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 anaerobic 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.

Phase I clinical and pharmacokinetic study of topotecan administered by a 24-hour continuous infusion.

PURPOSE: To determine the maximum-tolerable dose (MTD) and to investigate the pharmacokinetics and pharmacodynamics of topotecan in a phase I study. Topotecan is a novel semisynthetic derivative of the anticancer agent camptothecin and inhibits the intranuclear enzyme topoisomerase I. Broad preclinical activity rationalized further clinical evaluation. PATIENTS AND METHODS: In this phase I trial, topotecan was administered by 24-hour continuous infusion every 21 days to patients with solid malignant tumors. RESULTS: A total of 25 eligible patients, of whom 22 were pretreated, entered the study. They received the following dosages of topotecan: 2.5, 3.75, 5.60, 8.4, and 10.5 mg/m2 by 24-hour infusion. Reversible leukopenia and thrombocytopenia were dose-limiting, with mild anemia occurring regularly. Other toxicities, such as alopecia, mucositis, nausea, and vomiting were sporadic and mild. Responses were not observed. However, eight patients had stable disease. The plasma concentration-time curves were not compatible with standard linear pharmacokinetic models, and indications were found for the occurrence of nonlinear (saturation) kinetics at the dosages studied. CONCLUSION: The recommended dose for phase II studies is 8.4 mg/m2 when administered as a 24-hour infusion, which is well tolerated. Further studies will be necessary to account for the putative nonlinear behavior of the drug.

Phase I and pharmacokinetic study of a novel mitomycin C analog KW-2149.

KW-2149 is a new, semisynthetic, C-7-N-substituted, mitomycin C (MMC) analog showing equal or superior antitumor activity in both in vitro and in vivo assays. The preclinical activity profile combined with the hematological toxicity data in rodents and the water solubility of the compound compare favorably with MMC. The aim of this phase I study was to determine the toxicity profile and the optimal dosage of KW-2149. In this phase I study 37 patients received 97 courses of KW-2149 administered as an i.v. bolus injection every 21 days at sequential dose levels: 5, 10, 17, 25, 35, 47, 60, 75, 90 and 100 mg/m2. Hematological toxicity was moderate even at the 100 mg/m2 dose level. Grade IV leucopenia and thrombocytopenia were observed in one of three patients at the 100 mg/m2 dose level. There was some evidence of a delayed-type bone marrow toxicity. Pulmonary toxicity was dose limiting, with grade III toxicity occurring in all three patients treated at a dose of 100 mg/m2. The type of lung toxicity was similar to the one observed with other antitumor antibiotics. No renal or cardiac toxicity was observed. Other toxicities were generally mild. Antitumor activity was observed in four patients. Data of drug monitoring demonstrated rapid metabolism and/or distribution of KW-2149 with a short half-life and the emergence of the cytotoxic metabolites M-16 and M-18. The dose-limiting toxicity of KW-2149 is pulmonary toxicity.

Phase I and pharmacologic study of the novel indoloquinone bioreductive alkylating cytotoxic drug E09.

