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Results for “Maximum Tolerated Dose”

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At least 145 records · Page 8Linked to original sources

PubMed2002

Salvage chemotherapy with CPT-11 for recurrent oligodendrogliomas.

OBJECTIVE: A prospective Phase I study designed to establish the maximum tolerated dose and secondarily evaluate response rate to CPT-11 in patients with recurrent oligodendrogliomas (oligos) on anticonvulsant drugs (AEDs). BACKGROUND: Oligos, which constitute 1-2% for all adult brain tumors, are commonly treated with procarbazine, CCNU and vincristine (PCV) chemotherapy. How to treat oligos that have failed PCV, surgery and radiotherapy is more problematic. DESIGN/METHODS: Fifteen patients (age range 24-55 years; gender 10 males; 5 females) with recurrent oligos and on AEDs were treated prospectively with CPT-11. Four cohorts of patients defined by CPT-11 dose were treated. Three patients were treated with 400 mg/m2 every 3 weeks, 3 patients 500 mg/m2, 6 patients 600 mg/m2 and 3 patients 700 mg/m2. Neuroradiographic evaluation was performed after every other dose of CPT-11. In patients with stable or responding disease, two further doses of CPT-11 were administered. Alternative or supportive care was offered to patients with disease progression. RESULTS: Toxicity included neutropenia (3 patients; 1 each with Grade III and Grade IV toxicity); thrombocytopenia (2 patients; 1 with Grade IV toxicity); abdominal pain with or without diarrhea (5 patients; 1 with Grade III toxicity) nausea/vomiting (4 patients). No patient required hospitalization nor did a treatment-related death occur. One patient required a platelet transfusion. Toxicity was a function of CPT-11 dose and the maximum tolerated dose was 600 mg/m2. Cycles (2-12) of CPT-11 were administered (median 4). Response was as follows: partial response (2 patients); stable disease (5 patients); and progressive disease (8 patients). Duration of response ranged from 1.5 to 9 months with a median of 3. In patients with either stable disease or a partial response, response duration was 4.5-9 months (median 6 months). Progression-free survival at 6 months was 33% and 0% at 12 months. Overall survival following initiation of CPT-11 ranged from 2 to 12 months (median 3 months). In patients with either stable or responding disease, median survival was 7 months (range 6-12 months). CONCLUSION: In this small cohort of patients with recurrent low-grade oligos having been treated previously with PCV and on cytochrome P450 enzyme inducing AEDs, CPT-11 has modest palliative efficacy and acceptable toxicity. A dose of 600 mg/m2 every 3 weeks of CPT-11 in patients on AEDs is suggested based on toxicity analysis.

Adult↗

PubMedDate not supplied

Poly(ethylene glycol)-doxorubicin conjugates containing beta-lactamase-sensitive linkers.

7-Aminocephalosporin doxorubicin (AC-Dox) was condensed with monomethoxypoly(ethylene glycol)-propionic acid N-hydroxysuccinimide ester (5 kDa) or with a branched form of poly(ethylene glycol)-propionic acid N-hydroxysuccinimide ester (10 kDa), forming M-PEG-AC-Dox and B-PEG-AC-Dox, respectively. These polymer drug derivatives were designed such that doxorubicin would be released upon Enterobacter cloacae beta-lactamase (bL)-catalyzed hydrolysis. Both M-PEG-AC-Dox (IC50 = 80 microM) and B-PEG-AC-Dox (IC50 = 8 microM) were less toxic to H2981 human lung adenocarcinoma cells than doxorubicin (IC50 = 0.1-0.2 microM) and could be activated in an immunologically specific manner by L6-bL, a monoclonal antibody-bL conjugate that bound to H2981 cell surface antigens. In addition, the polymers were relatively stable in mouse plasma (< 26% hydrolysis after 24 h at 37 degrees C) and were less toxic to mice (maximum tolerated dose > 52 mumol/kg) than doxorubicin (maximum tolerated dose = 13.8 mumol/kg). Pharmacokientic studies were performed in mice bearing subcutaneous 3677 melanoma tumors. B-PEG-AC-Dox cleared from the blood more slowly than M-PEG-AC-Dox and was retained to a 2.1-fold greater extent in human 3677 melanoma tumor xenografts over a 4 h period. The intratumoral concentrations of both polymers far exceeded that of doxorubicin. Thus, the PEG-AC-Dox polymers offer the possibility of generating large intratumoral doxorubicin concentrations owing to their reduced toxicities, the amounts that accumulate in tumors, and the fact that doxorubicin is released upon beta-lactam ring hydrolysis.

