Clinical evaluation of mitoxantrone and piroxicam in a canine model of human invasive urinary bladder carcinoma.

PURPOSE: Cyclooxygenase inhibitors show promise in chemoprevention and therapy of certain carcinomas, an effect that may be additive to that of standard chemotherapy. The purpose of this study was to evaluate the efficacy of combined therapy using the cyclooxygenase inhibitor, piroxicam, and mitoxantrone against a relevant canine model of human invasive bladder cancer. EXPERIMENTAL DESIGN: Fifty-five dogs with transitional cell carcinoma of the urinary bladder were enrolled in this nonrandomized one-armed prospective multi-institutional clinical trial. Mitoxantrone was administered i.v. (5 mg/m(2)) every 21 days for four treatments, and piroxicam was administered p.o. (0.3 mg/kg/day) for the study duration. Tumor staging was performed at baseline, day 42 and every 3 months after protocol completion. Endpoints included time-to-treatment failure and survival time (ST). RESULTS: Response data were available for 48 dogs and included one complete response, 16 partial responses, 22 with disease stabilization, and 9 with progressive disease for an overall 35.4% measurable response rate. Subjective improvement occurred in 75% of treated dogs. Median time-to-treatment failure and ST were 194 and 350 days, respectively. Using censoring and end point definitions similar to those of previous reports of dogs treated with piroxicam alone, the median ST in this study was 291 days, compared with 181 days with piroxicam alone. Diarrhea and azotemia were the most common treatment complications. CONCLUSIONS: Mitoxantrone/piroxicam induced remission more frequently than previously reported for either drug as a single agent in this canine model of invasive human transitional cell carcinoma. Additional evaluation of these drugs in combination protocols should be explored.     

Cisplatin versus cisplatin combined with piroxicam in a canine model of human invasive urinary bladder cancer

Purpose: More than 12,000 people are expected to die from invasive transitional cell carcinoma (TCC) of the urinary bladder each year in the United States, indicating that more effective therapy is needed. Drugs inhibiting cyclooxygenase (cox) have recently been found to have chemopreventive and antitumor activity and may potentiate the effects of chemotherapy. The purpose of this study was to determine whether cisplatin combined with the cox-inhibitor piroxicam would induce remission more frequently than cisplatin alone in a relevant animal model of human invasive TCC. Methods: Pet dogs with naturally occurring, histopathologically confirmed, measurable TCC of the urinary bladder were randomized to receive cisplatin (60 mg/m² i.v. every 21 days) or cisplatin (same dosage) combined with piroxicam (0.3 mg/kg orally every 24 h). Complete staging was performed prior to and at 6-week intervals during therapy. Results: After eight dogs had been evaluated in each treatment group, a significant difference in remission rate was noted (Fisher's Exact test, P < 0.004). Tumor responses in the cisplatin/piroxicam group included two complete remissions (CR), four partial remissions (PR), two stable disease (SD), and no progressive disease (PD). Tumor responses to cisplatin alone in eight dogs were no CR, no PR, four SD, and four PD. Six additional dogs were treated with cisplatin/piroxicam, and in total 10 of 14 dogs had remission (two CR, eight PR). Renal toxicity of cisplatin/piroxicam was frequent and dose limiting. Conclusions: Cisplatin/piroxicam induced remission more frequently than cisplatin alone in a canine model of human invasive TCC. Strategies to reduce renal toxicity need to be developed prior to evaluation of cisplatin/piroxicam in humans or general use of this treatment in pet dogs. Received: 21 October 1999 / Accepted: 20 March 2000     

Preclinical evaluation of antiangiogenic thrombospondin-1 peptide mimetics, ABT-526 and ABT-510, in companion dogs with naturally occurring cancers.

