A phase I/II study of vinorelbine, doxorubicin, and methotrexate with leucovorin rescue as first-line treatment for metastatic breast cancer

Purpose: This study was performed to determine the maximum tolerated dose (MTD) and toxicity of vinorelbine when used in combination with doxorubicin and methotrexate with leucovorin rescue in women with metastatic breast cancer. Methods: Enrolled in the study were 23 women with metastatic breast cancer who had not received prior chemotherapy for metastatic disease. Patients treated at the first dose level received vinorelbine 20 mg/m² on day 1, doxorubicin 40 mg/m² on day 1, methotrexate 100 mg/m² on day 1 and leucovorin 20 mg orally every 6 h for six doses beginning on day 2. Treatment was repeated every 21 days. The vinorelbine dose was escalated by 5 mg/m² for patients treated at subsequent dose levels. The MTD was defined as the dose level at which fewer than one-third of patients enrolled experienced dose-limiting toxicity (DLT). When the MTD of vinorelbine had been determined, the doxorubicin dose was then escalated by 10 mg/m² with the vinorelbine dose held at its MTD. Results: total of 98 courses of treatment (median of 4 per patient, range 2–8) were administered. The MTD of this regimen was found to be vinorelbine 25 mg/m², doxorubicin 40 mg/m², and methotrexate 100 mg/m² with leucovorin rescue. At higher doses of vinorelbine, neutropenia, fatigue, arm pain, malaise, nausea and vomiting were dose-limiting. Higher doses of doxorubicin resulted in universal dose limiting neutropenia, and frequent nonhematologic DLT consisting of arm pain, malaise, stomatitis, nausea and vomiting. Amongst the 20 patients with measurable disease, there were 3 complete responses (15%, 95% confidence interval 3%–38%), 5 partial responses (25%, 95% confidence interval 9%–49%) and an overall response rate of 40% (95% confidence interval 19%–64%). The median survival was estimated to be 25 months from the start of chemotherapy. Conclusions: Vinorelbine at 25 mg/m² can be safely administered with doxorubicin at 40 mg/m² and methotrexate at 100 mg/m² with leucovorin rescue. Response rates observed with this regimen suggest that this combination of chemotherapeutic agents may not be more effective than the combination of vinorelbine and doxorubicin. Received: 27 April 1998 / Accepted: 17 September 1998     

A phase I trial of AUC-directed carboplatin with infusional doxorubicin and ifosfamide plus G-CSF in patients with advanced gynecologic malignancies

The effect of the addition of G-CSF to carboplatin, ifosfamide and doxorubicin (CIA) at the maximally tolerated dose (MTD) was studied in a phase I clinical trial. Nine patients with incurable solid tumors were treated: six endometrial and epithelial ovarian cancers, one colon cancer with pelvic masses and two unknown primary cancers. The carboplatin dose was calculated using the Calvert formula and administered in a standard 30-min intravenous infusion. The initial carboplatin dose was AUC 4.0 mg/ml per min. Fixed doses of ifosfamide (1.25 g/m² per day), mesna (1.0 g/m² per day, and doxorubicin (15 mg/m² per day) were combined and given as a 4-day continuous intravenous infusion in an attempt to decrease nonhematologic toxicity. The dose-limiting toxicity of CIA was myelosuppression, mainly neutropenia and thrombocytopenia. Nonhematologic toxicities were hemorrhagic cystitis, weakness, fatigue, and nausea and vomiting. The MTD for CIA was established at the first dose level of carboplatin (4.0 mg/ml per min). Following this, G-CSF was added to the regimen in an unsuccessful effort to escalate the carboplatin dose. Free and total carboplatin pharmacokinetics were determined using flameless atomic absorption spectroscopy. There was one complete response and one partial response among eight evaluable patients. Both responding patients had advanced ovarian cancer. We conclude that carboplatin dose intensification beyond an AUC of 4.0 mg/ml per min is not made feasible by the addition of G-CSF to infusional doxorubicin and ifosfamide in patients with advanced gynecologic cancer. Received: 22 December 1999 / Accepted: 28 April 2000     

Initial clinical trial and pharmacokinetics of ThymitaqTM (AG337) by 10-day continuous infusion in patients with advanced solid tumors

Purpose: To establish the maximum tolerated dose (MTD), dose-limiting and other major toxicities and the major pharmacokinetic parameters of a 10-day infusion of the nonclassical antifolate Thymitaq^TM. Methods: The drug was given by 10-day infusion via a portable pump. The starting dose was 286 mg/m² per day with escalation to 572 and 716 mg/m² per day. Thymitaq in plasma was assayed by a validated isocratic reverse-phase HPLC assay with detection at 273 nm. Results: The dose of 716 mg/m² per day × 10 was considered too high as none of three patients completed a 10-day infusion and two of three developed grade IV myelotoxicity. At 572 mg/m² per day three of four patients completed a 10-day infusion. Dose-limiting myelosuppression was seen in one of four but owing to a high incidence of thrombotic phenomena, no further patients were added. Conclusion: Continuous 10-day infusions of Thymitaq should be limited to low doses until further studies can be done. Received: 4 March 1997 / Accepted: 14 July 1997     

Clinical and pharmacokinetic studies of high-dose levamisole in combination with 5-fluorouracil in patients with advanced cancer

