Phase I pharmacokinetic and pharmacodynamic study of recombinant human endostatin in patients with advanced solid tumors.

PURPOSE: Endostatin is the first endogenous angiogenesis inhibitor to enter clinical trials. Laboratory investigations with endostatin have indicated broad antitumor activity coupled with remarkably low toxicity. A phase I trial of recombinant human endostatin was designed to evaluate toxicity and explore biologic effectiveness in patients with refractory solid tumors. PATIENTS AND METHODS: Endostatin was administered as a 1-hour intravenous infusion given daily for a 28-day cycle. A starting dose of 30 mg/m2 was explored with subsequent dose escalations of 60, 100, 150, 225, and 300 mg/m2. Assessment of serum pharmacokinetics was performed on all 21 patients. Western blot assay and mass spectroscopy were employed to evaluate endostatin metabolism. Circulating levels of endogenous proangiogenic growth factors were examined. Tumor and tumor blood supply were imaged by dynamic computed tomography (CT), magnetic resonance imaging, ultrasound, and positron emission tomography. RESULTS: Endostatin given on this schedule was essentially free of significant drug-related toxicity. Two transient episodes of grade 1 rash were observed. No clinical responses were observed. Endostatin pharmacokinetics were linear with dose, and serum concentrations were achieved that are associated with antitumor activity in preclinical models. No aggregate effect on circulating proangiogenic growth factors were seen, although several patients exhibited persistent declines in vascular endothelial growth factor levels while enrolled in the study. A few patients demonstrated changes in their dynamic CT scans suggestive of a decline in microvessel density, although overall, no consistent effect of endostatin on tumor vasculature was seen. CONCLUSION: Endostatin given daily as a 1-hour intravenous infusion was well tolerated without dose-limiting toxicity at doses up to 300 mg/m2.

A phase I trial of perifosine (NSC 639966) on a loading dose/maintenance dose schedule in patients with advanced cancer.

Perifosine (NSC 639966) is a synthetic, substituted heterocyclic alkylphosphocholine that acts primarily at the cell membrane targeting signal transduction pathways. Early clinical trials were limited because of dose-limiting gastrointestinal toxicity, and parenteral dosing of this class of agents is not possible because of their hemolytic properties; therefore, related compounds with an improved therapeutic index were developed. Toxicity was minimized and efficacy improved by using a loading dose/maintenance dose schedule, and therefore, this schedule was carried into clinical trials. This phase I trial enrolled 42 patients with incurable solid malignancies. The starting doses were 100 mg p.o. x four doses (every 6 hours) load followed by a 50 mg p.o. once daily maintenance dose with escalation of either component in successive dose levels. No treatment related deaths occurred. The maximum-tolerated dose was determined to be 150 mg p.o. x four doses load and 100 mg p.o. once daily maintenance. Dose-limiting toxicities such as nausea, diarrhea, dehydration, and fatigue were seen early during the loading phase and were surmountable with the use of prophylactic 5-HT3 receptor antagonists, dexamethasone, and loperamide. Toxicities during the chronic phase were difficult to manage and, given that pharmacokinetic data showed biologically active serum concentrations (based on preclinical data), raised the question of less frequent maintenance dosing. Pharmacokinetic data confirmed the maintenance of stable drug levels with chronic dosing and the long half-life. One partial response was seen, as were multiple patients with stable disease beyond course 2. These results suggest perifosine activity in sarcoma and perhaps renal cell carcinoma (stable disease in two patients who continued for 6 and 14 courses), thus justifying additional investigation of this agent in a phase II sarcoma trial.

Phase II study of 1alpha-hydroxyvitamin D(2) in the treatment of advanced androgen-independent prostate cancer.

