The bioavailability of oral GI147211 (GG211), a new topoisomerase I inhibitor.

Topoisomerase I inhibitors are new compounds of interest for cancer chemotherapy. We performed a study with GI147211, a new semisynthetic camptothecin analogue, to determine the absolute bioavailability of the drug given orally. Patients with a histologically confirmed diagnosis of a solid tumour refractory to standard forms of therapy were eligible for the study. GI147211 was given orally on day 1 and as a 30-min infusion daily on days 2-5. The treatment course was repeated every 3 weeks. In subsequent patient cohorts, the dose of the oral formulation was escalated from 1.5 mg m(-2) to 6.0 mg m(-2); the dose for i.v. administration was fixed at 1.2 mg m(-2). Plasma pharmacokinetics was performed on day 1 and 2 of the first course and on day 1 of the second course using a validated high-performance liquid chromatographic assay. Nineteen patients were entered into the study; one patient was not evaluable because the treatment course was stopped prematurely. Eighteen patients received a total of 47 treatment courses. The absolute bioavailability of GI147211 averaged 1.3 +/- 5.2%. Drug appeared quickly in plasma with a median Tmax at 0.5 h. Fasting or fed state had no significant influence on the bioavailability of GI147211. The terminal half-life after administration of oral GI147211 was 6.85 +/- 3.13 h, similar to the half-life after intravenous administration. The major toxicities were neutropenia and thrombocytopenia. Nadirs for neutropenia and thrombocytopenia occurred on day 8 and day 15 respectively. Other toxicities predominantly consisted of mild and infrequent nausea and vomiting, and fatigue. The oral administration of the drug is well tolerated. Oral administration of topoisomerase I inhibitor GI147211 results in a low bioavailability with relatively wide interpatient variation. The intravenous route of administration is advised for further development of this promising topoisomerase I inhibitor.     

A phase I clinical and pharmacokinetic study of the new topoisomerase inhibitor GI147211 given as a 72-h continuous infusion.

GI147211 is a novel, totally synthetic camptothecin with promising preclinical and early clinical activity. This study was designed to determine the maximum tolerated dose of {"type":"entrez-nucleotide","attrs":{"text":"Gl147211","term_id":"263536554"}}Gl147211 as a 72-h infusion and to describe its pharmacokinetics and pharmacodynamics on this schedule. In a single-arm, rising-dose study in patients with advanced cancer, eight cohorts of three or more patients received 72-h infusions of {"type":"entrez-nucleotide","attrs":{"text":"Gl147211","term_id":"263536554"}}Gl147211 at doses ranging from 0.25 to 2.5 mg m(-2) day(-1). Forty-four patients received a total of 124 cycles. All patients had refractory tumours and 40 had received prior chemotherapy and/or radiotherapy. Whole-blood {"type":"entrez-nucleotide","attrs":{"text":"Gl147211","term_id":"263536554"}}Gl147211 lactone, total blood and total concentrations were measured during and over the 12 h following the infusion. Myelosuppression was observed at all dose levels. Neutropenia was dose limiting at 2.0 mg m(-2) day(-1) in minimally pretreated patients, while both neutropenia and thrombocytopenia were limiting at 1.5 mg m(-2) day(-1) in those more heavily pretreated. Phlebitis occurred with infusions through peripheral veins early in this study, necessitating the use of central venous access. Other toxicities included mild nausea and vomiting, fatigue, headache, central venous catheter infections and alopecia. Three partial and two minor responses lasting 8-34+ weeks were noted in patients with ovarian, colon and breast carcinomas and hepatoma. Mean steady-state concentrations of {"type":"entrez-nucleotide","attrs":{"text":"Gl147211","term_id":"263536554"}}Gl147211 increased with dose over a range of 0.25-1.24 ng ml(-1). The mean terminal elimination half-life was 7.5 h, and the clearance averaged 1074 ml min(-1) m(-2) over the doses studied. The mean fractional excretion of unchanged drug in urine was 0.114. {"type":"entrez-nucleotide","attrs":{"text":"Gl147211","term_id":"263536554"}}Gl147211 lactone exposure correlated with haematological toxicity. The recommended phase II doses for this regimen are 1.75 mg m(-2) day(-1) and 1.2 mg m(-2) day(-1) for minimally pretreated and heavily pretreated patients respectively. At these doses, steady-state {"type":"entrez-nucleotide","attrs":{"text":"Gl147211","term_id":"263536554"}}Gl147211 concentrations within the range of those effective in vitro were achieved. Extensive phase II evaluation of this compound and further phase I trials evaluating more prolonged infusions are ongoing.     