Purpose: To determine the maximum tolerable dose (MTD) and activity of levamisole administered concurrently with 5-fluorouracil (5-FU) in a standard 5-day course. To determine the pharmacokinetics of levamisole during the course of treatment. Patients and methods: Levamisole was administered to 38 patients orally three times a day for 5 days concurrently with a course of 5-FU administered daily by rapid intravenous injection for 5 days. Toxicity was evaluated in 20 patients who received escalating doses of levamisole. The activity of the combination was evaluated in 18 patients who received levamisole at the MTD with 5-FU. The pharmacokinetics of levamisole were characterized in ten patients at the MTD level. Results: Intractable vomiting, confusion and vertigo were the major dose-limiting toxicities. The MTD of oral levamisole was 100 mg/m² administered three times a day concurrently with 450 mg/m² per day intravenous 5-FU for 5 consecutive days. Partial responses lasting 5 and 11 months were observed in 2/18 patients with measurable disease at the MTD. Peak plasma concentrations of 1 μg/ml (range 0.6–1.3 μg/ml) were achieved 90 min (range 60–360 min) after an oral dose of 100 mg/m² levamisole with a 3.5-fold accumulation noted following 4 days of administration. Peak plasma concentrations of p-hydroxylevamisole were about 5% of parent drug. Little parent drug (2–5%) was detected in urine. Conclusions: Levamisole may be administered safely with 5-FU at doses which are up to four to five times greater than those presently given in conventional regimens. The recommended dose of levamisole combined with 5-FU for future research protocols is 75 mg/m² t.i.d for 5 days. Received: 31 December 1996 / Accepted: 11 September 1997     

Phase I studies of fluorouracil, doxorubicin and vinorelbine without (FAN) and with (SUPERFAN) folinic acid in patients with advanced breast cancer

Purpose: The Breast Cancer Site Group of the National Cancer Institute of Canada – Clinical Trials Group (NCIC-CTG) undertook two parallel phase I studies to determine the maximum tolerated dose (MTD) and recommended phase II dose of vinorelbine in combination with doxorubicin and fluorouracil (with or without folinic acid) in metastatic breast cancer. Methods: Cohorts of five patients were to receive: (a) fluorouracil 500 mg/m² and doxorubicin 50 mg/m² on day 1 only and escalating doses of vinorelbine (15, 20, 25, 30 mg/m²) on days 1, 8 and 15 every 3 weeks (FAN regimen), or (b) fluorouracil 340 mg/m² and folinic acid 200 mg/m² on days 1, 2, 3, 4 and 5, doxorubicin 40 mg/m² on day 1 only and escalating doses of vinorelbine (15, 20, 25, 30 mg/m²) on day 1 and again on day 5 every 4 weeks (SUPERFAN regimen). Eligibility included measurable or evaluable metastatic breast cancer and having received neither previous chemotherapy for metastatic disease nor anthracycline-containing adjuvant therapy. Results: Of 26 and 12 patients enrolled in the FAN and SUPERFAN regimens, 26 and 12 were evaluable for toxicity and 21 and 9 for response, respectively. Median ages were 60.3 years (41–71 years) and 64.2 years (51–73 years). Both regimens required amendment after the first cohort with an original day-15 vinorelbine dose omitted from the FAN regimen and more prolonged nadir granulocyte counts allowed. Myelosuppression was dose limiting. MTDs in the FAN and SUPERFAN regimens were vinorelbine 25 mg/m² and 20 mg/m². Other toxicities included mucositis, septicemia and febrile neutropenia. Peripheral neuropathy and constipation were mild. Of the 21 FAN patients evaluable for response, 3 (14%) had complete responses and 7 (33%) had partial responses, for an overall response rate of 48%; 9 (43%) had stable disease and 2 (9%) had progressive disease as their best response. Of the nine SUPERFAN patients evaluable for response, none had a complete response. There were two (22%) with partial responses, and six (67%) had stable disease and one (11%) had progressive disease as their best response. Conclusions: The SUPERFAN regimen was too toxic to pursue even at the lowest dose. The recommended phase II starting dose for the FAN regimen was vinorelbine 20 mg/m². Although these were phase I studies response rates in evaluable patients were less than expected and toxicity did not allow the use of as much vinorelbine in the combinations as had been anticipated. The limited response data from our study would imply that combining vinorelbine with more toxic agents may not enhance response rates and may defeat the advantage of tolerability, especially in elderly patients. Received: 7 December 1996 / Accepted: 8 May 1997     

A phase I evaluation of multitargeted antifolate (MTA, LY231514), administered every 21 days, utilizing the modified continual reassessment method for dose escalation