PURPOSE: The angiogenic phenotype of malignant cancers has been established as a target for cancer therapy. ABT-526 and ABT-510, two peptide mimetics of thrombospondin-1 (TSP-1), block angiogenesis in vitro and in vivo and slow tumor growth in mice. To guide the clinical development of these drugs, translational studies in dogs with naturally occurring cancers were initiated. EXPERIMENTAL DESIGN: A prospective open-label trial using ABT-510 or ABT-526 in pet dogs with measurable malignant spontaneously arising tumors. Endpoints included safety, pharmacokinetics, antitumor activity, and preliminary assessment of changes in circulating endothelial cell populations. RESULTS: Two-hundred and forty-two dogs were sequentially entered to this open-label trial. The elimination half-life for ABT-510 and ABT-526 was 0.7 and 0.8 h, respectively (range, 0.5-1 h). No dose-limiting toxicities were seen in any dogs (N = 242). Forty-two dogs receiving peptide had objective responses (>50% reduction in tumor size; n = 6) or significant disease stabilization. Most objective responses were seen after 60 days of exposure to the TSP-1 peptide. Antitumor activity was similar for both peptides and was seen in several histologies, including mammary carcinoma, head and neck carcinoma, soft tissue sarcoma, cutaneous T-cell lymphoma, and non-Hodgkin's lymphoma. Assessment of circulating endothelial cell populations in a small subset of dogs suggested that effective exposure to TSP-1 peptides may be associated with reductions in circulating endothelial cells. CONCLUSIONS: These results support the safety and activity of ABT-526 and ABT-510 in dogs with naturally occurring malignant cancers. Data from this preclinical trial support the development of TSP-1 mimetic peptides as anticancer agents.     

Yoshi 864 (NSC 102627) 1-propanol, 3, 3'-iminodi-dimethanesulfonate (ester) hydrochloride: a phase 1 study.

Yoshi 864 was given i.v. push daily times 5 with 6 weeks' followup. Dose escalation was from 0.25 mg/kg to 2.7 mg/kg. Toxicity and effectiveness were first seen at 1.5 mg/kg. Twenty-five courses were given to 16 patients at or above this level. In 16 of 22 courses, exclusive of CML, thrombopenia and/or leukopenia occurred. Mean platelet and WBC nadirs occurred on day 24 and 29 with recovery taking 1-2 weeks and 2-3 weeks respectively. Hb fell in 11 courses. At 2.7 mg/kg, nausea and vomiting lasting 6-12 days occurred in 3 of 7 courses; during 5 coures patients slept 20 hours a day, and 1 was comatose for 2 days. Two patients with squamous cell carcinoma and 1 with an unknown primary responded. Both patients with CML had clinical remissions. It is recommended that a cooperative Phase II Study in a broad spectrum of human solid tumors including lymphomas and chronic myelocytic leukemia be undertaken at a dose level of 2 mg/kg.     

A phase I and pharmacokinetic study of amphethinile

Amphethinile is a new spindle poison with a novel structure that has shown activity in the L1210, ADJ/PC6 and Walker carcinoma rodent tumours. In addition the agent appeared to have an improved therapeutic ratio compared to existing spindle poisons and is well absorbed when administered orally. The starting dose for the phase I study was 40 mg m-2 (1/10th mouse LD10) and further patients were studied at 200, 400, 800 and 1200 mg m-2, dose escalation being based on pharmacological monitoring. Significant toxic effects were seen only at 800 and 1200 mg m-2. At these doses patients experienced nausea and vomiting, light headedness during the infusion and varying degrees of lethargy following therapy. Two of six patients at 800 mg m-2 developed severe pain in the tumour bearing area 1-2 h after treatment and one experienced colicky abdominal pain. At 1200 mg m-2 two patients died within 48 h of treatment from what appeared to be vascular causes. Following these episodes the trial was discontinued. Neutropenia and alopecia occurred in two patients, one at 800 and one at 1200 mg m-2. These patients achieved the highest drug exposure in terms of area under the concentration x time curve. It was not possible to achieve an AUC consistently high enough to produce cytotoxic effects due to the occurrence of dose limiting toxicities thus amphethinile cannot at present be recommended for phase II testing by the i.v. route. The dose escalation scheme based on pharmacological monitoring resulted in a considerable saving in the duration of the trial. Further evaluation of this methodology is recommended.     