Phase I and pharmacokinetics study of topotecan, a new topoisomerase I inhibitor

Purpose: A phase I study with topotecan (SKF 104864-A, NSC 609699),a semisynthetdc analog of camptothecin, was performed usinga daily-times-5 regimen, given i.v. q 3 weeks, to evaluate thepharmacokinetics and toxicities of the compound. Patients and methods: Patients with a histologically confirmeddiagnosis of a solid tumor no longer amenable to establishedforms of treatment were eligible for the study. Topotecan wasgiven as a 30 min. infusion daily on 5 successive days, repeatedevery three weeks. In subsequent patient cohorts the dose wasescalated from 0.5 to 1.5 mg/m²/ day. Weekly evaluations includedhematology and biochemistry. Response to treatment was assessedevery 2 cycles. Pharmacokinetics were performed using a HPLCmethod. Results: Forty-eight patients were entered. The maximal tolerateddose was 1.5 mg/m²day. The dose limiting toxicity was leucocytopenia.Other major toxicities were alopecia and moderate nausea/vomiting.Partial remissions were observed in one patient with pretreatedsmall-cell lung cancer, one with non-small-cell lung cancerand one with no-pretreated pancreatic cancer, lasting 130–240days. Pharmacokinetics showed a t     

Phase I clinical and pharmacokinetic study of trimetrexate using a daily x5 schedule

Trimetrexate (TMQ; NSC 352122) is a potent inhibitor of dihydrofolate reductase with good activity against murine i.p.-implanted B16 melanoma and colon 26 tumors. Preclinical antineoplastic activity, demonstrated schedule dependency, and data suggesting effectiveness against methotrexate-resistant cells prompted a Phase I clinical and pharmacokinetic study of trimetrexate using an i.v. daily x5 schedule. Forty-three good performance status patients were treated with 12 dose levels using daily doses varying from 0.5 to 15 mg/m2/d. Plasma and urine samples were obtained for pharmacokinetic analysis using a high-performance liquid chromatographic method. Myelosuppression was dose limiting and 15 mg/m2/d x5 was the maximum tolerated dose. White blood cell (WBC) and platelet toxicity were noted at doses of 1.6 mg/m2 and above. Median WBC and platelet nadirs occurred on approximately Days 11-12 with recovery by Days 15-18. Nonhematological toxicity included mucositis, nausea and vomiting, stomatitis, diarrhea, and rash. Evidence for antitumor activity was seen in seven patients. Trimetrexate elimination from plasma could be represented as either a bi- or triexponential process. Terminal elimination half-lives were in the range of 5-14 h in patients represented by a triexponential model. Approximately 10-20% of the dose administered was excreted in urine over a 24-h period. The recommended starting dose for patients in Phase II trials using the d x5 i.v. schedule is 8.0 mg/m2/d repeated every 21 days. Dose escalations may be possible depending on the extent of prior therapy and individual tolerance of the drug.     

Phase I and pharmacologic study of topotecan: a novel topoisomerase I inhibitor.