Purpose: To determine toxicities, maximally tolerated dose (MTD), pharmacokinetic profile, and potential antitumor activity of MTA, a novel antifolate compound which inhibits the enzymes thymidylate synthase (TS), glycinamide ribonucleotide formyltransferase (GARFT), and dihydrofolate reductase (DHFR). Methods: Patients with advanced solid tumors were given MTA intravenously over 10 min every 21 days. Dose escalation was based on the modified continual reassessment method (MCRM), with one patient treated at each minimally toxic dose level. Pharmacokinetic studies were performed in all patients. Results: A total of 37 patients (27 males, 10 females, median age 59 years, median performance status 90%) were treated with 132 courses at nine dose levels, ranging from 50 to 700 mg/m². The MTD of MTA was 600 mg/m², with neutropenia and thrombocytopenia, and cumulative fatigue as the dose-limiting toxicities. Hematologic toxicity correlated with renal function and mild reversible renal dysfunction was observed in multiple patients. Other nonhematologic toxicities observed included mild to moderate fatigue, anorexia, nausea, diarrhea, mucositis, rash, and reversible hepatic transaminase elevations. Three patients expired due to drug-related complications. Pharmacokinetic analysis during the first course of treatment at the 600 mg/m² dose level demonstrated a mean harmonic half-life, maximum plasma concentration (Cpmax), clearance (CL), area under the curve (AUC), and apparent volume of distribution at steady state (Vdss) of 3.08 h, 137 μg/ml, 40.0 ml/min per m², 266 μg · h/ml, and 7.0 l/m², respectively. An average of 78% of the compound was excreted unchanged in the urine. Partial responses were achieved in two patients with advanced pancreatic cancer and in two patients with advanced colorectal cancer. Minor responses were obtained in six patients with advanced colorectal cancer. Conclusions: The MTD and dose for phase II clinical trials of MTA when administered intravenously over 10 min every 21 days was 600 mg/m². MTA is a promising new anticancer agent. Received: 20 October 1998 / Accepted: 30 March 1999     

A phase I clinical and pharmacokinetic study of the dolastatin analogue cemadotin administered as a 5-day continuous intravenous infusion

Purpose: The dolastatins are a class of naturally occurring cytotoxic peptides which function by inhibiting microtubule assembly and tubulin polymerization. Cemadotin is a synthetic analogue of dolastatin 15 with potent antiproliferative and preclinical antitumor activity. This report describes a phase I study to evaluate the administration of cemadotin to adult cancer patients by a 5-day continuous intravenous (CIV) infusion. Methods: All patients had histologically confirmed refractory solid tumors. The dose was escalated from an initial level of 2.5 mg/m² (0.5 mg/m² daily) according to a modified Fibonacci algorithm. A minimum of three patients was evaluated at each dose level until the maximum tolerated dose (MTD) was established. Treatment was repeated every 21 days until patients were removed from the study due to toxicity or disease progression. Drug-related toxicities were evaluated and graded by the U.S. National Cancer Institute's Common Toxicity Criteria. A radioimmunoassay (RIA) that detected both the parent drug and its metabolites with an intact N-terminal region of the molecule was used for pharmacokinetic studies. Results: Twenty heavily pretreated patients received a total of 40 courses of cemadotin over five dose levels ranging from 2.5 to 17.5 mg/m². Reversible dose-related neutropenia was the principal dose-limiting toxicity and 12.5 mg/m² was established as the MTD. Nonhematologic toxicities attributed to the drug were moderate, and there was no evidence of the cardiovascular toxicity noted in the prior phase I studies of cemadotin given IV as a 5-min injection or 24-h infusion. There were no objective antitumor responses. Time courses of the cemadotin RIA equivalent concentration in whole blood were defined in 14 patients during the first cycle of therapy. The RIA-detectable species exhibited apparent first-order pharmacokinetics across the entire range of doses. The mean ± SD of the observed steady-state blood concentration at the 12.5 mg/m² MTD was 282 ± 7 nM (n=3). Blood levels decayed monoexponentially following the end of the infusion, with a mean half-life of 13.2 ± 4.3 h (n=14) in all patients. Mean values (n=14) of the total blood clearance and apparent volume of distribution at steady state were 0.52 ± 0.09 l/h/m² and 9.9 ± 3.3 l/m², respectively. Conclusions: The cardiotoxic effects of cemadotin were completely avoided by administering it as a 120-h CIV infusion. Thus, cardiovascular toxicity appears to be associated with the magnitude of the peak blood levels of the parent drug or its metabolites, whereas myelotoxicity is related to the duration of time that blood levels exceed a threshold concentration. Nevertheless, the data acquired during the extensive clinical experience with cemadotin requires careful examination to assess whether advancing this compound into disease-oriented efficacy studies is merited. Received: 8 November 1999 / Accepted: 28 April 2000     

Pharmacokinetic analysis of high-dose toremifene in combination with doxorubicin

Purpose: Toremifene (Fareston) is an orally administered triphenylethylene derivative with chemosensitizing activity in vitro in estrogen receptor-negative multidrug-resistant human breast cancer cells. The purpose of this study was to evaluate the effects of high-dose toremifene (600 mg/day for 5 days) on the plasma pharmacokinetics of doxorubicin in humans. The 600-mg dose had been previously established as the maximum tolerated dose in a phase I study of 35 patients. Methods: Doxorubicin was administered as an intravenous (i.v.) bolus over 15 min at a dose of 60 mg/m² to 11 patients in the absence of toremifene pretreatment to establish baseline doxorubicin pharmacokinetics. Six of these patients received 600 mg/day toremifene for 5 days 4 weeks later, followed by an i.v. bolus dose of doxorubicin (60 mg/m²) on day 5. During toremifene pretreatment, blood specimens (5 ml) were drawn at 0, 2, 4, and 24 h after dosing to assess peak levels. Following doxorubicin administration in each cycle, blood specimens were collected over a 72-h period for determination of the terminal half-life of elimination. Plasma concentrations of doxorubicin and toremifene were assessed by high-performance liquid chromatography (HPLC). Cumulative linear areas under the time-concentration curve (AUC) for doxorubicin were calculated using a noncompartmental model. Results: Prior to toremifene dosing, baseline doxorubicin pharmacokinetic studies showed an average terminal half-life of elimination of 40.04 ± 7.86 h in 4 patients, and an average AUC of 135 600 ± 67 600 μg/ml · h in 11 patients. In 4 of the patients receiving 600 mg/day toremifene for 5 days, the average terminal half-life of elimination was 38.12 ± 7.81 h, and the average AUC was 141 900 ± 62 900 μg/ml · h in 6 patients, i.e. a slight increase of 4.6%. No statistically significant change in the doxorubicin elimination kinetics with or without toremifene therapy was observed. Conclusions: Toremifene does not appear to interfere with the elimination kinetics of doxorubicin. Received: 1 July 1997 / Accepted: 16 December 1997     