In vitro and in vivo evaluation of combined calcitriol and cisplatin in dogs with spontaneously occurring tumors

PURPOSE: Calcitriol potentiates cisplatin-mediated activity in a variety of tumor models. We examine here, the effect of calcitriol and cisplatin pre-clinically and clinically in canine spontaneous tumors through in vitro studies on tumor cells and through a phase I study of calcitriol and cisplatin to identify the maximum-tolerated dosage (MTD) of this combination in dogs with cancer and to characterize the pharmacokinetic disposition of calcitriol in dogs. METHODS: Canine tumor cells were investigated for calcitriol/cisplatin interactions on proliferation using an MTT assay in a median-dose effect analysis; data were used to derive a combination index (CI). Cisplatin was given at a fixed dosage of 60 mg/m(2). Calcitriol was given i.v. and the dosage was escalated in cohorts of three dogs until the MTD was defined. Serum calcitriol concentrations were quantified by radioimmunoassay. RESULTS: In vitro, CIs < 1.0 were obtained for all combinations of calcitriol/cisplatin examined. The MTD was 3.75 mug/kg calcitriol in combination with cisplatin, and hypercalcemia was the dose-limiting toxicosis. The relationship between calcitriol dosage and either C (max )or AUC was linear. Calcitriol dosages >1.5 mug/kg achieved C (max) >/= 9.8 ng/mL and dosages >1.0 mug/kg achieved AUC >/= 45 h ng/mL. CONCLUSIONS: Calcitriol and cisplatin have synergistic antiproliferative effects on multiple canine tumor cells and high-dosages of i.v. calcitriol in combination with cisplatin can be safely administered to dogs. C (max) and AUC at the MTD 3.75 mug/kg calcitriol exceed concentrations associated with antitumor activity in a murine model, indicating this combination might have significant clinical utility in dogs.     

Decreased tumor oxygenation after cyclophosphamide, reoxygenation and therapeutic enhancement with a perflubron emulsion carbogen breathing

Oxygen profiles of the rat mammary 13672 carcinoma were determined using a pO2 histograph prior to treatment and 24 h and 48 h after i.p. administration of a single dose of cyclophosphamide (300 mg/kg). The tumors were severely hypoxic at 24 h post the administration of cyclophosphamide. There was little increase in oxygenation of the tumors at 48 h post therapy compared with 24 h post therapy indicating that reoxygenation after cyclophosphamide was occurring very slowly in this tumor. Carbogen breathing improved the oxygenation of the tumors under each of the conditions studied. Administration of the perflubron emulsion (8 ml/kg) produced little or no change in the oxygenation of the tumors under normal air breathing conditions. However, the addition of carbogen breathing to administration of the perflubron emulsion increased the oxygenation of the tumors to levels equal to or greater than carbogen breathing at the mean/median pO2's. Perhaps most significantly, administration of the perflubron emulsion with carbogen breathing increased the oxygenation of the most hypoxic regions of the tumors but carbogen breathing alone did not. The growth delay of the Lewis lung carcinoma increased with increasing dose.of the perflubron emulsion along with cyclophosphamide (3 x 150 mg/kg) and carbogen breathing (6 h). This combination treatment was most effective when the cyclophosphamide was prepared in the perflubron emulsion. The number of lung metastases decreased in a manner parallel with increased efficacy of the treatment toward the primary tumor.     