PURPOSE: A phase I and pharmacologic study was undertaken to determine the maximum-tolerated dose (MTD), describe the principal toxicities, and characterize the pharmacologic behavior of topotecan, which is a semisynthetic analog of camptothecin with broad preclinical antitumor activity and the first topoisomerase I-targeting agent to enter clinical development in the United States since studies of sodium camptothecin over 2 decades ago. PATIENTS AND METHODS: Thirty-minute infusions of topotecan were administered daily for 5 consecutive days every 3 weeks to patients with advanced solid malignancies at doses ranging from 0.5 to 2.5 mg/m2/d. RESULTS: At doses of 1.5 and 2.0 mg/m2, grade 3 and 4 neutropenia occurred in most courses; however, neutropenia was brief and rarely associated with fevers or treatment delays. Neutropenia was more severe in patients with extensive prior treatment than in minimally pretreated patients, but these differences were not substantial. At 2.5 mg/m2, topotecan induced profound and prolonged neutropenia that was frequently associated with fever and treatment delays in minimally pretreated patients. Topotecan also induced mild depressions in the hematocrit level in the majority of courses; however, precipitous drops requiring transfusional therapy occurred in 14% of courses and suggested a drug-induced hemolytic effect. Unlike sodium camptothecin, hemorrhagic cystitis was not observed. Thrombocytopenia, skin rash, diarrhea, and vomiting occurred infrequently and were modest in severity. Responses were observed in non-small-cell lung carcinoma and platinum-refractory ovarian carcinoma. Drug disposition in plasma was described by a biexponential model, with renal elimination accounting for 38.7% of drug disposition. Topotecan was rapidly hydrolyzed in vivo to a less active, open-ring form. CONCLUSIONS: Neutropenia is the dose-limiting toxicity, and 1.5 mg/m2 is the recommended starting dose of topotecan for both minimally and heavily pretreated patients in future phase II trials, with escalation to 2.0 mg/m2 if treatment is well tolerated. Non-small-cell lung and platinum-refractory ovarian carcinomas should be among those evaluated in phase II trials of topotecan.     

Phase I and pharmacokinetic study of the topoisomerase II catalytic inhibitor fostriecin

We conducted a phase I and pharmacokinetic study of the topoisomerase II catalytic inhibitor fostriecin. Fostriecin was administered intravenously over 60 min on days 1-5 at 4-week intervals. Dose was escalated from 2 mg m(-2) day(-1) to 20 mg m(-2) day(-1) in 20 patients. Drug pharmacokinetics was analysed with high performance liquid chromatography with UV-detection. Plasma collected during drug administration was tested in vitro for growth inhibition of a teniposide-resistant small-cell lung cancer (SCLC) cell line. The predominant toxicities were elevated liver transaminases (maximum common toxicity criteria (CTC) grade 4) and serum creatinine (maximum CTC grade 2). These showed only a limited increase with increasing doses, often recovered during drug administration and were fully reversible. Duration of elevated alanine-amino transferase (ALT) was dose-limiting in one patient at 20 mg m(-2). Other frequent toxicities were grade 1-2 nausea/vomiting, fever and mild fatigue. Mean fostriecin plasma half-life was 0.36 h (initial; 95% CI, 0-0.76 h) and 1.51 h (terminal; 95% CI, 0.41-2.61 h). A metabolite, most probably dephosphorylated fostriecin, was detected in plasma and urine. No tumour responses were observed, but the plasma concentrations reached in the patients were insufficient to induce significant growth inhibition in vitro. The maximum tolerated dose (MTD) has not been reached, because drug supply was stopped at the 20 mg m(-2) dose level. However, further escalation seems possible and is warranted to achieve potentially effective drug levels. Fostriecin has a short plasma half-life and longer duration of infusion should be considered.     

Phase I and pharmacological study of sequential intravenous topotecan and oral etoposide.