Phase I/II study of cisplatin, ifosfamide and irinotecan with rhG-CSF support in patients with stage IIIB and IV non-small-cell lung cancer

Purpose: We conducted a phase I/II study in previously untreated patients with stage IIIB or IV non-small-cell lung cancer (NSCLC) to: (1) determine the maximum tolerated dose (MTD) of cisplatin combined with a fixed schedule of ifosfamide and irinotecan with rhG-CSF support; and (2) to determine the overall response rate and median survival of patients entered on this study. Methods: Ifosfamide (1.5 g/m²) and irinotecan (60 mg/m²) were administered at fixed doses on days 1–4 and on days 1, 8 and 15, respectively. Cisplatin was given on day 1 at 60 mg/m² and was increased in 10-mg/m² increments. This regimen was repeated every 4 weeks. rhG-CSF (nartograstim) was administered subcutaneously at a dose of 1 μg/kg on days 5–18 except on the day of irinotecan treatment. Results: Between June 1995 and April 1998, 46 patients were registered onto this phase I/II study. The MTD of cisplatin was defined according to toxicity and the dose during three courses was increased. Since at the 80 mg/m² dose level more than one-third of the patients were treated with dose modification, the dose of 70 mg/m² was recommended for phase II study. The dose-limiting toxicity was leukopenia. The overall response rate was 62.2% (95% CI 48.0–76.4%), the median response duration was 144 days, and the median survival time was 393 days. Conclusion: For phase II study, we recommend doses of cisplatin 70 mg/m² on day 1 combined with ifosfamide and irinotecan with rhG-CSF support. Both the response rate and preliminary survival data in this study suggest a high degree of activity of this combination in previously untreated NSCLC. Received: 29 April 1999 / Accepted: 15 September 1999     

Phase I study of docetaxel and topotecan in patients with solid tumors

Purpose: Both docetaxel (DOC), a promoter and stabilizer of microtubule assembly, and topotecan (TOPO), a topoisomerase I inhibitor, have shown antitumor activity in a variety of solid tumor malignancies. This phase I trial was conducted to determine the overall and dose-limiting toxicities (DLT), the maximum tolerated dose (MTD) and the pharmacokinetics of the combination of DOC and TOPO in patients with advanced solid tumor malignancies. Methods: DOC was administered first at 60 mg/m² without G-CSF and at 60, 70, and 80 mg/m² with G-CSF by 1-h infusion on day 1 of the odd-numbered cycles (1, 3, 5, etc.) and on day 4 of the even-numbered cycles (2, 4, 6, etc.). TOPO 0.75 mg/m² was administered as a 30-min infusion on days 1, 2, 3 and 4 of each cycle. G-CSF 300 μg was administered subcutaneously (s.c.) on days 5–14. Cycles were repeated every 21 days. All patients were premedicated with dexamethasone 8 mg orally every 12 h for a total of six doses starting on the day before DOC infusion. Results: A total of 22 patients were treated. Six patients were treated in cohort I with DOC and TOPO doses of 60 and 0.75 mg/m², respectively, without G-CSF, and two patients developed DLT (febrile neutropenia). Four patients were treated in cohort II with DOC and TOPO doses of 60 and 0.75 mg/m², respectively, with G-CSF, and no DLT was observed. Four patients were treated in cohort III with DOC and TOPO doses of 80 and 0.75 mg/m², respectively, with G-CSF, and three developed DLT (febrile neutropenia). DOC was then de-escalated to 70 mg/m² and delivered with TOPO 0.75 mg/m² and G-CSF (cohort IV). Eight patients were treated at this dose level, and one DLT (febrile neutropenia) was observed. Two patients developed a severe hypersensitivity reaction shortly after the DOC infusion was started, one in cycle 1 and one in cycle 2. Both patients were removed from the study. Two patients developed severe dyspnea in the presence of progressive pulmonary metastases. Other nonhematological toxicities were mild. One patient with extensively pretreated ovarian carcinoma had a partial response, and eight patients with various solid tumor malignancies had stable disease with a median time to progression of 12 weeks (range 9–18 weeks). Administration of TOPO on days 1–4 and DOC on day 4 resulted in increased neutropenia. Conclusions: DOC 80 mg/m² given first as a 1-h infusion on day 1 with TOPO 0.75 mg/m² given as a 0.5-h infusion on days 1, 2, 3 and 4 with G-CSF was considered the MTD. The recommended phase II dose for DOC given on day 1 is 70 mg/m² with TOPO 0.75 mg/m² given on days 1, 2, 3 and 4 every 21 days with G-CSF 300 μg s.c. on days 5–14. The alternative schedule with DOC given on day 4 and TOPO on days 1–4 is not recommended. Received: 18 February 2000 / Accepted: 19 July 2000     

