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L Janisch

Publications and source records attributed to L Janisch.

At least 19 recordsLinked to original sources
PubMed2000

Development of a schedule-dependent population pharmacodynamic model for rhizoxin without quantitation of plasma concentrations.

In previous phase I reports of short bolus infusion of rhizoxin, problems in assay sensitivity prevented the description of pharmacokinetic-pharmacodynamic relationships, and a pharmacologically guided approach to dose escalation was deemed not feasible. In this report, we describe a mathematical model, which explains the schedule-dependent interpatient pharmacodynamic variability of rhizoxin administered on a continuous infusion schedule. Using patient demographic and toxicity data from 45 patients treated in a phase I dose and duration escalation study of rhizoxin, we sought to model the nadir neutrophil count. We hypothesized that a surrogate derived variable based on dose and duration would reflect a pharmacokinetic parameter that would be a significant covariate. Multiple linear regression analysis was carried out to determine the other significant covariates. Dose/m2 x Log(DUR/ALB) was significantly correlated with the LogANCnadir (Log10 neutrophil nadir; r = 0.56, P < 0.001). Other significant covariates included baseline performance status (PS), baseline serum bilirubin (BIL), and Log10 baseline neutrophil count (LogANCbaseline). Model bias and precision were assessed using the mean prediction error (MPE) and the root mean square error (RMSE) of the ANCnadir, respectively. We constructed 1-4 covariate models. The variability of ANCnadir was modeled with good precision and accuracy with a 4-covariate model (MPE and RMSE 0.113 +/- 0.182 x 10(3) cells/microl and 1.22 x 10(3) cells/microl, respectively). This model should be validated and improved on with further clinical data. We believe that such pharmacodynamic modeling should be explored further to determine its performance and clinical relevance compared with modeling using pharmacokinetic parameters.

Adult↗
PubMed2000

A phase I study of liposomal doxorubicin (Doxil) with topotecan.

New therapies are needed for patients with advanced ovarian cancer who relapse after initial treatment with platinum and/or paclitaxel-based regimens. This study sought to determine the toxicities of combined liposomal doxorubicin (Doxil) and topotecan, and to determine a regimen for future phase II testing in ovarian cancer. Nine patients with advanced malignancies were treated with topotecan 1.0 mg/m2/day X 5 days followed by liposomal doxorubicin at a starting dose of 30 mg/m2 on day 5. Cycles were repeated every 28 days. A total of 13 cycles of therapy were administered. Grade IV neutropenia and grade IV thrombocytopenia developed in both of the two patients treated at the first dose level. Subsequent patients received only 20 mg/m2 liposomal doxorubicin. At that dose level, three patients experienced dose-limiting toxicity (one grade IV neutropenia, two grade IV neutropenia and thrombocytopenia). No responses were observed. These data indicate that the described regimen of liposomal doxorubicin and topotecan is not feasible because of excessive hematologic toxicity. Escalation to doses of liposomal doxorubicin or topotecan that have previously demonstrated antitumor activity was not possible. Future strategies to minimize such toxicity may include limiting eligibility to patients with minimal prior therapy, reducing the number of days of topotecan administration, or use of oral topotecan.

Adult↗
PubMed1998

Phase I clinical and pharmacokinetic study of oral 9-aminocamptothecin (NSC-603071).

PURPOSE: 9-Aminocamptothecin (9-AC) is a topoisomerase I inhibitor with high antitumor activity but poor solubility in conventional vehicles. The purpose of this study was to evaluate the toxicities and pharmacokinetics of a colloidal dispersion (CD) formulation of 9-AC when administered orally on a 5 days per week every 2 weeks schedule. METHOD: This formulation, which was developed for intravenous administration, was orally administered in 20 ml orange juice. A group of 16 cancer patients were treated at doses of 0.2-0.68 mg/m2 daily. RESULTS: Grade 1-2 nausea (n = 9) was common, usually occurring during the last 2 days of dosing. No objective responses or cumulative toxicities were observed. Pharmacokinetic analysis of total 9-AC showed highly variable apparent oral 9-AC clearance and half-life. There was marked interpatient variability at each dose level in the 9-AC AUC and Cmax, and these parameters showed a poor correlation with dose (r2 = 0.07 and 0.38, respectively). CONCLUSIONS: We conclude that this formulation is not suitable for further clinical development because of poor bioavailability and highly variable and/or saturable absorption or elimination. Another formulation developed for oral administration is under study elsewhere.