Phase I study of melphalan alone and melphalan plus whole body hyperthermia in dogs with malignant melanoma

The maximum tolerated dose of melphalan combined with whole body hyperthermia (WBH) in dogs with spontaneous malignant melanoma was lower than in dogs not receiving WBH by a factor of 1.9 +/- 0.71. Thirty-three dogs were treated monthly with escalating doses of melphalan and followed weekly for toxicity and, when possible, tumour response. Toxicity was manifested as myelosuppression with nadir neutrophil and platelet counts occurring at 7-10 days post-treatment. The TD50 (+/- S.E.), defined by logistic regression analysis, was 0.63 (+/- 0.07) mg/kg and 0.33 (+/- 0.10) mg/kg for melphalan alone and combined with WBH, respectively. Objective tumour response in this limited series occurred in three of fourteen evaluable dogs (three of eleven treated with melphalan alone and none of three treated with WBH plus melphalan). It is concluded that melphalan combined with WBH can be safely administered, although a reduction in dose is necessary. A randomized clinical trial is required to investigate the possibility of achieving therapeutic benefit from combined melphalan and WBH.     

Selective expansion of 5,10-methylenetetrahydrofolate pools and modulation of 5-fluorouracil antitumor activity by leucovorin in vivo

Expansion of CH2THF pools in tissues of BALB/c mice bearing s.c.-implanted EMT6 mammary adenocarcinomas was measured after leucovorin administration. Twenty-four mice were treated with leucovorin at doses of 0, 45, 90, or 180 mg/kg/injection x 8 injections spaced over 48 h. Tumor and bone marrow cytosols were assayed for CH2THF by forming ternary complexes with thymidylate synthase and [3H]FdUMP. Tumor CH2THF pools were expanded significantly at the two higher doses. Marrow levels were not different from controls. Groups of tumor bearing mice were treated with saline, leucovorin, 5-fluorouracil or 5-fluourouracil plus leucovorin on an optimal dosage schedule. Measured plus leucovorin on an optimal dosage schedule. Measured from the last day of treatment, these tumors grew to 10 mm root-mean-square diameters in 3.5 +/- 1.4, 5.0 +/- 1.2, 6.5 +/- 1.5, and 9.3 +/- 1.2 days, respectively. Growth rates were significantly different from controls only in the latter two groups.     

Phase I study of melphalan alone and melphalan plus whole body hyperthermia in dogs with malignant melanoma

The maximum tolerated dose of melphalan combined with whole body hyperthermia (WBH) in dogs with spontaneous malignant melanoma was lower than in dogs not receiving WBH by a factor of 1.9±0.71. Thirty-three dogs were treated monthly with escalating doses of melphalan and followed weekly for toxicity and, when possible, tumour response. Toxicity was manifested as myelosuppression with nadir neutrophil and platelet counts occurring at 7–10 days post-treatment. The TD., (±S.E.), defined by logistic regression analysis, was 0.63 (±0.07) mg/kg and 0.33 (±0.10) mg/kg for rnelphalan alone and combined with WBH, respectively. Objective tumour response in this limited series occurred in three of fourteen evaluable dogs (three of eleven treated with melphalan alone and none of three treated with WBH plus melphalan). It is concluded that melphalan combined with WBH can be safely administered, although a reduction in dose is necessary. A randomized clinical trial is required to investigate the possibility of achieving therapeutic benefit from combined melphalan and WBH.     

Systemic administration of an attenuated, tumor-targeting Salmonella typhimurium to dogs with spontaneous neoplasia: phase I evaluation.