Adenocarcinoma↗

PubMed2003

A phase I study of gemcitabine and docetaxel for advanced stage solid tumors.

BACKGROUND: We conducted a phase I study to determine the maximum tolerated dose of docetaxel in combination with gemcitabine for patients with refractory solid tumors. METHODS: From January 1998 to November 1999, we treated 28 patients on a phase I protocol with gemcitabine given at a constant dose of 800 mg/m2 i.v. over 30 minutes on days 1, 8, and 15. Docetaxel was administered by a phase I schedule over 1 hour on day 1 of a 28-day cycle with a starting dose of 50 mg/m2 and increased by increments of 10 mg/m2 based on dose-limiting toxicity (DLT) that occurred in the first cycle. RESULTS: Neutropenia and thrombocytopenia were the dose-limiting toxicities. The maximum tolerated dose was 60 mg/m2. The most significant nonhematologic toxicities included fatigue, nausea, vomiting, mucositis, and hypersensitivity reactions. There was one partial response at 15 months in a patient with gastric cancer and six patients with stable disease for 4.0 to 15.0 months. CONCLUSIONS: The maximum tolerated dose of docetaxel with gemcitabine is 60 mg/m2. A Phase II study in selected primary sites is planned.

Adult↗

PubMed2005

Phase I trial and pharmacokinetic study of raltitrexed in children with recurrent or refractory leukemia: a pediatric oncology group study.

PURPOSE: To evaluate the toxicity, antileukemic activity, and pharmacology of raltitrexed administered weekly for 3 weeks to patients with refractory or recurrent leukemia. EXPERIMENTAL DESIGN: Raltitrexed was administered as a 15-minute infusion for 3 consecutive weeks every 5 weeks, at doses ranging from 1.3 to 2.8 mg/m(2). The first course was used to determine the dose-limiting toxicities and maximum tolerated dose. Correlative studies included an assessment of raltitrexed pharmacokinetics and measurement of plasma 2'-deoxyuridine concentrations, a surrogate measure of thymidylate synthase inhibition. RESULTS: Twenty-one children (18 evaluable) with refractory leukemia received 25 courses of raltitrexed. The dose-limiting toxicity was reversible elevation in liver transaminases at the 2.8-mg/m(2) dose level and the maximum tolerated dose was 2.1 mg/m(2) per dose. Pharmacokinetics were best characterized by a two-compartment model with a clearance of 139 mL/min/m(2) (8.3 L/h/m(2)), a 2.4-L volume of distribution, an initial half-life (t(1/2alpha)) of 6 minutes, and a terminal half-life (t(1/2beta)) of 45 minutes. There were three objective responses. CONCLUSIONS: Raltitrexed was well tolerated when administered as a single agent to children with recurrent or refractory leukemia. We observed preliminary evidence of antileukemia activity using this weekly dosing schedule and these observations support further evaluation of raltitrexed in this population.

Adolescent↗

PubMed1997

Combretastatin A-4, an agent that displays potent and selective toxicity toward tumor vasculature.

Selective induction of vascular damage within tumors represents an emerging approach to cancer treatment. Histological studies have shown that several tubulin-binding agents can induce vascular damage within tumors but only at doses approximating the maximum tolerated dose, which has limited their clinical applicability. In this study, we show that the combretastatin A-4 prodrug induces vascular shutdown within tumors at doses less than one-tenth of the maximum tolerated dose. In vitro studies indicate that a short drug exposure results in profound long-term antiproliferative/cytotoxic effects against proliferating endothelial cells but not cells that are quiescent prior to and during drug exposure. Vascular shutdown, within experimental and human breast cancer models in vivo following systemic drug administration, was demonstrated with a reduction in functional vascular volume of 93% at 6 h following drug administration and persisted over the next 12 h, with corresponding histology consistent with hemorrhagic necrosis resulting from vascular damage. These actions against tumor vasculature and the broad therapeutic window demonstrate the clinical potential of these drugs and warrant further study to elucidate the mechanisms responsible for the antivascular effects of combretastatin A-4.