Adult↗
PubMed1998

Phase I clinical and pharmacologic study of eniluracil plus fluorouracil in patients with advanced cancer.

PURPOSE: To determine the highest dose of fluorouracil (5-FU) that could be safely administered with Eniluracil (776C85; Glaxo Wellcome Inc, Research Triangle Park, NC), an inactivator of dihydropyrimidine dehydrogenase (DPD), on a daily schedule for 5 days, and to define the toxicities of the combination and the pharmacokinetics of 5-FU when administered with 776C85. PATIENTS AND METHODS: Patients with advanced solid tumors refractory to standard therapy were enrolled at two institutions. The study consisted of three periods designed to evaluate the safety, pharmacokinetics, and pharmacodynamics of 776C85 alone (period 1); the effects of 776C85 on the pharmacokinetics of 5-FU (period 2); and the maximum-tolerated dose (MTD) of 5-FU, with or without leucovorin, that could be safely administered with 776C85 (period 3). Cohorts of at least three patients each received oral 776C85 alone at doses of 3.7 mg/m2/d, 18.5 mg/m2/d and 0.74 mg/m2/d. After a 14-day washout period, each patient then received 776C85 daily for 3 days, with a single intravenous (i.v.) bolus dose of 5-FU 10 mg/m2 on day 2. After a second washout period, patients were treated with 776C85 daily for 7 days and 5-FU i.v. bolus on days 2 through 6. The starting dose of 5-FU 10 mg/m2/d was escalated until the MTD was determined. After determination of the MTD of 5-FU given with 776C85, oral leucovorin 50 mg/d on days 2 through 6 was added to determine the MTD of 5-FU with leucovorin in the presence of 776C85. Near the completion of the study, additional cohorts of patients were treated with 776C85 at 50 mg/d and oral 5-FU with or without leucovorin. RESULTS: Sixty-five patients were enrolled onto the study and 60 were assessable for toxicity and response. Bone marrow suppression was the primary and dose-limiting toxicity of this regimen. Other toxicities included diarrhea, mucositis, anemia, anorexia, nausea, vomiting, and fatigue. 776C85 suppressed DPD activity in peripheral-blood mononuclear cells (PBMCs) by at least 90% for at least 24 hours at all dose levels tested. In the presence of 776C85, 5-FU half-life was prolonged, clearance was reduced, and the drug displayed linear pharmacokinetics. Recommended doses for further testing on a daily for 5-day schedule are 776C85 10 mg/d with i.v. 5-FU 25 mg/m2/d; 776C85 10 mg/d with i.v. 5-FU 20 mg/m2/d plus leucovorin 50 mg/d; 776C85 50 mg/d with 5-FU given orally at 15 mg/m2/d with leucovorin at 50 mg/d. CONCLUSION: 5-FU can be safely administered with 776C85; however, the MTDs are considerably lower than those conventionally used, caused, at least in part, by marked alterations in 5-FU plasma pharmacokinetics.

Adult↗
PubMed1997

Evaluation of neuropathy in patients on suramin treatment.

Suramin, a promising chemotherapeutic agent, causes a dose-limiting sensorimotor polyneuropathy. We undertook a phase 1 study of suramin that included serial neurologic and electrophysiologic examinations as part of the safety evaluation. We found that 6 of 41 (15%) patients developed suramin-induced demyelinating neuropathy which resembled Guillain-Barre syndrome clinically. There was 1 asymptomatic patient with electrophysiologic abnormalities suggestive of a demyelinating neuropathy. In addition, 1 patient with mild axonal neuropathy at baseline had deterioration of his symptoms during suramin treatment. Four asymptomatic patients developed electrophysiologic findings suggestive of a mild axonal neuropathy. We conclude that: (1) serial electrophysiologic monitoring is helpful for early detection of suramin-induced neuropathy; and (2) fixed dosing schedule of suramin without adaptive control does not lead to an increased incidence of demyelinating neuropathy when compared to adaptively controlled dosing schedules.