PURPOSE: Genetically modified bacteria are a potentially powerful anticancer therapy due to their tumor targeting capacity, inherent antitumor activity, and ability to serve as efficient vectors for gene delivery. This study sought to characterize the acute and short-term toxicities and tumor colonization rates of a genetically modified Salmonella typhimurium (VNP20009) in dogs with spontaneous tumors, in the context of a phase I dose escalation trial. EXPERIMENTAL DESIGN: Forty-one pet dogs with a variety of malignant tumors received weekly or biweekly i.v. infusions of VNP20009, at doses ranging from 1.5 x 10(5) to 1 x 10(8) cfu/kg. Vital signs and clinicopathologic variables were monitored regularly. Incisional biopsies were obtained before and 1 week following the first infusion for histopathology and bacterial culture. RESULTS: The nominal maximum tolerated dose was 3 x 10(7) cfu/kg, with refractory fever and vomiting being the dose-limiting toxicities. One treatment-related acute death occurred. Bacteria were cultured from tumor tissue in 42% of cases. Thirty-five patients were evaluable for antitumor response. Major antitumor responses were seen in 15% (4 complete response and 2 partial response), and disease stabilization for at least 6 weeks in 10%. CONCLUSIONS: Administration of VNP20009 at doses with acceptable toxicity results in detectable bacterial colonization of tumor tissue and significant antitumor activity in tumor-bearing dogs.     

Application of a continual reassessment method to a phase I clinical trial of capecitabine in combination with cyclophosphamide and epirubicin (CEX) for inoperable or recurrent breast cancer

A phase I clinical trial was started in order to determine the recommended doses of capecitabine and epirubicin, when administered in combination with a fixed dose of cyclophosphamide (600 mg/m(2) day 1 q3 weeks) in patients with inoperable or recurrent breast cancer. This study consists of five dose levels with combinations of three levels of epirubicin (75, 90 and 100 mg/m(2) day 1 q3 weeks) and three levels of capecitabine (1255, 1657 and 1800 mg/m(2)/day consecutive administration for 2 weeks followed by 1 week of rest). Dose escalation and de-escalation decisions are based on a continual reassessment method (CRM). We conducted a survey of the clinical oncologists participating in this trial to determine the dose escalation/de-escalation rule, including a prior distribution for model parameters used in the CRM.     

Phase I trial of topotecan plus vinorelbine with/without filgrastim (G-CSF) in patients with refractory malignancies

The purpose of this study was to determine the maximum tolerated dose (MTD) of topotecan plus vinorelbine with and without filgrastim (granulocyte colony-stimulating factor) in refractory solid tumors. Cohorts of three patients with recurrent solid tumors previously treated with no more than one chemotherapy regimen were entered. All patients had a performance status of 0 to 1 with adequate hepatic, renal, and bone marrow function and were treated with topotecan 1.5 mg/m2 intravenously on days 1 to 3 followed by vinorelbine 25 mg/m2 intravenously on days 1 and 8 without filgrastim every 3 weeks. Dose escalation was based on standard criteria for phase I escalation with a maximum of five patients in a cohort until an MTD was defined (first without then with filgrastim). Three patients were treated at dose level 1 (topotecan 1.5 mg/m2 days 1-3 and vinorelbine 25 mg/m2 days 1 and 8) without filgrastim. All three experienced hematologic dose-limiting toxicity (DLT) including grade IV neutropenia in two patients and grade III thrombocytopenia in one patient. An additional two patients, supported with filgrastim, treated at dose level 1 experienced DLT. One patient had dose-limiting neutropenia and the other had significant nonhematologic toxicity. No objective responses were seen, and all patients died within 6 months of entering the trial. The combination of topotecan and vinorelbine was poorly tolerated in the dose and schedule tested in this phase I trial. Subsequent combinations of these drugs, if warranted, should focus on alternate doses, schedules, or routes of administration.     

Effects of the cyclooxygenase inhibitor, piroxicam, on tumor response, apoptosis, and angiogenesis in a canine model of human invasive urinary bladder cancer.

The mechanisms by which cyclooxygenase inhibitors exert antitumor effects are not completely defined but are postulated to involve antiangiogenic effects and induction of apoptosis. In this study, we determined the effects of the cox inhibitor, piroxicam, on tumor response, apoptotic index, proliferative index, cyclooxygenase-2 expression, prostaglandin E(2) concentration, tumor microvessel density, and urine basic fibroblast growth factor and vascular endothelial growth factor concentrations in pet dogs with naturally occurring invasive transitional cell carcinoma of the urinary bladder. Piroxicam caused reduction in tumor volume in 12 of 18 dogs, and this was strongly associated with induction of apoptosis (Fisher's exact test P < 0.015) and reduction in urine basic fibroblast growth factor concentration.     