PURPOSE: In this single institution Phase II trial, we evaluated the efficacy of the vitamin D analogue, 1alpha-OH-D(2), in patients with advanced hormone-refractory prostate cancer. EXPERIMENTAL DESIGN: The patients initially received 1alpha-OH-D(2) at 12.5 micro g p.o. every day, which was dose adjusted for hypercalcemia. Given the cytostatic nature of the drug, the primary study end point was progression-free survival for a minimum of 6 months. The secondary end point was further characterization of drug toxicity. RESULTS: A total of 26 patients was enrolled. Using the intent-to-treat population, stable disease was seen for an average of 19.2 weeks (median 12 weeks, range 3-108 weeks). Twenty patients were evaluable for response. The one patient that achieved disease stabilization for >2 years elected to come off-study because of patient preference. His last disease evaluation showed no evidence of progression. No objective responses were seen. Previous and ongoing clinical observations strongly imply that PSA could be a misleading surrogate marker for clinical effect with this type of drug. Therefore, prostate-specific antigen was not used as a marker for disease response. Toxicity was as expected with mild hypercalcemia and associated symptoms like constipation and prerenal azotemia seen in some patients. Six (30%) evaluable patients experienced stable disease for >6 months, suggesting possible cytostatic activity. CONCLUSION: The results of this and other trials suggest further clinical investigation in this disease with vitamin D analogues alone or in combination with other agents, such as chemotherapy, should be pursued.

Phase I clinical and pharmacokinetic study of NSC 655649, a rebeccamycin analogue, given in both single-dose and multiple-dose formats.

PURPOSE: NSC 655649 was given in both single- and multiple-dose formats, to characterize maximum tolerated dose (MTD), toxicity, and pharmacokinetic profile. EXPERIMENTAL DESIGN: Patients with advanced malignancies were treated with escalating doses of NSC 655649 in either a single-dose format (step 1) or a multiple-dose format (step 2). In step 1, NSC 655649 was given as a 30-60 min infusion. In step 2, the NSC 655649 dose was divided into three consecutive daily doses. Plasma and urine were sampled to assess the pharmacokinetic and excretory characteristics of NSC 655649. A total of 12 patients were enrolled at the MTD for the purpose of gender equity. RESULTS: Forty-three patients were treated with NSC 655649 for a total of 108 cycles in step 1, and 26 patients were treated for a total of 41 cycles in step 2. The MTD for both steps 1 and 2 was determined to be 572 mg/m(2). Myelosuppression was the dose-limiting toxicity. Local venous irritation was generally grade 1-2 in severity but could only be adequately prevented by administration of study drug through central i.v. access. One patient with adenocarcinoma of unknown primary experienced a partial response on step 1. Four patients experienced stable disease of >100 days duration. CONCLUSIONS: NSC 655649 may be safely given at an MTD of 572 mg/m(2) in both single-dose and multiple-dose formats. Optimally, this drug should be administered through central i.v. access.

Phase I and pharmacokinetic study of a micronized formulation of carboxyamidotriazole, a calcium signal transduction inhibitor: toxicity, bioavailability and the effect of food.

PURPOSE: This Phase I study was conducted to evaluate the toxicity profile and determine the maximum tolerated dose (MTD) of an oral micronized formulation of the signal transduction inhibitor carboxyamidotriazole (CAI). Bioavailability of the micronized formulation relative to a gelatin capsule (gelcap) formulation was assessed. The effects of food intake and timing on CAI steady-state plasma concentrations (C(ss)) were also investigated. EXPERIMENTAL DESIGN: Patients received continuous daily CAI (28-day cycles). Starting dose was 150 mg/m(2) daily and escalations were by 50 mg/m(2) increments. The first three patients enrolled were given test doses of the original gelcap formulation and two different micronized formulations to determine relative bioavailability. Toxicity and pharmacokinetic assessments were performed weekly. Additional cohorts were added after MTD determination to assess the effect of food intake and duration of fast on CAI C(ss). RESULTS: The micronized formulation was absorbed more slowly than the gelcap formulation. Twenty-nine patients were enrolled in the dose-escalation portion of the study. After dose escalation to 300 mg/m(2), dose-limiting neurotoxicities occurred including reversible vision loss in two patients. Other toxicities were mild. The final MTD was 150 mg/m(2). Pharmacokinetics appeared linear with significant inter- and intrapatient variability. Patients with C(ss) of > or = 4.0 mg/liter were more likely to have neurotoxicity. Nine patients with renal cell cancer and one with hepatocellular cancer had prolonged stable disease. CAI plasma concentrations were higher when taken with food. CONCLUSIONS: Micronized CAI was well tolerated at the MTD of 150 mg/m(2). Higher doses were limited by significant neurotoxicity. The variability in CAI pharmacokinetics may be partially attributable to concomitant food intake and timing of the dose.