Adult↗
PubMed1996

Mineralocorticoid insufficiency due to suramin therapy.

BACKGROUND: During a Phase I trial of suramin, a novel antineoplastic agent with activity against hormone-refractory prostate carcinoma, the authors observed two patients with clinical mineralocorticoid insufficiency in spite of hydrocortisone replacement therapy. METHODS: The authors retrospectively assessed adrenal cortical function in 20 such patients via adrenocorticotropic stimulation testing, measuring both cortisol and aldosterone responses, either at the time or treatment of immediately after discontinuation of treatment. RESULTS: Two of 9 patients (22%) treated at relatively low dose levels (< or = 1200 mg/m2 on Day 1) demonstrated adrenal cortical insufficiency, as compared with 9 of 11 patients (32%) treated with relatively high doses (> 1200 mg/m2 on Day 1) (P = 0.03 by 1-tailed Fisher's exact test). There appeared to be a cumulative dose-response relationship to the development of glucocorticoid insufficiency, with no instances being observed at doses < 4.8 g/m2 and uniform toxicity occurring at doses > 7.6 g/m2. Long term glucocorticoid insufficiency was present in 1 of 5 patients (20%) tested at an interval of > 90 days after discontinuation of suramin treatment. All instances of glucocorticoid insufficiency were associated with mineralocorticoid insufficiency. Suramin did not affect the absorption or excretion of exogenously administered glucocorticoid in one patient. CONCLUSIONS: Suramin causes both primary mineralocorticoid and primary glucocorticoid insufficiency. This may occur in a dose-dependent manner. Long term glucocorticoid insufficiency appears to occur in a minority of patients treated with low doses of suramin. Patients receiving high doses of suramin for treatment of advanced carcinoma should receive at least physiologic replacement doses of both mineralocorticoid and glucocorticoid. Higher doses of glucocorticoid may be required in selected patients.

Addison Disease↗
PubMed1996

Phase I study of escalating doses of mitoxantrone and paclitaxel with granulocyte-macrophage colony stimulating factor support.

BACKGROUND: Both paclitaxel and mitoxantrone demonstrate significant antineoplastic activity in breast cancer patients. Colony stimulating factor support allows significant dose escalation of each of these drugs when administered as a single agent. METHODS: We performed a Phase I study employing escalating doses of paclitaxel and mitoxantrone with granulocyte-macrophage colony stimulating factor (GM-CSF) support. Initially the paclitaxel dose was fixed at 175 mg/m2 and an attempt was made to escalate mitoxantrone from the starting dose of 14 mg/m2. Subsequently, the dose of mitoxantrone was fixed at 14 mg/m2 and the dose of paclitaxel was increased. Treatments were given every three weeks. RESULTS: In neither case could we safely escalate beyond a combination of paclitaxel 175 mg/m2 and mitoxantrone 14 mg/m2 which is, therefore, the recommended Phase II dose. The dose limiting toxicity was neutropenia. No unexpected toxicities were observed, although two patients were removed from the study because of chest pain possibly related to GM-CSF. There were no complete or partial remissions. CONCLUSIONS: We conclude that GM-CSF does not allow significant dose escalation of this combination of agents.

Adult↗
PubMed1996

Individualized dosing of amonafide based on a pharmacodynamic model incorporating acetylator phenotype and gender.