Effect of temozolomide and dacarbazine on O6-alkylguanine-DNA alkyltransferase activity and sensitivity of human tumor cells and xenografts to 1,3-bis(2-chloroethyl)-1-nitrosourea

We investigated the ability of 5-(dimethyltriazeno)imidazole-4-carboxamide (DTIC, dacarbazine) and an analogue, temozolomide, to deplete cells or tumors of O⁶-alkylguanine-DNA alkyltransferase (AGT) and to enhance the antitumor effects of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). Human colon cancer (HT29) cell survival was decreased by almost 1 log when treated with 500 M temozolomide prior to 150 M BCNU. Administration of the maximal tolerated dose of DTIC (300 mg/kg) to nude mice carrying HT29 xenografts resulted in complete depletion of AGT activity in tumors at 4 h and 16 h. Administration of 150 mg/kg DTIC caused a 76% reduction in AGT activity at 4 h, but only a 28% reduction at 16 h. The maximally tolerated doses of DTIC and BCNU, alone and in combination, were used to treat nude mice bearing HT29 xenografts. No difference in tumor growth occurred when animals were treated with either BCNU alone (50 mg/kg), DTIC alone (300 mg/kg), DTIC (150 mg/kg) followed by BCNU (12.5 mg/kg), or BCNU (25 mg/kg) followed by DTIC (150 mg/kg). These data suggest that methylating agents such as DTIC may be too toxic to be used in combination with BCNU to deplete tumor alkyltransferase levels effectively and increase the therapeutic index of BCNU.This work was supported by National Institutes of Health Grants CA-47228 (M.E.D.) and 5T32-DK-07134 (R.B.M.).     

Comparative preclinical toxicology and pharmacology of isophosphoramide mustard, the active metabolite of ifosfamide

Background Isophosphoramide mustard (IPM) is the cytotoxic alkylating metabolite of Ifosfamide (IFOS). IPM is being readied for a phase I clinical trial. In the present preclinical study, IPM was evaluated for usage in multidose intravenous (IV) infusion protocols.Methods Mice and dogs received IV IPM daily for 3 days. Single-day dosing—oral and IV—to mice, rats, and monkeys is also reviewed for comparison. Complete toxicology studies were completed in the mice and dogs. For mice, dogs and monkeys, IV pharmacokinetic studies were conducted and compared.Results For mice, the LD₁₀ for the 3-day IV schedule for IPM was calculated to be 119 mg/kg (with 95% confidence limits of 87–134 mg/kg) (combined sexes), and for adult male dogs the maximum tolerated dose (MTD) was 5 mg/kg. Pharmacokinetic studies in mice, dogs and monkeys were compared and projected to human dosing. For dogs that received 10 mg/kg of IPM, T_1/2 was 0.99 h, and clearance was constant (1.01 l/h/kg). IPM was detected from 0 h to 1.5 h after the 5 mg/kg dose and from 0 h to 2 h after the 10 mg/kg dose; none was detected after 2 h. The IV MTD in dogs was 5 mg/kg per day for 3 days. Renal tubular necrosis and bone marrow failure were the causes of death. Transient liver, renal and bone marrow toxicity and gastrointestinal dysfunction were seen at low doses (<5 mg/kg) in dogs. In mice (receiving 100 mg/kg IV) plasma concentrations disappeared in less than 1 h (T_1/2 2 min), with a clearance of 8.44 l/h/kg. For monkeys, the mean T_1/2 was 4.2 h. Median clearance was 1.65 l/h/kg and no IPM was detected 4 h after dosing. No potential IPM metabolites could be detected in any of the studies. In vitro, plasma protein bound 90% of IPM within 5 min of incubation.Conclusions Predictions for human pharmacokinetic parameters and dosing are made from allometric analysis using the above three species. Data predicted an acceptable starting dose of 30 mg/m² with a clearance of 39.5 l/h, and a T_1/2 of 1 h 45 min for a 70-kg patient.     