We performed a phase I and pharmacological study to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of a cytotoxic regimen of the novel topoisomerase I inhibitor topotecan in combination with the topoisomerase II inhibitor etoposide, and to investigate the clinical pharmacology of both compounds. Patients with advanced solid tumours were treated at 4-week intervals, receiving topotecan intravenously over 30 min on days 1-5 followed by etoposide given orally twice daily on days 6-12. Topotecan-etoposide dose levels were escalated from 0.5/20 to 1.0/20, 1.0/40, and 1.25/40 (mg m-2 day-1)/(mg bid). After encountering DLT, additional patients were treated at 3-week intervals with the topotecan dose decreased by one level to 1.0 mg m-2 and etoposide administration prolonged from 7 to 10 days to allow further dose intensification. Of 30 patients entered, 29 were assessable for toxicity in the first course and 24 for response. The DLT was neutropenia. At doses of topotecan-etoposide 1.25/40 (mg m-2)/(mg bid) two out of six patients developed neutropenia grade IV that lasted more than 7 days. Reduction of the treatment interval to 3 weeks and prolonging etoposide dosing to 10 days did not permit further dose intensification, as a time delay to retreatment owing to unrecovered bone marrow rapidly emerged as the DLT. Post-infusion total plasma levels of topotecan declined in a biphasic manner with a terminal half-life of 2.1 +/- 0.3 h. Total body clearance was 13.8 +/- 2.7 l h-1 m-2 with a steady-state volume of distribution of 36.7 +/- 6.2 l m-2. N-desmethyltopotecan, a metabolite of topotecan, was detectable in plasma and urine. Mean maximal concentrations ranged from 0.23 to 0.53 nmol l-1, and were reached at 3.4 +/- 1.0 h after infusion. Maximal etoposide plasma concentrations of 0.75 +/- 0.54 and 1.23 +/- 0.57 micromol l-1 were reached at 2.4 +/- 1.2 and 2.3 +/- 1.0 h after ingestion of 20 and 40 mg respectively. The topotecan area under the plasma concentration vs time curve (AUC) correlated with the percentage decrease in white blood cells (WBC) (r2 = 0.70) and absolute neutrophil count (ANC) (r2 = 0.65). A partial response was observed in a patient with metastatic ovarian carcinoma. A total of 64% of the patients had stable disease for at least 4 months. The recommended dose for use in phase II clinical trials is topotecan 1.0 mg m-2 on days 1-5 and etoposide 40 mg bid on days 6-12 every 4 weeks.     

Phase I and pharmacokinetic study of the topoisomerase I inhibitor, exatecan mesylate (DX-8951f), using a weekly 30-minute intravenous infusion, in patients with advanced solid malignancies.

BACKGROUND: The topoisomerase I inhibitor exatecan mesylate (DX-8951f ) is a water-soluble hexacyclic analogue of camptothecin that does not require enzymatic activation. This study determined the toxicity, maximum tolerated dose (MTD), pharmacokinetics and pharmacodynamics of a weekly intravenous (i.v.) schedule of DX-8951f. PATIENTS AND METHODS: Thirty-five patients with advanced solid malignancies, stratified as minimally (MP) or heavily (HP) pre-treated, received escalating doses of DX-8951f as 30-min i.v. infusions for three out of every 4 weeks. Pharmacokinetics were described after the first infusion of DX-8951f. RESULTS: Infusions (244) of DX-8951f were administered with a median of two cycles (range 1-10). The main toxicity observed was haematological. There was no significant gastrointestinal toxicity. Two patients (6%) had confirmed partial responses. Twelve patients (39%) had stable disease. DX-8951f had a terminal elimination half-life of approximately 8 h and a clearance of 2 l/h/m(2). The area under the plasma concentration versus time curve (AUC( infinity )) and the maximum plasma concentration (C(max)) increased linearly with the dose. A linear relationship was present for the percentage decrease in neutrophil counts or platelet counts and AUC( infinity ) as well as C(max). CONCLUSIONS: The dose-limiting toxicity of DX-8951f is neutropenia for MP patients and neutropenia and thrombocytopenia for HP patients. Evidence for clinical activity was seen, suggesting phase II study of the drug is indicated. Using this schedule the recommended dose is 2.75 mg/m(2)/week for MP patients and 2.10 mg/m(2)/week for HP patients.     

Phase I and clinical pharmacological study of mercaptopurine administered as a prolonged intravenous infusion

The bioavailability of oral mercaptopurine (MP) is poor, and plasma levels following p.o. dosing are highly variable. In an attempt to circumvent these problems, we conducted a Phase I trial and clinical pharmacological study of MP administered as a prolonged i.v. infusion. An infusion rate of 50 mg/sq m/h, which was designed to achieve therapeutic drug levels in plasma, was used in all patients. The infusion duration was escalated in 12-h increments. Thirty-eight patients were evaluated. The dose-limiting toxicity was mucositis. Other reversible toxicities were myelosuppression and hepatotoxicity. An infusion duration of 48 h was found to be safe, unassociated with dose-limiting toxicity. Objective responses were seen in five patients. The mean plasma steady-state MP concentration achieved was 6.9 microM with little interpatient variability seen. Allopurinol coadministration had no effect on the plasma pharmacokinetics of i.v. MP. However, allopurinol did alter the urinary metabolite pattern, decreasing thiouric acid and increasing MP and thioxanthine levels. The steady-state cerebrospinal fluid:plasma ratio for MP was 0.27, suggesting that this approach may be of value in the treatment of central nervous system cancer. MP can be safely administered as a 48-h i.v. infusion at a dose rate which reliably achieves MP levels associated with optimal antileukemic activity in vitro.     