Amonafide is extensively metabolized, including conversion by N-acetylation to an active metabolite. Our previous studies have shown that fast acetylators of amonafide have increased toxicity, and we have recommended doses of 250 and 375 mg m-2 day-1 for 5 days, for fast and slow acetylators, respectively. Despite phenotype-specific dosing, significant variability in leukopenia persisted. The goal of this study was to construct and validate a pharmacodynamic model-based dosing strategy for amonafide, to try to further decrease inter-patient variability in leukopenia. The model was based on a training data set of 41 patients previously treated with amonafide. The first cycle nadir WBC was modelled as a function of dose, acetylator phenotype and baseline patient factors. This model was validated prospectively on patients similar to those in our previous studies. Based on the training data set, the optimal model was defined by three factors: acetylator phenotype, gender, and pretreatment WBC. Using this model and a target WBC nadir of 1700 microliters-1, six dosing strata were prospectively evaluated. A total of 24 fast acetylators received either 238 or 276 mg m-2 day-1 and 20 slow acetylators received between 345 and 485 mg m-2 day-1. The mean (+/- SE) error (deviation from target nadir) was 430 (+/- 240) cells microliters-1. Submaximal treatment (yielding grade 0-1 leukopenia) was limited to 20% of patients, while 55% experienced grade 2-3 toxicity. A complex dosing strategy for amonafide is feasible, employing prospective acetylator phenotyping, model-guided dosing, and adaptive control.

Acetylation↗
PubMed1995

Encephalopathy is the dose-limiting toxicity of intravenous hepsulfam: results of a phase I trial in patients with advanced hematological malignancies.

Hepsulfam is a bisulfamic ester which is similar in structure to busulfan and is believed to act as a bifunctional alkylator inducing both DNA-DNA and DNA-protein crosslinks. Prior studies in patients with refractory solid tumors have identified the dose-limiting toxicity of hepsulfam to be cumulative myelosuppression resulting in prolonged leukopenia and thrombocytopenia. This phase I trial was designed to determine the maximally tolerated dose of hepsulfam administered intravenously in patients with refractory leukemias and other advanced hematologic malignancies. Hepsulfam was administered as a 30-min or 2-h intravenous infusion to 21 patients with advanced leukemia or multiple myeloma. All patients had been extensively treated and had progressive disease. Cycles were repeated every 5 weeks. Cohorts of patients were treated at 360, 480, 640, and 800 mg/m2. The dose-limiting toxicity of intravenous hepsulfam was severe encephalopathy. The single patient treated at 800 mg/m2 became comatose within 48 h and required 3 weeks for his mental status to return to baseline. There were, however, no irreversible neurological sequelae. Several patients treated at 640 mg/m2 had clinical evidence of toxic deliriums and slowing of alpha rhythm waves on electroencephalograms indicative of a gray-matter encephalopathy. When hepsulfam was infused over 30 min, patients complained of uncomfortable parasthesias, but when the drug was administered over 2 h, these acute symptoms were less common. Myelosuppression was observed in most patients. Among those patients who had some suppression of their leukemia, peripheral blood counts recovered to pretreatment levels after 3-5 weeks. Apart from CNS toxicity, non-hematologic toxicity was minimal. Pharmacokinetic studies demonstrated rapid clearance of hepsulfam so that the drug was not reliably detected in the plasma after 24 h. The recommended phase II dose of hepsulfam as a single 2-h intravenous infusion is 480 mg/m2, but this dose provided relatively little clinical benefit for patients with refractory leukemia. The dose-limiting toxicity is CNS toxicity with increasingly severe encephalopathy at doses > or = 640 mg/m2. It would be reasonable to investigate further dose escalation of hepsulfam in a divided dose schedule to minimize the peak concentrations which may be related to the encephalopathy. EEG monitoring is recommended for early detection of slowing of alpha rhythm waves. Hematopoietic stem cell support will probably be required at total doses exceeding 800 mg/m2.

Adult↗
PubMed1994

Prognostic factors for survival in patients treated in phase I clinical trials.