Phase I trial of 1alpha-hydroxyvitamin d(2) in patients with hormone refractory prostate cancer.

This Phase I study of 1alpha-hydroxyvitamin D(2), an p.o. administered vitamin D analogue, in patients with advanced hormone-refractory prostate cancer was designed to assess the toxicity, pharmacokinetic and biological markers of drug activity, and lastly tumor response data to recommend a dose for Phase II studies. 1alpha-Hydroxyvitamin D(2) was administered daily at doses ranging from 5 to 15 microg/day. Patients were monitored for toxicity and tumor response, and blood and urine samples were collected for pharmacokinetics (1alpha,25-dihydroxyvitamin D(2) levels) and other parameters of biological activity (bone markers, parathyroid hormone, urine calcium, and serum phosphorus levels). Twenty-five patients were enrolled. Main toxicities were hypercalcemia with associated renal insufficiency. No other significant toxicity was seen. Pharmacokinetics showed an increase in the active metabolite 1alpha,25-dihydroxyvitamin D(2) that reached a plateau by week 4 despite continuous drug dosing. Elevation in daily urinary calcium excretion and serum phosphorus levels was seen, whereas a decrease in serum parathyroid hormone was evident. Two patients showed evidence of a partial response, whereas 5 others achieved disease stabilization for > or =6 months. 1alpha-Hydroxyvitamin D(2) was well tolerated with main toxicities being hypercalcemia and renal insufficiency. All of the toxicity was reversible with drug discontinuation. Evidence for drug activity was seen in surrogate markers, and pharmacokinetic analysis showed substantial increases in vitamin D metabolite levels among the various cohorts. Whereas the defined maximum tolerated dose was not reached, the recommended Phase II dose was 12.5 microg/day given continuously.

Continuous 28-day iododeoxyuridine infusion and hyperfractionated accelerated radiotherapy for malignant glioma: a phase I clinical study.

PURPOSE: To investigate the maximal tolerated dose of a continuous 28-day iododeoxyuridine (IUdr) infusion combined with hyperfractionated accelerated radiotherapy (HART); to analyze the percentage of IUdr-thymidine replacement in peripheral granulocytes as a surrogate marker for IUdr incorporation into tumor cells; to measure the steady-state serum IUdr levels; and to assess the feasibility of continuous IUdr infusion and HART in the management of malignant glioma. METHODS AND MATERIALS: Patients were required to have biopsy-proven malignant glioma. Patients received 100 (n = 4), 200 (n = 3), 300 (n = 3), 400 (n = 6), 500 (n = 4), 625 (n = 5), or 781 (n = 6) mg/m(2)/d of IUdr by continuous infusion for 28 days. HART was started 7 days after IUdr initiation. The total dose was 70 Gy (1.2 Gy b.i.d. for 25 days with a 10-Gy boost [2.0 Gy for 5 Saturdays]). Weekly assays were performed to determine the percentage of IUdr-DNA replacement in granulocytes and serum IUdr levels using standard high performance liquid chromatography methods. Standard Phase I toxicity methods were used. RESULTS: Between June 1994 and August 1999, 31 patients were enrolled. No patient had Grade 3 or worse HART toxicity. Grade 3 or greater IUdr toxicity predominantly included neutropenia (n = 3), thrombocytopenia (n = 3), and elevated liver function studies (n = 3). The maximal tolerated dose was 625 mg/m(2)/d. Thymidine replacement in the peripheral granulocytes peaked at 3 weeks and increased with the dose (maximal thymidine replacement 4.9%). The steady-state plasma IUdr level increased with the dose (maximum, 1.5 microM). CONCLUSION: In our study, continuous long-term IUdr i.v. infusion had a maximal tolerated dose of 625 mg/m(2)/d. Granulocyte incorporation data verified the concept that prolonged IUdr infusion results in IUdr-DNA replacement that corresponds to a high degree of cell labeling. IUdr steady-state plasma levels increased with increasing dose and attained levels needed for clinical radiosensitization. Continuous IUdr infusion and HART were both feasible and well tolerated.