Phase I study of sequentially administered topoisomerase I inhibitor (irinotecan) and topoisomerase II inhibitor (etoposide) for metastatic non-small-cell lung cancer.

We conducted a phase I study of irinotecan (CPT-11) and etoposide (VP-16) given sequentially to untreated patients with metastatic non-small-cell lung cancer. Arm A: CPT-11 was given over 90 min on days 1-3 and VP-16 was given over 60 min on days 4-6. Arm B: VP-16 was given on days 1-3 and CPT-11 on days 4-6. G-CSF was given to all patients daily on days 7-17. Twenty-seven patients were entered randomly at the two arms. The major dose-limiting toxicities in arms A and B were granulocytopenia and diarrhoea. Transient elevations of transaminases and bilirubin were observed in both arms. The degree of the toxicities did not differ between the two arms. The maximum tolerated doses (MTDs) were 60 mg m-2 CPT-11 and 60 mg m-2 VP-16 in both arms. Of the 13 patients who received more than two cycles, two out of five achieved partial response (PR) at the first level of arm A and one out of four achieved PR at the second level of arm B. We conclude that these schedules of sequential CPT-11 and VP-16 administration were inappropriate because of severe toxicities.     

Phase I and pharmacokinetic study of DACA (XR5000): a novel inhibitor of topoisomerase I and II. CRC Phase I/II Committee.

DACA, also known as XR5000, is an acridine derivative active against both topoisomerase I and II. In this phase I study, DACA was given as a 3-h intravenous infusion on 3 successive days, repeated every 3 weeks. A total of 41 patients were treated at 11 dose levels between 9 mg m(-2) d(-1) and the maximum tolerated dose of 800 mg m(-2) day(-1). The commonest, and dose-limiting, toxicity was pain in the infusion arm. One patient given DACA through a central venous catheter experienced chest pain with transient electrocardiogram changes, but no evidence of myocardial infarction. At the highest dose levels, several patients also experienced flushing, pain and paraesthesia around the mouth, eyes and nose and a feeling of agitation. Other side-effects, such as nausea and vomiting, myelosuppression, stomatitis and alopecia, were uncommon. There was one minor response but no objective responses. DACA pharmacokinetics were linear and did not differ between days 1 and 3. The pattern of toxicity seen with DACA is unusual and appears related to the mode of delivery. It is possible that higher doses of DACA could be administered using a different schedule of administration.     

Bioavailability and pharmacokinetics of oral topotecan: a new topoisomerase I inhibitor.

The results of preclinical and clinical studies indicate enhanced antineoplastic activity of topotecan (SKF 104864-A) when administered as a chronic treatment. We determined the apparent bioavailability and pharmacokinetics of topotecan administered orally to 12 patients with solid tumours in a two-part crossover study. The oral dose of 1.5 mg m-2 was administered as a drinking solution of 200 ml on day 1. The i.v. dose of 1.5 mg m-2 was administered as a 30 min continuous infusion on day 2. The bioavailability was calculated as the ratio of the oral to i.v. area under the curve (AUC) calculated up to the last measured time point. The oral drinking solution was well tolerated. The bioavailability revealed moderate inter-patient variation and was 30% +/- 7.7% (range 21-45%). The time to maximum plasma concentration after oral administration (Tmax) was 0.78 h (median; range 0.33-2.5). Total i.v. plasma clearance of topotecan was 824 +/- 154 ml min-1 (range 535-1068 ml min(-1)). The AUC ratio of topotecan and the lactone ring-opened hydrolysis product (hydroxy acid) was of the same order after oral (0.34-1.13) and i.v. (0.47-0.98) administration. The bioavailability of topotecan after oral administration illustrates significant systemic exposure to the drug which may enable chronic oral treatment.     