A phase I and pharmacokinetic study of the novel aza-anthracenedione compound BBR 2778 in patients with advanced solid malignancies.

BBR 2778 is a novel aza-anthracenedione with no cardiotoxicity in preclinical models. This Phase I dose escalation trial of BBR 2778 was conducted to determine the maximum tolerated dose, the dose-limiting toxicity, and the pharmacokinetic profile of BBR 2778 in patients with advanced solid tumors. BBR 2778 was given in three consecutive weekly 30-min i.v. infusions over a 4-week cycle (cy). Thirty patients (pts) were treated with BBR 2778 at doses ranging from 5 to 150 mg/m2/week. The dose levels 5, 10, 16.5, 25, 37.5, 75, 112.5, and 150 mg/m2/week were investigated in 4 pts (9 cy), 3 pts (3 cy), 3 pts (5 cy), 6 pts (9 cy), 1 pt (1 cy), 4 pts (9 cy), 6 pts (18 cy), and 3 pts (4 cy), respectively. The dose-limiting toxicity was neutropenia, typically occurring at day 14. Other toxicities were mild to moderate and were principally thrombocytopenia, lymphopenia, alopecia, nausea, and vomiting and blue coloration of the skin and urine. No significant cardiac toxicity was observed. The plasma dose concentration curve fitted a biexponential profile, with a rapid distribution phase followed by a prolonged elimination phase (mean t1/2,z, 12 h). BBR 2778 displayed a large volume of distribution (range, 9.7-29.7 l/kg) with a high plasma clearance rate (0.75-1.31 l/h/kg). Less than 10% of the dose was recovered in urine as unchanged drug. The maximum tolerated dose was 150 mg/m2/week for 3 weeks, every 4 weeks. On the basis of this study, the recommended dose for Phase II studies is 112.5 mg/m2/week days 1 and 8 with individual optional administration at day 15, every 4 weeks. Antitumor activity was observed in patients with breast, small cell lung carcinoma, and facial cylindroma. This trial showed that BBR 2778 has a manageable toxicity profile on a weekly schedule. This lead compound of the aza-anthracenedione family shows promising antitumor activity and deserves Phase II investigation in patients with high risk of cumulative cardiotoxicity, such as anthracycline-pretreated breast cancer patients.     

Phase I trial of docetaxel with filgrastim support in pediatric patients with refractory solid tumors: a collaborative Pediatric Oncology Branch, National Cancer Institute and Children's Cancer Group trial.

Neutropenia is the dose-limiting toxicity of docetaxel in children. This Phase I trial was designed to determine the maximum tolerated dose, the dose-limiting toxicities, and the incidence and severity of other toxicities of docetaxel with filgrastim (G-CSF) support in children with refractory solid tumors. Docetaxel was administered as an i.v. infusion for 1 h every 21 days with a starting dose of 150 mg/m2 and an escalation to 185 mg/m2 and 235 mg/m2 in subsequent patient cohorts. G-CSF (5 microg/kg/day) was administered s.c., starting 48 h after docetaxel and continuing until the post-nadir neutrophil count reached 10,000/microl. Seventeen patients received 27 courses of docetaxel with G-CSF support. Generalized erythematous desquamating skin rash and myalgias were dose-limiting at 235 mg/m2. Localized and generalized rashes were seen at all of the three dose levels. Neutropenia (median nadir, 95/1microl) occurred at all of the dose levels but was brief in duration and not dose-limiting. Thrombocytopenia was minimal (median platelet count nadir, 139,000/microl), and the severity of neutropenia and thrombocytopenia did not seem to be related to the docetaxel dose. Other docetaxel-related toxicities included hemorrhage (associated with mucositis), sepsis, hypersensitivity reaction, transient elevation of liver enzymes, stomatitis, back pain, asthenia, and neuropathy. One minor response was observed in a patient with colon cancer. The maximum tolerated dose of docetaxel with G-CSF support in children is 185 mg/m2, which is 50% higher than the maximum tolerated dose of docetaxel alone in children and 85 % higher than the recommended adult dose.     