Phase I clinical and pharmacokinetic trial of the cyclin-dependent kinase inhibitor flavopiridol.

PURPOSE: Flavopiridol (NSC 649890) is a synthetic flavone possessing significant antitumor activity in preclinical models. Flavopiridol is capable of inducing cell cycle arrest and apoptosis, presumably through its potent, specific inhibition of cyclin-dependent kinases. We conducted a phase I trial and pharmacokinetic study of flavopiridol given as a 72-h continuous intravenous infusion repeated every 2 weeks. METHODS: A total of 38 patients were treated at dose levels of 8, 16, 26.6, 40, 50 and 56 mg/m(2)/24 h. During the first infusion, plasma was sampled at 24, 48 and 72 h to determine steady-state concentrations, and peripheral blood lymphocytes were assessed by flow cytometry for evidence of apoptosis. Additional postinfusion pharmacokinetic sampling was done at the 40 and 50 mg/m(2)/24 h dose levels. RESULTS: Gastrointestinal toxicity was dose limiting, with diarrhea being the predominant symptom. Symptomatic orthostatic hypotension was also frequently noted. Several patients experienced tumor-specific pain during their infusions. The maximum tolerated dose (MTD) was determined to be 40 mg/m(2)/24 h. A patient with metastatic gastric cancer at this dose level had a complete response and remained disease-free for more than 48 months after completing therapy. Plasma concentrations at 24 h into the infusion were 94% of those achieved at steady state. Steady-state plasma flavopiridol concentrations at the MTD were 416.6+/-98.9 micro M. These concentrations are at or above those needed to see cell cycle arrest and apoptosis in vitro. The mean clearance of flavopiridol over the dose range was 11.3+/-3.9 l/h per m(2), similar to values obtained preclinically. Elimination was biphasic. The terminal half-life at the MTD was 26.0 h. No significant differences in pharmacokinetic parameters were noted between males and females. Patients taking cholestyramine to ameliorate flavopiridol-induced diarrhea had lower steady-state plasma concentrations. There was no significant change in the cell cycle parameters of peripheral blood lymphocytes analyzed by flow cytometry. CONCLUSIONS: The MTD and recommended phase II dose of flavopiridol given by this schedule is 40 mg/m(2)/24 h. The manageable gastrointestinal toxicity, early signs of clinical activity and lack of hematologic toxicity make further exploration in combination trials warranted.

A phase I trial of perillyl alcohol administered four times daily for 14 days out of 28 days.

PURPOSE: Perillyl alcohol (POH) has been shown to have both chemopreventative and chemotherapeutic activities in preclinical studies. The underlying mechanism(s) of action of POH have yet to be delineated but may involve effects on the transforming growth factor beta (TGFbeta) and/or the Ras signaling pathways. A phase I study of POH for 14 days out of every 28 days in subjects with advanced malignancies was performed to evaluate dose escalation, toxicity, pharmacokinetics, and effects on TGFbeta and Ras. METHODS: POH was administered orally (500 mg capsules containing 250 mg POH) to 20 patients four times a day on a continuous basis for 14 days followed by a 14-day rest period, for up to three courses. The starting dose was 1200 mg/m(2) per dose. A minimum of three patients were treated and evaluated at each escalating POH dose. Pharmacokinetic analysis was performed on days 1 and 14 of course 1 and day 1 of selected later courses. Plasma TGFbeta levels were measured on days 1 and 14. Peripheral blood lymphocyte (PBLs) Ras levels were assayed on days 1 and 2 of the first course. RESULTS: The 20 patients, of whom 15 were evaluable, received doses between 1200 and 2000 mg/m(2) per dose for a total of 43 courses. The most common observed toxicities were nausea, gastrointestinal distress, and fatigue. Other toxicities included diarrhea or constipation, hypokalemia, and one incidence of acute pancreatitis. Due to these toxicities, four of the patients declined further treatment either during or after the second course. While POH was not detected in plasma, perillic acid (PA) and dihydroperillic acid (DHPA) were detected in plasma, and the peak levels at 2000 mg/m(2) per dose were approximately 600 micro M (PA) and 50 micro M (DHPA). There was some evidence for linearity in the peak plasma levels and area under the concentration-time curve of the metabolites from the starting dose to the highest dose. Metabolite pharmacokinetics were not significantly affected by ingestion in the fed or fasting state, or repeated exposure to POH. No evidence for an effect of POH on plasma TGFbeta or PBL Ras protein was observed. No objective responses were observed. CONCLUSIONS: In adults with advanced malignancies, an interrupted administration schedule of POH did not reveal significant advantages over continuous dosing schedules.