Adenocarcinoma↗

PubMed2005

Phase I clinical trial of mafosfamide in infants and children aged 3 years or younger with newly diagnosed embryonal tumors: a pediatric brain tumor consortium study (PBTC-001).

PURPOSE: A phase I trial of intrathecal (IT) mafosfamide was performed to determine the optimal dose, dose-limiting toxicities, and incidence and severity of other toxicities when administered in association with concomitant multiagent systemic chemotherapy to children younger than 3 years with newly diagnosed embryonal tumors. PATIENTS AND METHODS: Twenty-five assessable patients received IT mafosfamide at one of six dose levels ranging from 5 mg to 17 mg. Patients were premedicated with dexamethasone (0.15 mg/kg) and morphine (0.1 mg/kg) before receiving IT mafosfamide. Serial samples of CSF for pharmacokinetic studies were obtained in a subset of patients with Ommaya reservoirs. RESULTS: Irritability, presumably secondary to pain or headache during mafosfamide administration, was dose limiting in two of three patients at the 17-mg dose level. The maximum-tolerated dose of IT mafosfamide following premedication with dexamethasone and morphine was 14 mg. CONCLUSION: The maximum tolerated dose and recommended phase II dose of IT mafosfamide in patients younger than 3 years with newly diagnosed embryonal CNS tumors is 14 mg. A trial to assess the efficacy of regional therapy with IT mafosfamide administered with intensive systemic chemotherapy in children younger than 3 years with primary intracranial embryonal tumors is now in progress.

Affect↗

PubMed1997

Phase I trial of docetaxel administered as a 1-hour infusion in children with refractory solid tumors: a collaborative pediatric branch, National Cancer Institute and Children's Cancer Group trial.

PURPOSE: A phase I trial of docetaxel was performed to determine the maximum-tolerated dose (MTD), the dose-limiting toxicities, and the incidence and severity of other toxicities in children with refractory solid tumors. PATIENTS AND METHODS: Forty-four children received 103 courses of docetaxel administered as a 1-hour intravenous infusion every 21 days. Doses ranged from 55 to 150 mg/m2, MTD was defined in heavily pretreated and less heavily pretreated (< or = 2 prior chemotherapy regimens, no prior bone marrow transplantation [BMT], and no radiation to the spine, skull, ribs, or pelvic bones) patients. RESULTS: Dose-related neutropenia was the primary dose-limiting toxicity. The MTD in the heavily pretreated patient group was 65 mg/m2, but the less heavily pretreated patients tolerated a significantly higher dose of docetaxel (maximum-tolerated dose, 125 mg/m2). Neutropenia and constitutional symptoms consisting of malaise, myalgias, and anorexia were the dose-limiting toxicities at 150 mg/m2 in the less heavily pretreated patients. Thrombocytopenia was not prominent, even in patients who experienced dose-limiting neutropenia. Common nonhematologic toxicities of docetaxel included skin rashes, mucositis, and mild elevations of serum transaminases. Neuropathy was uncommon. Peripheral edema and weight gain were observed in two of five patients who received more than three cycles of docetaxel. A complete response (CR) was observed in one patient with rhabdomyosarcoma, a partial response (PR) in one patient with peripheral primitive neuroectodermal tumor (PPNET), and a minimal response (MR) in two patients with PPNET. Three of the four responding patients were treated at doses > or = 100 mg/m2. CONCLUSION: The recommended phase II dose of docetaxel administered as a 1-hour intravenous infusion in children with solid tumors in 125 mg/m2. Because neutropenia was the dose-limiting toxicity and thrombocytopenia was mild, further escalation of the dose should be attempted with granulocyte colony-stimulating factor (G-CSF) support.

Adolescent↗

PubMed2000

A phase I and pharmacologic evaluation of the DNA intercalator CI-958 in patients with advanced solid tumors.