BACKGROUND: A novel bioreductive alkylating indoloquinone compound, E09 [3-hydroxy-5-aziridinyl-1-methyl-2-(1H-indole-4,7-indione)- prop-F128b-en-alpha-ol], has been shown to have distinct antitumor activity against solid tumors, excellent activity under hypoxic conditions, but no notable bone marrow toxicity in preclinical models. PURPOSE: A phase I study was carried out to determine the toxicity, maximum tolerated dose (MTD), pharmacology, and antitumor response of E09. METHODS: E09 was administered as a 5-minute intravenous infusion once every 3 weeks to 32 patients with solid tumors. The starting dose of 2.7 mg/m2 was one tenth of the mouse equivalent of lethal dose to 10% of animals (MELD10). Dose was escalated by 100% until the area under the curve (AUC) at the MELD10 was reached, following a Fibonacci-like schedule. The pharmacokinetics of E09 and its metabolite E05A with an open aziridine ring was determined using a new high-pressure liquid chromatographic method and noncompartmental calculation of kinetic parameters. The sigmoid Emax model was used to fit pharmacokinetic parameters to toxicity. The renal function and proteinuria were quantitated and were further evaluated by determining renal clearance ratios of immunoglobulin G (IgG) to albumin and pancreatic amylase to salivary amylase. RESULTS: The 32 patients were treated with a total of 85 assessable courses of E09. The dose-limiting toxicity was proteinuria, which was accompanied by sodium and water retention. All symptoms were reversible on day 15 except in two patients, who developed acute renal failure. The ratios of IgG to albumin and pancreatic amylase to salivary amylase suggested a loss of glomerular negative charge consistent with a minimal change glomerulopathy. The pharmacokinetics of E09 showed its rapid elimination from the central compartment but with wide interpatient variation in the overall disposition of the drug. Total plasma clearance of E09 ranged from 3.2 to 24 L/min. The AUC of E09 was linearly related to the administered dose. The relationship between the AUC and proteinuria was best fitted by the sigmoid Emax model (r = .98). In two patients with adenocarcinoma of unknown primary site and in a third patient with bile duct cancer, a partial response was observed. CONCLUSIONS: The MTD of E09 was determined to be 27 mg/m2. The standard approach of drug administration is considered unsuitable because of potential renal toxicity and wide variability in the pharmacokinetics of E09. Individual dose adjustments based on plasma concentration measurements are recommended to combine maximally achievable exposure with tolerable toxicity.

Clinical studies with EO9, a new indoloquinone bioreductive alkylating cytotoxic agent. EORTC Early Clinical Trials Group.

EO9 [3-hydroxy-5-aziridinyl-1-methyl-2-(1H-indole-4,7-indione)-prop-be ta- en-alpha-ol] is a new bioreductive alkylating indoloquinone with a distinct antitumor activity against solid tumors, excellent activity under hypoxic conditions, and lack of bone marrow toxicity in preclinical models. Clinical phase I studies were performed to determine the toxicities, maximally tolerated dose, and pharmacology of EO9. The drug was administered as a 5-min IV infusion at intervals of 3 weeks or weekly to 59 patients with solid tumors. The starting dose of 2.7 mg/m2 was one-tenth of the mouse-equivalent dose lethal to 10% of mice. Doses were escalated according to a Fibonacci-like schedule. The pharmacokinetics of EO9 and its aziridine ring-opened metabolite EO5A were determined using a new high performance liquid chromatography method and noncompartmental calculation of kinetic parameters. The sigmoid maximal effects (Emax) model was used to fit pharmacokinetic parameters to toxicities. The 59 patients received in total 150 evaluable courses of EO9. The dose-limiting toxicity was proteinuria, which was accompanied by sodium and water retention. With the 3-weekly schedule, all symptoms were reversible on day 15 except in 2 patients, who developed acute renal failure. The renal function and proteinuria were quantitated and further evaluated by determining renal clearance ratios of immunoglobulin G/albumin and pancreatic/salivary amylase. The immunogobuline G/albumin and pancreatic/salivary amylase ratios pointed to a loss of glomerular negative charge consistent with a minimal change glomerulopathy. The maximum tolerated dose was 27 mg/m2, the recommended dose 22 mg/m2. The pharmacokinetics showed rapid elimination from the central compartment and wide interpatient variation in disposition.(ABSTRACT TRUNCATED AT 250 WORDS)