BACKGROUND: Patients with advanced or metastatic cancer treated in Phase I clinical trials are considered to have a poor prognosis. Survival from first treatment in a Phase I trial was determined for 349 patients. Univariate and multivariate survival analyses were performed to determine whether potential prognostic factors and distinct risk groups could be identified. METHODS: Patients were identified retrospectively from a large data base of patients with advanced or metastatic cancer treated in Phase I clinical trials at the University of Chicago between February 1987 and October 1991. RESULTS: With a median follow-up of 29 months, 10% of patients were alive at the time of analysis. Twenty-nine percent were alive 1 year after the initiation of Phase I chemotherapy, and the median survival from first treatment in a Phase I study was 6.5 months. Multivariate analysis indicated that a better pretreatment performance status, a higher pretreatment serum albumin concentration, a lower pretreatment platelet count, no prior cisplatin chemotherapy, and a genitourinary or gynecologic cancer diagnosis were predictive of better survival. Three risk groups incorporating these five variables were identified, with median survivals of 12.7, 7.4, and 3.5 months for the good, intermediate, and poor risk groups, respectively. CONCLUSION: Patients treated in Phase I clinical trials have a median survival of 6.5 months, even though some patients have been treated at early (subtoxic and potentially subtherapeutic) dose levels. The results of this study may allow the identification of patients who are likely to survive long enough to contribute information on acute and cumulative drug-related toxicities and, possibly, tumor response.

Adult↗
PubMed1994

Phase I and pharmacokinetic study of a new antineoplastic agent: pyrazine diazohydroxide (NSC 361456).

Pyrazine diazohydroxide (PZDH) is a novel antineoplastic agent that appears to form DNA adducts via the reactive pyrazine diazonium ion and produces substantial antitumor activity in preclinical models. We conducted a phase I trial to determine the maximally tolerated dose of PZDH that could be administered as a 5-min i.v. bolus for 5 consecutive days repeated every 28 days. Thirty-one patients with advanced cancer refractory to standard therapy received a total of 65 cycles of therapy at 7 sequential PZDH dose levels: 18, 36, 45, 56, 75, 100, and 133 mg/m2/day. At the maximally tolerated dose (133 mg/m2/day x 5), all 4 patients experienced grade 3-4 thrombocytopenia, and 3 of 4 had grade 3-4 neutropenia. At the recommended phase II dose (100 mg/m2/day x 5), the median WBC nadir following the first cycle was 2.5 x 10(3)/microliters (range, 0.6-7.6) occurring on day 36, and the median platelet nadir was 87 x 10(3)/microliters (range, 9-155) occurring on day 26. Nausea and vomiting occurred at all dose levels, but were well controlled with ondansetron. No evidence of hepatic, renal, pulmonary, cardiac, venous, dermatological, or neurological toxicity was observed. Pharmacokinetic evaluations were performed on 28 of the 31 patients using an analytical method including derivatization of the parent drug to 2-chloropyrazine. We report the total 2-chloropyrazine, which represents PZDH converted per method plus PZDH converted in vivo. Although the assay quantitation limit is 10 ng/ml, PZDH could only be detected at the first dose level for 30-90 min after the i.v. bolus. Compartmental modeling of the first 4 dose levels was most consistent with a 2-compartment model. Subsequent dose levels revealed a third phase to the plasma decay curve. The area under the plasma drug concentration-time curve increased proportionally with dose; there was no evidence for dose-dependent pharmacokinetics. Pharmacokinetic parameters for 12 patients analyzed by the 3-compartment model revealed an alpha-half-life (t1/2 alpha) of 2.83 +/- 1.57 (mean +/- SD), a t1/2 beta of 11.9 +/- 4.42, and a t1/2 gamma of 161 +/- 47.1 min, with a mean clearance of 1.86 +/- 0.91 liters/min. At the 100- and 133-mg/m2 dose levels, the mean areas under the plasma drug concentration-time curve were 105 and 169 micrograms min/ml, respectively. There was a moderate correlation between body surface area and clearance (r = 0.45, P = 0.015) but a better correlation between weight and clearance (r = 0.53, P = 0.004).(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1994

Sequential therapy with dacarbazine and carmustine: a phase I study.