In vivo measurement of myocardial oxidative metabolism and blood flow does not show changes in cancer patients undergoing doxorubicin therapy

Purpose: The aim was to investigate in patients receiving doxorubicin whether any alteration in myocardial oxidative metabolism or blood flow as assessed by positron emission tomography (PET) could be observed either after the first dose of the drug, or during its chronic administration. Methods: Six female non-heart-failure cancer patients treated with doxorubicin were included in a longitudinal study. Resting radionuclide cineangiography and PET scanning with carbon-11 acetate were performed the day before the initiation of doxorubicin treatment at a dosage of 50 mg/m² every 3 weeks, and 3 weeks after the cumulative administration of 300 mg/m² (chronic toxicity). In addition, PET was performed 24 h after the first administration of doxorubicin (evaluation of acute toxicity). Myocardial oxidative metabolism and blood flow were assessed by PET (acute and chronic toxicity), and left ventricular ejection fraction was measured by radionuclide angiography (chronic toxicity). Results: Using PET for both acute and chronic toxicity evaluations, no significant effect of doxorubicin was observed either on the flux through the tricarboxylic acid (TCA) cycle or on myocardial blood flow. However, systolic left ventricular function showed a small but significant impairment after the administration of 300 mg/m² of doxorubicin. Conclusions: Other hypotheses should be explored to better explain the predominant mechanisms of the cardiotoxicity of anthracyclines in humans. Received: 18 August 1999 / Accepted: 3 December 1999     

Dose escalation and pharmacokinetic study of irinotecan in combination with paclitaxel in patients with advanced cancer

Purpose: Based on preclinical data demonstrating synergy between camptothecin analogues and taxanes, we determined the maximum tolerated dose (MTD) of irinotecan that could be given in combination with a fixed dose of paclitaxel of 75 mg/m², when both drugs were delivered on a weekly schedule. The pharmacokinetics of this combination were explored to determine whether the sequence of administration affected the elimination of irinotecan. Methods: For the first cycle patients with advanced cancer were treated with irinotecan given as a 90-min infusion followed immediately by paclitaxel given at a dose of 75 mg/m² over 1 h. The sequence of drug administration was reversed in subsequent cycles for most patients. Chemotherapy was given weekly for 4 weeks, followed by a 2-week rest. In selected patients, plasma concentrations of irinotecan were determined by high-performance liquid chromatography during the first 24 h of cycle 1 and after the first dose of cycle 2 to determine whether the order of drug administration affected the elimination of irinotecan, or the toxicologic effects of the chemotherapy. Results: A total of 53 cycles were delivered to 21 patients. Reversible neutropenia was dose-limiting. Suppression of the other blood cell elements was modest. There was one partial response in a man with a previously treated cholangiocarcinoma that lasted 26 weeks. Prolonged stabilization of disease (6 months or more) was observed in five of the patients (24%). At the recommended dose of irinotecan (50 mg/m²), transfusions of red cells and platelets were not required. The sequence of drug administration produced no significant differences in the pharmacokinetic parameters of irinotecan or SN-38, which were similar to the values reported when irinotecan is administered alone. The most prominent nonhematologic toxicities were mild diarrhea and fatigue. Conclusions: The recommended dose of irinotecan on this schedule is 50 mg/m². The sequence of drug administration affects neither the elimination of irinotecan nor the chemotherapy-related toxicity. This combination is well tolerated and causes minimal clinical side effects. Received: 5 July 1999 / Accepted: 3 February 2000     

Pharmacokinetic behavior of vincristine sulfate following administration of vincristine sulfate liposome injection

The pharmacokinetic behavior of vincristine sulfate (VINC) following administration of vincristine sulfate liposome injection (VSLI), 0.16 mg/ml, as an intravenous infusion over 60 min in 24 of 25 patients enrolled in a phase I clinical study of this drug is described. Plasma samples for determination of the pharmacokinetic behavior of VINC were collected during the infusion at 15, 30 and 60 min as well as at 2, 4, 8, 12, 48 and 72 h postinfusion. Total VINC concentration was determined using a validated high-performance liquid chromatographic (HPLC) assay. Patients receiving doses of 0.5 to 1.5 mg/m² VSLI did not provide useful pharmacokinetic data at late time-points owing to the limit of quantitation of the HPLC assay (28.6 ng/ml). Sufficient concentration-time data were available for seven of the patients receiving doses of VSLI from 2.0 to 2.8 mg/m² for compartmental modelling. A two-compartment open model (PCNONLIN Model 10) was the best fit for the observed VINC plasma data for these patients. The mean maximum observed concentration values were significantly greater for patients receiving VSLI at 2.8 mg/m² (2260 ± 212 ng/ml, n = 2) than for those receiving 2.0 mg/m² and 2.4 mg/m² (891 ± 671 ng/ml, n = 6; 679 ± 634 ng/ml, n = 6, respectively). No significant differences were observed in maximum concentration values between patients at 2.0 mg/m² and those at 2.4 mg/m². A trend towards higher parametric AUC (0 to ∞) values with increasing dose (on a milligram per meter squared basis) was observed but statistical significance was not reached. Comparison of the pharmacokinetic behavior of VSLI observed in this study with nonencapsulated VINC demonstrated that (1) the variability observed for VSLI pharmacokinetic parameters was similar to nonencapsulated VINC, (2) although variability in absolute concentration was observed␣between patients, the behavior of VSLI in individual patients followed a two- rather than a three-compartment open model, and (3) VINC plasma concentrations were significantly greater following administration of VSLI than described for nonencapsulated VINC. Overall, the results for patients treated with VSLI from 2.0 to 2.8 mg/m² suggest that this formulation protects VINC from the early phase of rapid elimination seen with nonencapsulated drug, resulting in significantly elevated VINC plasma concentrations over extended periods of time. Received: 19 November 1996 / Accepted: 25 July 1997     