5-[(2-Aminoethyl)amino]-2-[2-(diethylamino)ethyl]-2H-[1]benzothiopyra no[4,3,2-cd]-indazol-8-ol trihydrochloride (CI-958) is the most active member of a new class of DNA intercalating compounds, the benzothiopyranoindazoles. Because of its broad spectrum and high degree of activity as well as a favorable toxicity profile in preclinical models, CI-958 was chosen for further development. The Phase I study described here was undertaken to determine the toxicity profile, maximum tolerated dose, and pharmacokinetics of CI-958 given as an i.v. infusion every 21 days. Adult patients with advanced refractory solid tumors who had adequate renal, hepatic, and hematological function, life expectancy, and performance status were eligible for this study. Written informed consent was obtained from all patients. Patients received a 1- or 2-h infusion of CI-958 at 21-day intervals. The starting dose was 5.2 mg/m2, and at least three patients were evaluated at each dose level before proceeding to a new dose level. A pharmacokinetically guided dose escalation design was used until reaching a predetermined target area under the plasma concentration versus time curve (AUC), after which a modified Fibonacci scheme was used. Forty-four patients (21 men and 23 women; median age, 59 years) received 162 courses of CI-958. Neutropenia and hepatorenal toxicity were the dose-limiting toxicities, which defined the maximum tolerated dose of CI-958 to be 875 mg/m2 when given as a 2-h infusion every 21 days. There were no tumor responses. Two patients had stable disease for >250 days. The recommended Phase II dose is 560 mg/m2 for patients with significant prior chemotherapy and 700 mg/m2 for patients with minimal prior chemotherapy. Pharmacokinetic analysis of plasma and urine concentration-time data from each patient was performed. At the recommended Phase II dose of 700 mg/m2, mean CI-958 clearance was 370 ml/min/m2, mean AUC was 33800 ng-h/ml, and mean terminal half-life (t1/2) was 15.5 days. The clearance was similar at all doses, and plasma CI-958 AUC increased proportionally with dose, consistent with linear pharmacokinetics. The percentage reduction in absolute neutrophil count from baseline was well predicted by AUC using a simple Emax model. The pharmacokinetically guided dose escalation saved five to six dose levels in reaching the maximum tolerated dose compared with a standard dose escalation scheme. This may represent the most successful application to date of this dose escalation technique.

Adult↗

PubMed2005

Rhodamine-123: therapy for hormone refractory prostate cancer, a phase I clinical trial.

Rhodamine-123, a lipophilic, cationic, rhodocyanine dye, has been reported to have carcinoma selective toxicity in vitro and in vivo. This phase I clinical trial established the safety and pharmacokinetics of Rhodamine-123 administered to men with hormone refractory prostate cancer. A single dose toxicity study of Rhodamine-123 determined the maximum tolerated dose. A multiple dose toxicity study assessed the safety of Rhodamine-123 at the maximum tolerated dose level. Transient and variable toxicities noted following Rhodamine-123 infusion resolved within 6 hours following infusion. Pharmacokinetic analyses of sera showed no accumulation of drug with repeated monthly administrations. Drug retention was confirmed in prostatic tissue following Rhodamine-123 administration. PSA doubling times lengthened variably suggesting drug efficacy but the data were not statistically significant. The maximum tolerated dose of Rhodamine-123 is 96 mg/m2. The drug can be safely administered at monthly intervals without detectable drug accumulation in serum. Rhodamine-123 is retained by prostatic tumor tissue.

Aged↗

PubMed1994

Phase I and pharmacologic study of irinotecan and etoposide with recombinant human granulocyte colony-stimulating factor support for advanced lung cancer.