Depletion of the DNA-repair protein O6-alkylguanine-DNA alkyltransferase (AGT) increases the sensitivity of cells in culture and of human tumor xenografts to chloroethylnitrosoureas such as carmustine (BCNU). We have previously demonstrated that dacarbazine (DTIC) can deplete AGT activity in cells in culture and in human tumor xenografts. A phase I trial of DTIC followed immediately by BCNU was conducted to determine the DTIC dose resulting in maximal depletion of AGT in the peripheral blood mononuclear cells (PBMC) of cancer patients and to determine the maximally tolerated dose of DTIC given as a 4-h infusion immediately prior to a fixed dose of BCNU. A 4-h infusion of DTIC followed by a 2-h infusion of BCNU was given to 42 patients with refractory solid tumors. Complete depletion of AGT activity was not achieved at DTIC doses of up to 750 mg/m2. The dose-limiting toxicity was hematologic, although at higher doses of BCNU (> or = 100 mg/m2) we observed significant nonhematologic toxicity. Our recommended phase II doses are 1,000 mg/m2 DTIC followed by 75 mg/m2 BCNU. AGT activity in PBMC of the 28 patients studied decreased to a mean of 62% +/- 11% (SE) of the baseline value at 4 h after initiation of the DTIC infusion. At 24 h after initiation of the DTIC infusion, AGT activity in PBMC was depleted to a mean of 65% +/- 14% of the baseline value. There was no direct correlation between the DTIC dose and the extent of AGT depletion. Baseline PBMC AGT levels varied widely among patients.

Adult↗
PubMed1993

Phase I study of amonafide dosing based on acetylator phenotype.

Amonafide is extensively metabolized, including N-acetylation to an active metabolite. Prior studies have demonstrated that patients who are fast acetylators of amonafide (and other drugs) have increased toxicity at standard doses of amonafide. The primary objective of this study was to define the recommended phase II dose of amonafide separately for slow and fast acetylators. Twenty-six patients with advanced cancer underwent acetylator phenotyping with caffeine and were assigned to a dose level. Slow acetylators were treated at 375 mg/m2 (daily for 5 days) and had a median WBC nadir of 1600/microliters. Fast acetylators were treated at both 200 and 250 mg/m2, resulting in median WBC nadirs of 5300 and 2000/microliter, respectively. Two patients were not typeable, and two patients appear to have been misphenotyped, one in each phenotype category. Pharmacodynamic analysis yielded a model for nadir WBC including acetylator phenotype, 24-h N-acetyl-amonafide plasma concentration, gender, and pretreatment WBC. We recommend doses of 250 and 375 mg/m2 (for 5 days) for further phase II testing of amonafide in fast and slow acetylators, respectively.

Acetylation↗
PubMed1993

A phase I study of subcutaneous recombinant interleukin-2 and interferon alfa-2a.

BACKGROUND: Both recombinant interferon alfa and interleukin-2 (IL-2) have been shown to have some activity as single agents in metastatic renal cell cancer (RCC), although their activity is minimal in more common solid tumors. Recent preclinical studies have suggested that the combination of these two agents is especially promising. METHODS: Subcutaneous recombinant interferon alfa-2a and IL-2 were administered at one of five dose levels to 33 patients with refractory solid tumors, including 21 patients with RCC. A constant ratio of 5:1 of interferon alfa-2a to IL-2 was used. Interferon alfa-2a and IL-2 were administered three and five times weekly, respectively, for a total of 4 weeks, followed by a rest of 1-3 weeks between cycles. RESULTS: The dose-limiting toxic effects included hypotension, nephrotoxicity, and fatigue. At the recommended Phase II dose of 7.5 million units (MU)/m2 of interferon alfa-2a and 1.5 MU/m2 of IL-2, 12 patients were treated. Ten of 12 completed the 4-week cycle without modification. Four patients at that dose level had Grade 3-4 toxic effects. Partial responses were observed in 4 of 16 assessable patients with RCC. CONCLUSIONS: Subcutaneous interferon alfa-2a and IL-2 can be self-administered safely on an outpatient basis. At tolerable doses, responses can be achieved in metastatic RCC.