Phase I trial with weekly EO9, a novel bioreductive alkylating indoloquinone, by the EORTC Early Clinical Study Group (ECSG)

Purpose: EO9 is a new synthetic bioreductive alkylating indoloquinone, with preferential activity against solid tumors and higher antitumor activity under anaereobic conditions compared with aerobic conditions. In preclinical models EO9 demonstrated no major organ toxicity. The aim of the present phase I study was to determine the toxicities and the maximal tolerated dose (MTD) of EO9 administered as a 5-min i.v. infusion weekly to patients with solid cancers. Methods: Twenty-eight patients entered the study. The dose was escalated from 2.7 mg/m² according to a Fibonacci-like schedule. Results and conclusion: The dose-limiting toxicity was proteinuria. No other major toxicities were detected and in particular there was no significant increase in serum creatinine. This was in contrast to findings in a previous phase I trial using EO9 in a 3-weekly schedule, where a number of patients experienced severely decreased kidney function. The MTD in the present study was 15.0 mg/m² weekly and the recommended dose for phase II studies was 12.0 mg/m² weekly. Compared with 3-weekly EO9, the dose intensity could be increased from 22 mg/m² to 36 mg/m² with the weekly administration. Phase II studies have been performed by the EORTC Early Clinical Study Group in advanced breast, gastric, colorectal, pancreatic, and non-small-cell lung cancer. Received: 5 July 1999 / Accepted: 20 July 1999     

Plasma pharmacokinetics of N -[2-(dimethylamino)ethyl]acridine-4-carboxamide in a phase I trial

DACA {N-[2-(dimethylamino)ethyl]acridine-4-carboxamide} is an acridine derivative with high activity against solid tumours in mice and a dual mode of cytotoxic action involving topoisomerases I and II. The plasma pharmacokinetics of DACA were studied in 28 patients with solid tumours in a phase I trial. A single dose was given every 3 weeks, being escalated from a starting dose of 18 mg/m² (as the dihydrochloride trihydrate salt) to a maximal dose, limited by severe pain in the infusion arm, of 1000 mg/m². Drug was given by constant intravenous infusion with a target delivery period of 3 h. Blood samples were taken from the contralateral arm before, during and for up to 72 h after the infusion. DACA was separated from plasma by solid-phase extraction and was analysed by reversed-phase high-performance liquid chromatography (C18 column) using fluorescence detection. A two-compartment pharmacokinetic model provided the best fit for the concentration-time profiles obtained for most patients showing clearance of 1.00 ± 0.36 l h⁻¹ kg⁻¹, a volume of distribution of the central compartment of 0.72 ± 0.55 l/kg, an initial half-life of 0.28 ± 0.19 h and a terminal half-life of 2.04 ± 0.94 h. All pharmacokinetic parameters were independent of dose, indicating first-order kinetics. As DACA binds strongly to α₁-acid glycoprotein, plasma concentrations of this protein were determined and used to estimate free-drug fractions in plasma. Estimated values for the free fraction varied from 0.9% to 3.3% and were lower than those determined by equilibrium dialysis for mice and rats (15% and 16%, respectively). At the maximum tolerated dose (MTD) of 750 mg/m², the area under the drug concentration-time curve (AUC) was 46.2 ± 4.4 μM h, exceeding that obtained in mice treated at the MTD (23.4 μM h). On the other hand, the corresponding free-drug AUC was 0.92 ± 0.03 μM h, much lower than the corresponding value (3.5 μM h) determined for mice. These results suggest that free-drug rather than total drug concentrations are more appropriate for interspecies dose comparisons when significant differences exist in the free plasma fraction. Received: 27 August 1998 / Accepted: 10 December 1998     

Interaction of dexrazoxane with red blood cells and hemoglobin alters pharmacokinetics of doxorubicin