Phase I study of docetaxel and topotecan in patients with advanced malignancies.

BACKGROUND: Docetaxel and topotecan are drugs with different mechanisms of action and significant activity against various tumour types. Topotecan may influence docetaxel metabolism by inhibiting the CYP3A4 enzyme. We designed a phase I study to evaluate the maximum tolerated dose of this combination and to assess the impact of pharmacokinetic interactions of the two drugs on toxicity. METHODS: Docetaxel and topotecan were administered intravenously on day 1, and days 1 - 5 respectively, using a phase I dose escalation design. Plasma samples were analysed to determine docetaxel and topotecan concentration by HPLC with subsequent pharmacokinetic analysis using NONMEM. RESULTS: Of the 17 patients enrolled in the trial, 11 had grade 3 and 4 neutropenia and 1 had grade 4 thrombocytopenia. Nonhaematological toxicities were less frequent. The maximum tolerated dose for docetaxel and topotecan were 60 mg/m(2) on day 1 and 0.75 mg/m(2) days 1 - 5, respectively. One patient had stable disease. Subjects with grade >or= 3 haematologic toxicity had higher plasma docetaxel or topotecan area under the curve (AUC) (docetaxel 1.03 +/- 0.11 mg-hr/L versus 0.73 +/- 0.13 mg-hr/L; topotecan 65.8 +/- 14.6 mcg-hr/L versus 41.6 +/- 13.9 mcg-hr/L). There was no additive effect of the AUC of the two drugs on the likelihood of grade >or= 3 haematologic toxicity by multiple logistic regression. CONCLUSION: The dose-limiting toxicity seen with the combination of docetaxel and topotecan was myelosuppression. Future trials will require growth factor support if this combination is pursued.

Phase I trial of the polyamine analog N1,N14-diethylhomospermine (DEHSPM) in patients with advanced solid tumors.

BACKGROUND: This phase I study was conducted to determine maximal tolerated dose (MTD) and dose-limiting toxicities (DLT) in patients with advanced solid tumors treated with the polyamine analog N1, N14-diethylhomospermine (DEHSPM). METHODS: Patients were treated with DEHSPM administered as a subcutaneous (SC) injection daily for five consecutive days repeated every 4 weeks. Three dose levels were examined starting at 12.5 mg/m2/day, escalating to 37.5 mg/m2/day. RESULTS: A total of 15 patients were enrolled. Dose limiting toxicities (grade 3 or 4) included nausea, vomiting, constipation, ileus, elevations of aspartate aminotransferase (AST) and alkaline phosphatase, hyperbilirubinemia, and ventricular bigeminy. CONCLUSION: DEHSPM given as a SC injection is overall well tolerated at lower doses, but significant toxicities were observed at the 37.5mg/m2/day dose level. MTD was established at 25 mg/m2/day but further investigation with this study drug is not recommended secondary to the potential for neurotoxicities and hepatic damage as a result of cumulative doses.