Adult↗
PubMed1993

Phase I clinical and pharmacological study of iododeoxyuridine and bleomycin in patients with advanced cancer.

Studies previously performed in our laboratory demonstrated synergistic cytotoxicity and DNA strand break formation in human tumor cells following exposure to a combination of bromodeoxyuridine and bleomycin. Synergy was evident when bromodeoxyuridine was administered prior to or simultaneously with bleomycin and occurred over a wide range of concentration ratios. We therefore undertook a phase I clinical trial of the combination of iododeoxyuridine (IdUrd) and bleomycin to determine the maximally tolerated dose of IdUrd that could be administered with a standard dose of bleomycin and to determine the toxicities of the combination. Eligible patients were those with advanced cancer refractory to standard therapy who had a performance status of 0-2, measurable or evaluable disease, and adequate organ function. IdUrd was administered as a 5-day continuous i.v. infusion beginning at a dose of 250 mg/m2/day with escalation in cohorts of 3-6 patients according to a modified Fibonacci scheme. Bleomycin was administered at a dose of 15 mg/m2/day as a continuous i.v. infusion during the last 3 days of the IdUrd infusion. Cycles of therapy were repeated every 28 days. Plasma levels of IdUrd and iodouracil were determined by high performance liquid chromatography. Thirty patients received a total of 79 cycles of IdUrd/bleomycin. Dose-limiting toxicity was bone marrow suppression. At the maximally tolerated IdUrd dose of 2780 mg/m2/day, the median neutrophil nadir after the first cycle of therapy was 805/microliters and the median platelet nadir was 48,000/microliters. Other toxic effects included mucositis, fatigue, nausea, diarrhea, fever, and skin toxicity. Plasma steady-state concentrations of IdUrd increased proportionally to administered IdUrd dose. IdUrd clearance varied from 0.253 liters/min/m2 to 0.503 liters/min/m2 and did not correlate with IdUrd dose. IdUrd dose and concentration correlated significantly with granulocyte and platelet nadirs, and a pharmacodynamic model for white blood cell count nadir could be defined by pretreatment white blood cell count, IdUrd dose, and gender. The recommended IdUrd dose for phase II testing of this combination is 2140 mg/m2/day. Phase II studies will be of particular interest in those diseases, such as carcinomas of the head, neck, and esophagus, where bleomycin has documented activity as a single agent.

Adult↗
PubMed1993

Phase I clinical and pharmacology study of 502U83 given as a 24-h continuous intravenous infusion.

502U83 is an arylmethylaminopropanediol that displays significant antitumor activity in a number of murine and human tumor-model systems. In the present phase I study, a 24-h continuous intravenous infusion of this agent was given every 28 days to patients with advanced or refractory solid tumors. In all, 46 patients received a total of 96 cycles of 502U83 at doses ranging from 25 to 8,000 mg/m2. No significant hematologic, gastrointestinal, or neurologic toxicity was observed. At doses of 2,000 mg/m2 and higher, prolongation of the corrected QT interval on ECG was evident in most patients but was completely reversible, was not associated with arrhythmias, and was not dose-limiting. Dose-limiting pulmonary toxicity characterized by acute onset of dyspnea, severe hypoxemia, interstitial pulmonary edema, and death occurred in three patients treated at the highest dose levels. Plasma concentrations of 502U83 and its metabolites were measured by high-performance liquid chromatography. The 502U83 maximal concentration (Cmax) and area under the concentration-time curve (AUC) were proportional to the delivered dose; however, substantial interpatient variability in total body clearance was noted at all dose levels. Significant conversion of 502U83 to two glucuronide metabolites was detected. Metabolite concentrations were highest in the three patients who succumbed to pulmonary toxicity, although the precise contribution of these metabolites to the observed toxic effects is unknown. In view of the unfavorable clinical profile of QTc prolongation and pulmonary toxicity produced by 502U83, further clinical development of this agent has been suspended.

Adult↗