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 semisynthetic analog of camptothecin, was performed using a daily-times-5 regimen, given i.v. q 3 weeks, to evaluate the pharmacokinetics and toxicities of the compound. PATIENTS AND METHODS: Patients with a histologically confirmed diagnosis of a solid tumor no longer amenable to established forms of treatment were eligible for the study. Topotecan was given as a 30 min. infusion daily on 5 successive days, repeated every three weeks. In subsequent patient cohorts the dose was escalated from 0.5 to 1.5 mg/m2/day. Weekly evaluations included hematology and biochemistry. Response to treatment was assessed every 2 cycles. Pharmacokinetics were performed using a HPLC method. RESULTS: Forty-eight patients were entered. The maximal tolerated dose was 1.5 mg/m2/day. The dose limiting toxicity was leucocytopenia. Other major toxicities were alopecia and moderate nausea/vomiting. Partial remissions were observed in one patient with pretreated small-cell lung cancer, one with non-small-cell lung cancer and one with no-pretreated pancreatic cancer, lasting 130-240 days. Pharmacokinetics showed a t 1/2 (alpha) of 8.1 +/- 7.6 min., t 1/2 (beta) of 132 +/- 48 min., Vd,ss 72.7 +/- 26.9 L/m2 and Cltot of 0.57 +/- 0.16 L/min/m2. CONCLUSION: Topotecan is an interesting new topoisomerase I inhibitor exerting antitumor activity in this phase I trial. Leucocytopenia is dose-limiting. The recommended dose for phase II studies is 1.5 mg/m2/day for 5 consecutive days every 3 weeks.

Phase I and pharmacokinetic study of rhizoxin.

Rhizoxin is a tubulin-binding cytotoxic compound, isolated from the fungus Rhizopus chinensis, with significant antineoplastic activity in several murine and human tumor models. In this Phase I study, the drug was administered by i.v. bolus injection at 3-wk intervals. Twenty-four patients with refractory solid tumors were treated; 60 courses of rhizoxin were given, at doses ranging from 0.8 to 2.6 mg/m2. Grade 3 mucositis, Grade 4 leukopenia, and Grade 3 diarrhea were dose limiting but reversible at 2.6 mg/m2, the maximum tolerated dose for both previously untreated and heavily pretreated patients. Alopecia and moderate discomfort at the injection site occurred at all doses. Other sequelae, including peripheral neuropathy, phlebitis, and nausea and vomiting, were sporadic and mild. Two heavily pretreated patients with recurrent breast cancer had minor responses to rhizoxin, one at 1.6 mg/m2 and the other at 2.6 mg/m2. Plasma concentrations of rhizoxin were measured by high-performance liquid chromatography. The drug was not detectable (less than 5 ng/ml) at doses of 0.8 mg/m2 and 1.6 mg/m2 and was not measurable 10 min after injection at 2.0 mg/m2. At 2.6 mg/m2, there was considerable intersubject variation in the plasma concentration-time profiles; the area under the curve ranged from 0.29 to 0.96 microgram/ml.min. Rhizoxin has shown some clinical activity in this Phase I study, and a dose of 2.0 mg/m2 is recommended for Phase II studies using this schedule.

Replacement of cisplatin with carboplatin in combination chemotherapy against ovarian cancer: long-term treatment results of a study of the Gynaecological Cancer Cooperative Group of the EORTC and experience at The Netherlands Cancer Institute.

Carboplatin-based chemotherapy has been evaluated in three studies of ovarian cancer patients. In the first, combination cisplatin and carboplatin plus doxorubicin/hexamethylmelamine/cyclophosphamide were compared as first-line treatment of ovarian cancer in 341 women with stage IIB to IV disease. There were no observed differences in results between the two treatment groups. In the second study, conventional doses of intravenous carboplatin (350 mg/m2, given on day 1) plus oral cyclophosphamide (100 mg/m2 days 2 to 6) were given to late-relapsing patients (12 to 72 months) previously treated with cisplatin. Mature data showed a 55% overall response rate, acceptable toxicity, and an absence of additive neurotoxicity. Finally, 65 patients with refractory disease or in early relapse after cisplatin therapy (within 12 months) were treated with high-dose carboplatin (800 mg/m2). Toxicity was severe, but the 45% combined response rate was considered encouraging and worthy of further evaluation. It was concluded that carboplatin is an appropriate replacement for cisplatin in the treatment of ovarian cancer.