Purpose: The mechanism of the cardioprotective action of dexrazoxane against doxorubicin cardiotoxicity is not fully understood. It has been suggested that its hydrolysis product, ICRF-198, chelates and removes free iron and iron associated with doxorubicin-iron complex and, therefore, prevents the formation of free radical, lipid peroxidation and cardiotoxicity. Dexrazoxane is also known to inhibit topoisomerase II, to prevent the inactivation of cytochrome c oxidase by Fe³⁺-doxorubicin and to increase the levels of transferrin receptor (trf-rec) mRNA and cellular iron uptake. This sequestration of iron and its effect on cellular iron homeostasis may also contribute to its protective effect against doxorubicin cardiotoxicity. The present project was designed to investigate the interaction of dexrazoxane with hemoglobin and red blood cells and the subsequent effect on the pharmacokinetics and toxicodynamics of doxorubicin. Methods: In an in vitro investigation the binding of doxorubicin (0.5–25 μg/ml) to red blood cells, erythrocyte ghosts and hemoglobin in the presence of dexrazoxane was evaluated. In an in vivo study female Sprague Dawley rats were pretreated with 100 mg/kg of dexrazoxane by intravenous injection 1 h before the injection of ¹⁴C-doxorubicin (specific activity 0.4 μCi/mg, 10 mg/kg). The time-course of doxorubicin associated with blood cells and plasma was evaluated with simultaneous characterization of doxorubicin and its metabolites in the bile and urine. The serum concentration of endothelin was measured as a biomarker of cardiotoxicity in separate groups of animals. Results: The in vitro data indicated that dexrazoxane inhibited the binding of DOX to red blood cells in a concentration-dependent manner. At 1 μg/ml it reduced the binding of doxorubicin to red blood cells by about 30% and at 100 μg/ml by about 60%. It had no effect on the association of doxorubicin with erythrocyte ghosts. The investigation of binding of doxorubicin to hemoglobin revealed the existence of two distinct binding sites and dexrazoxane reduced the association constant of doxorubicin with the low-affinity and high-capacity class of binding sites significantly. The pharmacokinetic analysis showed that pretreatment with dexrazoxane (100 mg/kg) reduced the area under plasma concentration-time curve of doxorubicin, its mean residence time and plasma clearance significantly. Similar reductions were also shown with the pharmacokinetic analysis of doxorubicin associated with blood cells. The biliary and urinary elimination of unchanged doxorubicin increased significantly. The pretreatment reduced the serum concentration of endothelin from about 20 ng/ml to about 12 ng/ml. The per cent of this reduction was proportional to the reduction in the AUC of blood cells. Conclusion: The cardioprotective effect of dexrazoxane is due, in part, to its interaction with hemoglobin and red blood cells and this interaction modifies the pharmacokinetics of DOX. Received: 29 July 1999 / Accepted: 11 February 2000     

Pharmacokinetics of paclitaxel administered in combination with cisplatin, etoposide and bleomycin in patients with advanced solid tumours

 Purpose: 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. Methods: Patients were recruited to a phase I trial where escalating doses of paclitaxel (125 to 200 mg/m²) were administered in combination with etoposide 100 or 120 mg/m², and fixed dose of cisplatin 20 mg/m² 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. Results: The mean paclitaxel area under the plasma concentration-versus-time curves (AUC) for the 125-mg/m² dose level (II) was 7.0 ± 3.6 h μmol⁻¹ l⁻¹, for the 175-mg/m² dose level (III) 10.6 ± 2.8 h μmol⁻¹ l⁻¹, for the 200-mg/m² dose level (IV) it was 16.0 ± 5.0 h μmol⁻¹ l⁻¹, and for the 175-mg/m² dose level (V) it was 12.5 ± 6.1 h μmol⁻¹ l⁻¹. The mean peak plasma concentration (C_max) values for dose levels II–V were 1.9 ± 1.1 μmol/l, 3.4 ± 1.2 μmol/l, 4.3 ± 1.0 μmol/l and 3.8 ± 1.2 h μmol/l, respectively. Conclusion: In this study, relevant pharmacokinetic parameters of paclitaxel like AUC, C_max and the paclitaxel plasma concentration above the pharmacologically relevant 0.1-μmol/l threshold concentration (t > 0.1 μM) 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. Received: 29 June 1998 / Accepted: 29 January 1999     

A phase I study of carboplatin and etoposide administered in conjunction with dipyridamole, prochlorperazine and cyclosporine A

Purpose: In recognition of the variety of available chemotherapeutic modulating agents and their potential to enhance the efficacy of platinum-based therapy, we embarked upon a phase I study to investigate the feasibility of combining fixed doses of carboplatinum (CBDCA) and etoposide (VP-16) with 24-h concurrent infusions of dipyridamole (DP), prochlorperazine (PCZ) and cyclosporine A (CSA) administered in escalating doses. Methods: Patients received intravenous VP-16 (200 mg/m²) and CBDCA (300 mg/m²), each over 30 min, starting at hour 6 of the modulator infusions. Resistance modulators were escalated sequentially to determine their respective maximally tolerated doses (MTDs). The pharmacokinetics (PK) of VP-16, CBDCA, and the three drug resistance (DR) modifiers were studied in eight patients. Results: A total of 59 patients were entered on study. The MTD was established at DP 5 mg/kg per day, PCZ 24 mg/h, and CSA 9.5 mg/kg per day. Dose-limiting toxicities included hypotension and severe sedation, presumably related to PCZ. No objective responses were seen. PK studies were performed when PCZ and DP doses were 24 mg/h and 3.3 mg/kg, and the CSA dose was either 8.5 mg/kg (five patients) or 9.5 mg/kg (three patients). The median clearance of VP-16 was 0.96 l/h per m² (range 0.8–1.5 l/h per m²), which is lower than for VP-16 alone and similar to previously reported effects of CSA on VP-16 elimination. The median measured CBDCA AUC was 3.0 mg/ml · min (range 2.4–4.8 mg/ml · min). CBDCA AUC predicted by the Calvert formula using measured creatinine clearance underestimated the actual AUC in seven of the eight patients, in one case by as much as twofold. The median end of infusion PCZ and total DP plasma concentrations were 1.2 μM (range 0.5–2.2 μM) and 4.4 μM (range 1.3–5.9 μM), respectively, consistent with in vitro resistance modulatory levels. However, free DP was only 0.02 μM (range 0.004–0.04 μM). The median CSA level at 24 h of 1450 μg/l (range 1075–1640 μg/l) is in agreement with concentrations required for partial DR reversal in vitro, although it is much lower than levels achieved in our previous phase I study of CBDCA + CSA alone using similar doses of CSA. The CSA dose on the current trial was escalated beyond the MTD for the previous phase I study, suggesting that there may be an interaction between CSA and one of the other modulators. Conclusion: These results demonstrate that in vitro DR- reversing levels of two of the three agents used in this study can be achieved in vivo, and that this combination of DR modulators has significant effects on the pharmacokinetics of VP-16. Received: 2 September 1999 / Accepted: 25 April 2000     