PURPOSE: We conducted a phase I trial of irinotecan (CPT-11), a topoisomerase I inhibitor, combined with etoposide, a topoisomerase II inhibitor, and recombinant human granulocyte colony-stimulating factor (rhG-CSF) support because of the overlapping neutrophil toxicity of both drugs. The aim was to determine the maximum-tolerated dose of CPT-11 combined with a fixed dose of etoposide in patients with advanced lung cancer, as well as the dose-limiting toxicities of this combination. PATIENTS AND METHODS: Twenty-five patients with stage III or IV lung cancer, 15 (60%) with prior chemotherapy, were treated at 4-week intervals using CPT-11 (90-minute intravenous infusion on days 1, 8, and 15) plus etoposide (80 mg/m2 intravenously on days 1 to 3). In addition, rhG-CSF (2 micrograms/kg/d) was given from day 4 to day 21, except on the days of CPT-11 administration. The starting dose of CPT-11 was 60 mg/m2, and it was escalated in 10-mg/m2 increments until the maximum-tolerated dose was reached. RESULTS: The maximum-tolerated dose of CPT-11 was 90 mg/m2, since two of the three patients developed grade 3 to 4 leukopenia or grade 3 to 4 diarrhea during the first cycle of treatment at this dose level. Diarrhea and leukopenia were the dose-limiting toxicities, while thrombocytopenia was only a moderate problem. Elimination of CPT-11 was biphasic, with a mean +/- SD beta half-life of 18.17 +/- 9.09 hours. The mean terminal half-life of 7-ethyl-10-hydroxycamptothecin (SN-38; the major metabolite of CPT-11) was 43.40 +/- 37.84 hours. There was one complete response (5%) and eight partial responses (38%) among 21 assessable patients, for an overall response rate of 43%. The response rates for small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC) were 58% (seven of 12 patients) and 22% (two of nine patients), respectively. CONCLUSION: The combination of CPT-11 and etoposide with rhG-CSF support seems to be active against lung cancer, especially SCLC, with acceptable toxicity. The recommended dose for phase II studies in previously untreated patients is 80 mg/m2 of CPT-11 (days 1, 8, and 15) and 80 mg/m2 of etoposide (days 1 to 3) plus 2 micrograms/kg of rhG-CSF (days 4 to 21, except when CPT-11 is given). In addition, 70 mg/m2 of CPT-11 appears to be the appropriate dose for previously treated patients receiving this regimen.

Adult↗

PubMed2003

A Phase I trial of the farnesyl protein transferase inhibitor R115777 in combination with gemcitabine and cisplatin in patients with advanced cancer.

PURPOSE: This Phase I study was undertaken to define the toxicity, pharmacodynamics, and maximum tolerated dose of the combination of R115777, a farnesyl transferase inhibitor, with gemcitabine and cisplatin in patients with advanced solid tumors. PATIENTS AND METHODS: Thirty patients with solid tumors received a median of 2.5 cycles (range 1-30+) through five dose levels. R115777 was administered p.o. twice daily for 14 days. Gemcitabine was infused 15 min after the ingestion of R115777 on days 1 and 8. Cisplatin was administered starting 30 min after completion of the gemcitabine infusion on day 1. Cycles were repeated every 21 days. Toxicities were graded by the National Cancer Institute Common Toxicity Criteria and recorded as maximum grade per patient for each treatment cycle. At the maximum tolerated dose, accumulation of prelamin A in buccal mucosa cells of patients was evaluated as a marker of farnesyl transferase inhibition by R115777. RESULTS: Neutropenia and thrombocytopenia were the most common toxicities. Dose-limiting toxicity in cycle 1 was myelosuppression with thrombocytopenia alone (4 patients), neutropenia alone (1 patient), or a combination of both (3 patients). Common nonhematologic toxicities were anorexia, rash, nausea, vomiting, and fatigue, none of which was dose limiting in the first cycle. At the maximum tolerated dose, defined as R115777 300 mg twice daily p.o., 1000 mg/m(2) gemcitabine, and 75 mg/m(2) cisplatin, inhibition of prelamin A farnesylation in buccal mucosa cells of patients was demonstrated, confirming that R115777 inhibits protein farnesylation in vivo. Nine objective responses (one complete response and eight partial responses) were documented in 27 evaluable patients. CONCLUSION: The combination of R115777 with gemcitabine and cisplatin was well tolerated and showed evidence of antitumor activity. The maximum tolerated dose of R115777 successfully inhibits farnesyltransferase in patients in vivo. This combination warrants further evaluation in a number of tumor types.

Adult↗

PubMed1991

The effect of exposure to nicotine, carbon monoxide, cigarette smoke or cigarette smoke condensate on the mutagenicity of rat urine.