Phase I and pharmacological study of the oral farnesyltransferase inhibitor SCH 66336 given once daily to patients with advanced solid tumours

A single-agent dose-escalating phase I study on the farnesyl transferase inhibitor SCH 66336 was performed to determine the safety profile and recommended dose for phase II studies. Plasma pharmacokinetics were determined as well as the SCH 66336-induced inhibition of farnesyl protein transferase in vivo. SCH 66336 was given orally once daily (OD) without interruption to patients with histologically-confirmed solid tumours. Routine antiemetics were not prescribed. 12 patients were enrolled into the study. Dose levels studied were 300 mg (6 patients) and 400 mg (6 patients) OD. Pharmacokinetic sampling was performed on days 1 and 15. Although at 400 mg OD only 1 patient had a grade 3 diarrhoea, 3 out of 6 patients interrupted treatment early due to a combination of various grade 1-3 toxicities (diarrhoea, uremiacreatinine, asthenia, vomiting, weight loss) indicating that this dose was not tolerable for a prolonged period of time. At 300 mg OD, the same pattern of toxicities was observed, but all were grade 1-2. Therefore, this dose can be recommended for phase II studies. Pharmacokinetic analysis showed that peak plasma concentrations as well as the AUCs were dose-related, with increased parameters at day 15 compared with day 1, indicating some accumulation upon multiple dosing. Plasma half-life ranged from 5 to 9 h and appeared to increase with increasing dose. Steady state plasma concentrations were attained by day 14. A large volume of distribution at steady state suggested extensive distribution outside the plasma compartment. There is evidence of inhibition of protein prenylation in some patients after OD oral administration of SCH 66336. SCH 66336 can be safely administered using a continuous oral OD dosing regimen. The recommended dose for phase II studies using this regimen is 300 mg OD.     

Phase I/pharmacokinetic study of the topoisomerase I inhibitor GG211 administered as a 21-day continuous infusion

Background: Preclinical results support a prolonged schedule of administration for topoisomerase I inhibitors, and we have previously demonstrated the safety and activity of the novel water-soluble topoisomerase I inhibitor GG211 when given as a 72-hour continuous infusion to cancer patients.Patients and methods: In a three-center international phase I trial, 38 patients received GG211 doses from 0.3 to 0.5 mg/m2/day by continuous intravenous infusions for seven, 14, and 21 days. Patients' median performance status was 1; nearly half had colorectal cancer, and 35 patients had prior chemotherapy.Results: The first patient cohort received 0.3 mg/m2/day for seven days with no significant toxicities. Subsequent cohorts received continuous infusions for 14 and 21 days at this dose level with only mild myelosuppression noted. Dose-escalation on the 21-day schedule was then performed. No dose-limiting toxicity occurred at the 0.4 mg/m2/day dose level. Thrombocytopenia was dose-limiting with 0.5 mg/m2/day dosing but was not cumulative. Other grade 3–4 toxicities included neutropenia, nausea, vomiting, diarrhea, and fatigue. Partial responses occurred with 21-day infusion in two patients with breast and ovarian cancer at the 0.3 and 0.4 mg/m2/day dose levels, respectively. Mean GG211 lactone Css ranged from 0.17 to 0.64 ng/ml.Conclusion: The maximum tolerated dose of GG211 administered as a 21-day continuous infusion is 0.4 mg/m2/day with antitumor activity noted at tolerable doses.     

Phase I and pharmacological study of daily oral administration of perifosine (D-21266) in patients with advanced solid tumours

Alkylphosphocholines are a novel class of antitumour agents structurally related to ether lipids that interact with the cell membrane and influence intracellular growth signal transduction pathways. We performed a phase I trial with an analogue of miltefosine, perifosine (D-21266), which was expected to induce less gastrointestinal toxicity. Objectives of the trial were: to determine the maximum-tolerated dose (MTD) for daily administration, to identify the dose-limiting toxicity (DLT) of this schedule, to assess drug accumulation and to determine the relevant pharmacokinetic parameters. 22 patients with advanced solid tumours were treated at doses ranging from 50 to 350 mg/day for 3 weeks, followed by 1 week of rest. Toxicity consisted mainly of gastrointestinal side-effects: nausea was reported by 11 patients (52%, 10 patients Common Toxicity Criteria (CTC) grades 1-2 and 1 patient CTC grade 3), vomiting by 8 (38%, all CTC grades 1-2), and diarrhoea by 9 (43%, 8 patients CTC grades 1-2 and 1 patient CTC grade 3). The severity of these side effects appeared to increase with increasing doses. Another common side-effect was fatigue, occurring in 9 patients (43%). No haematology toxicity was observed. Dose-limiting toxicity (DLT) was not reached, but gastrointestinal complaints led to an early treatment discontinuation in an increasing number of patients at the higher dose levels. Therefore, MTD was established at 200 mg/day. The pharmacokinetic studies suggested dose proportionality.     

