subcutaneously starting on day 6. RESULTS: Twenty-one patients received a total of 116 courses at four different dose levels. The DLT was neutropenia. At the first dose level, all six patients experienced grade 4 myelosuppression. G-CSF support permitted further dose escalation of cisplatin and topotecan. Nonhematologic toxicities, primarily fatigue, nausea/vomiting, and neurosensory neuropathy, were observed but were generally mild. Of 15 patients assessable for response, nine had a complete response, four achieved a partial response, and two had stable disease. CONCLUSION: Neutropenia was the DLT of this combination of paclitaxel, cisplatin, and topotecan. The recommended phase II dose is paclitaxel 110 mg/m2 (day 1), followed by cisplatin 75 mg/m2 (day 2) and topotecan 0.3 mg/m2/d (days 2 to 6) with G-CSF support repeated every 3 weeks.

Menogaril, a new semisynthetic anthracycline antibiotic, was administered to 35 patients with advanced colorectal cancer. The drug was infused over 2 hr at a dose of 160 mg/sqm or 200 mg/sqm repeated every 4 weeks. Twenty-seven patients were evaluable for response and no objective responses were achieved. Myelosuppression, only leukopenia, was usually of mild-moderate degree and occurred in 63% of the patients. Twenty-seven percent of the patients experienced severe leukopenia. Local erythema and phlebitis were frequently observed and were severe in 13% of the patients. Nausea/vomiting (66%) and alopecia (50%) were. of mild-moderate degree. This study suggests that menogaril at these doses and schedule had no activity in advanced colorectal cancer.

A total of 66 patients with advanced renal cell cancer received a combination of recombinant interferon alpha-2a (18 times 10(6) units subcutaneously 3 times weekly) and vinblastine (0.1 mg. per kg. intravenously every 3 weeks). Four patients were ineligible and 6 were inevaluable for response but evaluable for toxicity. There were no complete and 9 partial responses among the 56 evaluable patients, for a response rate of 16 per cent. Median duration of response was 26 weeks, with a range of 8 to 50 weeks. Responses were observed predominantly in patients with lung and soft tissue metastases. Patients who had undergone nephrectomy did not show a better response rate than those who had not. Almost all patients had a flu-like syndrome, fatigue and anorexia. Other side effects included leukopenia, nausea, vomiting, liver function disturbances and neurotoxicity. Most of the side effects were World Health Organization grade 1 or 2; no grade 4 toxicity was observed. Antibodies against interferon developed in 6 patients during the course of treatment. However, there was no relationship between the appearance of antibodies and disease progression. The combination of recombinant interferon alpha-2a and vinblastine has modest but definite activity in patients with advanced renal cell carcinoma, although the role of vinblastine is unclear.

In the early stages of this phase I study the tolerance of carboplatin intraperitoneally was good. Pharmacokinetic profiles suggest a possible therapeutic advantage for giving the drug intraperitoneally for the treatment of tumour nodules situated in the peritoneum. The extent of penetration of carboplatin through tumour nodules has not yet been assessed but tumour nodules are being processed for nuclear activation analysis.

Three cases of acute leukemia are reported following aggressive therapy for inoperable germ cell tumors. Two patients were treated by radiation plus cytotoxic chemotherapy and the third received only drugs. The time between onset of these therapies to death from leukemia was 4, 17 and 61 months.

INTRODUCTION COMPARATIVE preclinical data suggested that menogaril, a semisynthetic analogue of nogalamycin, had a better therapeutic index than doxorubicin, since menogaril was 5-10 times less active in murine tumours but 15 times less active in inducing cardiotoxicity in the chronic rabbit model [ 11. When menogaril was given as a 2 h infusion every 4 weeks, leukopenia was the dose-limiting toxicity [2]; erythema and phlebitis, which were dosedependent and occurred at the site ofinjection, were the other major manifestations of toxicity. A single intermittent schedule for menogaril was chosen by the Early Clinical Trials Group for a programme of disease-orientated Phase II studies. The present report focuses on the results achieved in patients with advanced ovarian carcinoma.