Phase I studies of nogitecan hydrochloride for Japanese

Background. SmithKline Beecham synthesized camptothecin analogs and identified nogitecan hydrochloride (topotecan) with a broad spectrum of antitumor activity and less toxicity than camptothecin. Because preclinical and overseas clinical data indicated the antitumor effect of nogitecan hydrochloride with a 5-day repeat-dose schedule, we carried out phase I studies in Japan to determine the maximum tolerated dose (MTD), pharmacokinetics, and antitumor effect of nogitecan hydrochloride. Methods. Phase I studies of nogitecan hydrochloride given by single and 5-day repeat dosing were carried out in patients with various solid tumors at 15 medical institutions in Japan. Pharmacokinetic evaluations were performed for both single and 5-day repeated dosing. Results. The dose-limiting factor (DLF) was reversible leucopenia, and the maximum tolerated dose (MTD) was higher than 22.5 mg/m² in the single-dose study. In the 5-day repeat-dose study, the DLF was also reversible leucopenia, and the MTD was estimated to be 1.5 mg/m² per day. The plasma concentration of nogitecan hydrochloride increased with increasing dose, and the half-life after single dosing ranged from 3 to 5 h. There was no evidence of accumulation or delayed excretion during 5-day repeat dosing. Conclusion. Based on these results and the finding that there were responders among patients treated at 1.5 mg/m² per day by 5-day repeat dosing in overseas studies, 5-day repeat dosing of 1.2 mg/m² per day, one dose level lower than the MTD, was selected for phase II studies in Japan. Received: July 30, 2001 / Accepted: February 28, 2002     

Inability to escalate vinorelbine dose intensity using a daily × 3 schedule with and without filgrastim in patients with metastatic breast cancer

Purpose: Vinorelbine (Navelbine) is a semisynthetic vinca alkaloid with documented activity in breast cancer. The major dose-limiting toxicity (DLT) when given weekly is myelosuppression with minimal neurologic toxicity. This phase I study attempted to define the maximally tolerated dose (MTD) and the DLT of vinorelbine on a daily ×3 schedule with and without filgrastim support. Methods: A total of 19 patients with stage IV breast cancer were enrolled in separate studies at Duke University Medical Center (DUMC) and the Dana-Farber Cancer Institute (DFCI). Eligible patients could have received up to two prior chemotherapy regimens in the metastatic setting and had to have an ANC >1500/mm², PLT >100 000 m³, creatinine <2.0 mg/dl, bilirubin <2.0 mg/dL, SGOT not more than three times normal, and performance status 0–1. Vinorelbine was administered using a daily ×3 schedule every 3 weeks. The protocols were designed to study dose escalation with and without growth factor support. At DUMC, in the initial phase of the study, the starting dose was 15 mg/m² per day and dose escalations of 5 mg/m² were planned until DLT developed and the MTD was defined. DLT was defined as granulocytopenia <500/mm³ for >7 days, grade IV thrombocytopenia, febrile neutropenia, or grade III or greater nonhematologic toxicity. In the second phase of the study, growth factor support was given with vinorelbine at the MTD. Filgrastim at a dose of 5 g/kg was started on day 4 of the 21-day cycle and was continued until the neutrophil count exceeded 10 000 cells/mm³. At DFCI, all patients received growth factor starting on day 4 and the starting dose of vinorelbine was 25 mg/m². Results: At DUMC, DLT was seen at 20 mg/m² in three of three patients and included febrile neutropenia, grade IV neutropenia >7 days, grade III neurotoxicity, and grade III vomiting. Despite the addition of filgrastim, DLT was again seen at 20 mg/m² and included grade III neurotoxicity (jaw pain, abdominal pain, constipation, ileus) and grade IV mucositis. Three patients at DFCI were treated with vinorelbine at a dose of 25 mg/m² with growth factor support, and two developed DLT including febrile neutropenia, neutropenia >7 days, and grade III stomatitis. Conclusions: Our effort to escalate the dose intensity of vinorelbine on this schedule was not successful and was complicated by hematologic and nonhematologic toxicity. A daily ×3 schedule of vinorelbine should not be pursued as an alternative treatment regimen in patients with previously treated metastatic breast cancer. Received: 27 October 1997 / Accepted: 16 April 1998