Phase I and pharmacokinetic study of prinomastat, a matrix metalloprotease inhibitor.

PURPOSE: Prinomastat is a matrix metalloprotease (MMP) inhibitor with selectivity for MMPs 2, 3, 9, 13, and 14. Inhibition of these MMPs has been postulated to block tumor invasion and metastasis. This Phase I, dose-escalation study was designed to evaluate the acute and chronic toxicities of various doses of prinomastat and to determine prinomastat pharmacokinetics. Experimental Design: Seventy-five patients with advanced cancer were given 1, 2, 5, 10, 25, 50, or 100 mg prinomastat orally twice daily until tumor progression or development of significant toxicities. Prinomastat pharmacokinetics were measured on day 29 of therapy. RESULTS: The primary toxicities identified were joint and muscle-related pain, which were generally reversible with treatment rest and/or dose reduction. No dose-limiting toxicities were noted within the first 4 weeks of treatment, but grade 2-3 arthralgias and myalgias were noted 2-3 months after initiation of therapy in >25% of patients at doses >25 mg twice a day. The frequency and severity of symptoms were dose related. Plasma prinomastat concentrations greater than the K(i) for MMPs 2 and 9 were achieved at all of the dose levels. CONCLUSIONS: Doses of 5-10 mg bid were recommended for additional trials, because this dose range was well tolerated for a treatment duration of at least 3 months and achieves trough plasma concentrations 10-100-fold greater than the K(i) (in vitro inhibition constant) for the targeted MMPs (2 and 9).     

Phase I study of mitozolomide on a once daily for 5 days schedule

Summary 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.     

Phase I clinical and pharmacological study of chloroquinoxaline sulfonamide.

Chloroquinoxaline sulfonamide (CQS) is a halogenated heterocyclic sulfanilamide identified by the in vitro human tumor colony-forming assay as an active agent in a variety of human solid tumors. In this phase I study, 182 courses of CQS were administered intravenously every 28 days to 88 patients at doses ranging from 18 to 4870 mg/m2. Hypoglycemia associated with hyperinsulinemia was the dose-limiting adverse effect at 4870 mg/m2. Supraventricular tachyarrhythmias were observed at doses > 4000 mg/m2. Less common reactions included infusion site phlebitis, nausea, anemia, alopecia, perioral numbness, and diarrhea. Cumulative toxicity was not observed. Minor objective antitumor responses were noted in 7 patients; 6 of the 7 responses occurred in patients with non-small cell lung cancer. Results of pharmacokinetic studies were consistent with the preclinical observations that CQS is highly bound to plasma protein. Plasma elimination followed a two-compartment model; the mean t 1/2 alpha was 2.7 +/- 0.3 h and the t 1/2 beta was 52 +/- 6 h (+/- SE). The total body clearance and the volume of distribution at steady state of CQS both increased with the dose (distribution at steady state, 3.7-10.5 liter/m2; total body clearance, 53-264 ml/h/m2 for doses of 18-4060 mg/m2) and may reflect saturation of the protein binding and "free" drug clearance. Although inactive against common animal tumors in preclinical screening systems both in vitro and in vivo, CQS has demonstrated definite activity in the human tumor stem cell colony-forming assays, as well as modest anticancer activity in this phase I study in patients with advanced solid tumors. The pharmacokinetic results and the limiting effect of transient hypoglycemia suggest that considerably higher cumulative doses of CQS could be administered using a more frequent dosing schedule.     