Gemcitabine, Paclitaxel, and piritrexim: a phase I study.

Piritrexim is a new antifolate that has shown activity in methotrexate-resistant tumors. Gemcitabine is an antimetabolite similar in structure to cytosine arabinoside with early studies demonstrating activity in a variety of cancers. It also has apparent synergistic activity with antifolates from initial work in tumor models. Paclitaxel is an antimicrotubule agent that has a wide spectrum of activity against a variety of solid tumors. The combination of gemcitabine, paclitaxel, and piritrexim was assessed in this phase I trial. Thirty patients were enrolled. The starting doses were piritrexim 25 mg orally twice daily (days 1-4, 15-18), paclitaxel 75 mg/m2 (days 1, 15), and gemcitabine 750 mg/m2 (days 1, 15), which then was escalated in a stepwise fashion. Four patients achieved stable disease while on study, whereas one patient with a poorly differentiated neuroendocrine tumor achieved a partial response. The main toxicity was myelosuppression. The maximum tolerated dose was thought to be piritrexim 25 mg orally three times daily (days 1-4), paclitaxel 150 to 175 mg/m2 (days 1, 15), and gemcitabine 1,000 mg/m2 (days 1, 15). The combination of these new antifolates with paclitaxel and gemcitabine appears safe and should be considered for phase II trials in known responsive tumors such as transitional cell carcinomas.

Phase I study of eniluracil, oral 5-fluororacil and gemcitabine in patients with advanced malignancy.

PURPOSE: The objectives of this trial were to assess the maximal tolerated dose and toxicity of the combination of oral eniluracil and 5-fluorouracil and intravenous gemcitabine. PATIENTS AND METHODS: Patients with histologically confirmed, incurable malignancy (solid tumor or lymphoma) refractory to standard therapy or for which no standard therapy exists were enrolled. The treatment plan consisted of weekly gemcitabine for three weeks with twice daily dosing of 5-FU and eniluracil for 21 days beginning on day one of gemcitabine. Cycles repeated on an every four week schedule. The initial cohort received gemcitabine 800 mg/m2, oral 5-FU 0.6 mg/m2 and eniluracil 6.0 mg/m2. RESULTS: Twenty-six patients were enrolled. Eight patients received less than 2 cycles of therapy. Hematologic and gastrointestinal toxicity predominated, with 48% of courses resulted in grade one or two neutropenia. Hematologic toxicity was dose limiting. One treatment related death occurred. CONCLUSIONS: The combination of eniluracil, 5-fluorouracil and gemcitabine offers an oral alternative for 5-FU administration. The recommended phase II dose is gemcitabine 1000 mg/m2, 5FU 1.2 mg/m2 and eniluracil 12 mg/m2.

Phase II trial of perillyl alcohol (NSC 641066) administered daily in patients with metastatic androgen independent prostate cancer.

OBJECTIVE: We conducted a phase II multicenter trial of perillyl alcohol in patients with advanced hormone refractory prostate cancer (HRPC). The primary endpoint was to evaluate the 6-month progression-free survival given the potential cytostatic nature of the drug. Secondary objectives included assessing acute and chronic toxicities, as well as measuring objective response rates. METHODS: Patients with metastatic androgen-independent prostate cancer that failed at least one prior chemotherapeutic or experimental regimen were eligible. Perillyl alcohol was administered orally at 1200 mg/m2/dose four times daily and continued until disease progression or development of unacceptable toxicity. RESULTS: Fifteen patients were eligible. Six patients received less than one cycle (4 weeks) of drug, four of which stopped because of drug intolerance. Only six patients received more than two cycles of therapy and were considered evaluable for response. Main toxicity included grade 1-2 gastrointestinal intolerance (nausea/vomiting in 60% of the patients) and fatigue (47%). One patient developed a grade 4 hypokalemia that was felt likely attributable to the drug. No objective responses were seen. All patients either progressed or withdrew from the study secondary to drug intolerance before the 6-month time period. CONCLUSION: Perillyl alcohol administered at this dose and formulation did not have any objective clinical activity in this patient population.