Phase I and pharmacokinetic study of the cytotoxic ether lipid ilmofosine administered by weekly two-hour infusion in patients with advanced solid tumors.

PURPOSE: A Phase I trial was performed to determine the dose-limiting toxicity and maximum tolerated dose, and to describe the pharmacokinetics of the alkyl-lysophospholipid, ilmofosine, when administered as a weekly 2-h infusion in patients with solid tumors. EXPERIMENTAL DESIGN: Thirty-nine patients were entered into a trial of ilmofosine administered weekly for 4 weeks followed by a 2-week rest period. Dose escalation occurred in 10 levels from 12 to 650 mg/m(2). RESULTS: Thirty-six patients were evaluable for toxicity. The median number of cycles per patient was 1 (range, 1-4). Dose-limiting gastrointestinal toxicity occurred at 650 mg/m(2) with grade 3 nausea in two patients and grade 3 vomiting and diarrhea in one patient. Grade 2 diarrhea was observed in four of six patients treated at 550 mg/m(2). In addition, two patients treated at 550 mg/m(2) and two patients treated at 650 mg/m(2) experienced a decline in performance status of two or more levels that was determined to be due to treatment. There were no tumor responses. Stabilization of disease for at least 8 weeks occurred in six patients. Plasma concentrations of ilmofosine and its sulfoxide metabolite were evaluated by high-pressure liquid chromatography. The elimination of both compounds was biexponential with terminal half-lives of approximately 40 h for ilmofosine and 48 h for the sulfoxide. The area under the concentration-time curve was dose-proportional for each compound, and there was no evidence of saturable kinetics. CONCLUSIONS: The dose-limiting toxicity of ilmofosine is gastrointestinal and the recommended dose for Phase II trials is 450 mg/m(2) as a 2-h weekly infusion. The relatively long half-life of ilmofosine and its active metabolite support the use of this intermittent schedule.     

SHORT COMMUNICATION: Piroxicam-induced regression of azoxymethane-induced aberrant crypt foci and prevention of colon cancer in rats

Piroxicam has been shown to prevent azoxymethane (AOM)-inducedaberrant crypt foci and colon cancer in rats. In this communicationwe evaluate whether piroxicam can also cause regression of precancerouslesions identified as aberrant crypt foci, thus preventing theoccurrence of cancer. Male Fischer-344 rats were administered0.125g/kg piroxicam in theirdiet starting either 1 week priorto or 12 weeks after a single subcutaneous injection of AOM(30 mg/kg body wt). The yield of aberrant crypt foci and ofcolon adenomas and adenocarcinomas was determined at 5, 12,27 and 37 weeks after administering the AOM respectively. Whenpiroxicam was administered starting 1 week prior to AOM theyield of aberrant crypt foci at the three initial time pointswas reduced. When the administration of piroxicam was delayeduntil 12 weeks afterAOM the yield of aberrant crypt foci wasreduced from 53.8±8.1 foci/colon at 12 weeks to 11.1±2.0at 27 weeks. At 37 weeks after administering AOM the yield ofcolon tumors was 0.59±0.11 tumors/animal, while in ratsadministered piroxicam beginning either 1 week prior to or 12weeks after AOM the yield was similarly reduced to 0.14±0.07and 0.17±0.07 tumors/animal respectively. Thus piroxicamwas demonstrated not only to prevent, but also to cause regressionof aberrant crypt foci, both of which were associated with theprevention of colon tumors.