Phase I and pharmacokinetic study of BIBX 1382 BS,an epidermal growth factor receptor (EGFR) inhibitor,given in a continuous daily oral administration

The pyrimido-pyrimidine BIBX 1382 BS inhibits the intracellular tyrosine kinase domain of the epidermal growth factor receptor (EGFR), thus specifically reverting the aberrant enzymatic activity from overexpressed and constitutively activated EGFR. A phase I and pharmacokinetic study of this new specific molecule was carried out. After initially performing an accelerated titration design from the first toxicities onwards, a modified Fibonacci scheme was used to escalate the daily oral dose. The following dosages and cycles (defined as treatment during 28 days) were applied: 25 mg: 6; 50 mg: 3; 100 mg: 6; 200 mg: 7; 150 mg: 3. Over a 10 months accrual phase, 11 patients (pts) (7 females, 4 males) with a median age of 63 years (range 50-73 years), World Health Organization Performance Status (WHO PS) 0:5 pts, 1:6 pts and miscellaneous solid tumours were entered. The median number of cycles applied per pt was 2 (range 1-7). Reversible, dose-dependent increase of liver enzymes (maximal Common Toxicity Criteria (CTC) grades: gamma-glutamyl transferase (GGT): 4, aspartate aminotransferase (GOT): 3, alanine aminotransferase (GPT): 3, alkaline phosphatase (AP): 3, bilirubin: 3) occurred. Oral medication yielded plasma levels far below those expected to be efficacious. In conclusion, target plasma levels could not be reached via the oral route at a reasonable dosage. Meanwhile, a preclinically unknown metabolite was identified from the urine of one patient. Subsequently, this metabolite was found to be abundant in patient plasma. The metabolite was demonstrated to be pharmacologically inactive. Due to a dose-limiting increase of liver enzymes, low bioavailability of BIBX 1382 BS and the detection of a pharmacologically inactive metabolite, this trial was discontinued.     

Activity of topotecan, a new topoisomerase I inhibitor, against human tumor colony-forming units in vitro.

BACKGROUND: Topotecan [(S)-9-dimethylaminomethyl(10-hydroxy-camptothecin), NSC 609699, SK&F 104864A], a semisynthetic analogue of the natural product camptothecin, is a cell cycle-specific drug that exerts antineoplastic activity through inhibition of topoisomerase I. Currently, topotecan is undergoing phase I and early phase II clinical trials. The dose-limiting toxicity for topotecan is myelosuppression. PURPOSE: Our purpose was to determine plasma concentrations and exposure times necessary for optimal clinical activity and tumor types that may be responsive in phase II clinical studies of topotecan. METHODS: A soft-agar cloning system assay was used to determine the in vitro effects of topotecan against cells from biopsy specimens of colorectal, breast, lung, ovarian, renal cell, and gastric cancers and cancers of unknown primary origin. We studied 141 freshly explanted tumor specimens, using 1-hour exposure to topotecan, and 80 were studied using continuous exposure. A decrease in tumor colony formation resulting from drug exposure was considered an in vitro response if survival of colonies was up to 50% of that in controls. RESULTS: With 1-hour exposure, in vitro responses were seen in 10% and 25% of assessable tumor specimens at final topotecan concentrations of 1.0 and 10.0 micrograms/mL, respectively. With continuous exposures at concentrations of 0.1 and 1.0 micrograms/mL, in vitro response rates were 34% and 76%, respectively. Specific activity was seen against colorectal, breast, non-small-cell lung, ovarian, and renal cell cancers, with responses observed in 27%, 25%, 32%, 39%, and 83%, respectively, of assessable tumor specimens after continuous exposure to 0.1 micrograms/mL topotecan. A subset of tumor specimens resistant to doxorubicin or fluorouracil was sensitive to topotecan, and the difference in sensitivity was statistically significant. In addition, some of the tumor specimens resistant to cyclophosphamide and etoposide were also sensitive to topotecan. CONCLUSIONS: Topotecan appears to be active in vitro against a variety of human tumors, including a subgroup resistant in vitro to standard antineoplastic agents. If plasma levels of 0.1 micrograms/mL can be achieved for prolonged periods of time in ongoing clinical trials, topotecan should have substantial clinical activity. IMPLICATIONS: Further clinical development of topotecan is warranted.