Cigarette smokers have been reported to void urine which is more mutagenic than that voided by non-smokers, but the specific urinary mutagen(s) have not been identified. Since mechanistic studies are best performed in animal models, the objective of this study was to determine if a model to study the role of cigarette smoke and its components in urinary mutagenicity could be developed in rats. XAD-2 resin was used to concentrate the urine and the microsuspension modification of the Ames test used to quantify mutagenicity. Nicotine administered by intraperitoneal injection at 0.8 mg/kg (the maximum tolerated dose) or inhalation of carbon monoxide for 14 days at the maximum tolerated dose (1800 ppm, resulting in 68% carboxyhemoglobin) did not increase urinary mutagenicity. Cigarette smoke condensate (CSC) prepared by electrostatic precipitation of mainstream smoke increased urinary mutagenicity at doses of 100 and 200 mg/kg when administered acutely by either i.p. injection or gavage, verifying that the assay system was capable of detecting cigarette smoke-related mutagens in the urine. However, cigarette smoke administered by the appropriate route of exposure, nose-only inhalation, for 1, 7, 14 or 90 days (1 h per day) did not increase urinary mutagenicity. The smoke concentration administered was at or near the maximum tolerated dose as evidenced by carboxyhemoglobin concentrations of approximately 50%, and of 10% or more weight loss in exposed animals. Thus, although cigarette smoke condensate is mutagenic in vitro and mutagenic urine was observed when rats were given high doses of CSC by inappropriate routes of administration, acute or subchronic inhalation exposure to the maximum tolerated dose of whole cigarette smoke did not increase urinary mutagenicity in rats. These results indicate that the rat may be an inappropriate model to study urinary mutagenicity following the inhalation of tobacco smoke.

Administration, Inhalation↗

PubMed2000

Single dose radiosurgical treatment of recurrent previously irradiated primary brain tumors and brain metastases: final report of RTOG protocol 90-05.

PURPOSE: To determine the maximum tolerated dose of single fraction radiosurgery in patients with recurrent previously irradiated primary brain tumors and brain metastases. METHODS AND MATERIALS: Adults with cerebral or cerebellar solitary non-brainstem tumors </= 40 mm in maximum diameter were eligible. Initial radiosurgical doses were 18 Gy for tumors </= 20 mm, 15 Gy for those 21-30 mm, and 12 Gy for those 31-40 mm in maximum diameter. Dose was prescribed to the 50-90% isodose line. Doses were escalated in 3 Gy increments providing the incidence of irreversible grade 3 (severe) or any grade 4 (life threatening) or grade 5 (fatal) Radiation Therapy Oncology Group (RTOG) central nervous system (CNS) toxicity (unacceptable CNS toxicity) was < 20% within 3 months of radiosurgery. Chronic CNS toxicity was also assessed. RESULTS: Between 1990-1994, 156 analyzable patients were entered, 36% of whom had recurrent primary brain tumors (median prior dose 60 Gy) and 64% recurrent brain metastases (median prior dose 30 Gy). The maximum tolerated doses were 24 Gy, 18 Gy, and 15 Gy for tumors </= 20 mm, 21-30 mm, and 31-40 mm in maximum diameter, respectively. However, for tumors < 20 mm, investigators' reluctance to escalate to 27 Gy, rather than excessive toxicity, determined the maximum tolerated dose. In a multivariate analysis, maximum tumor diameter was one variable associated with a significantly increased risk of grade 3, 4, or 5 neurotoxicity. Tumors 21-40 mm were 7.3 to 16 times more likely to develop grade 3-5 neurotoxicity compared to tumors < 20 mm. Other variables significantly associated with grade 3-5 neurotoxicity were tumor dose and Karnofsky Performance Status. The actuarial incidence of radionecrosis was 5%, 8%, 9%, and 11% at 6, 12, 18, and 24 months following radiosurgery, respectively. Forty-eight percent of patients developed tumor progression within the radiosurgical target volume. A multivariate analysis revealed two variables that were significantly associated with an increased risk of local progression, i.e. progression in the radiosurgical target volume. Patients with primary brain tumors (versus brain metastases) had a 2.85 greater risk of local progression. Those treated on a linear accelerator (versus the Gamma Knife) had a 2.84 greater risk of local progression. Of note, 61 % of Gamma Knife treated patients had recurrent primary brain tumors compared to 30% of patients treated with a linear accelerator. CONCLUSIONS: The maximum tolerated doses of single fraction radiosurgery were defined for this population of patients as 24 Gy, 18 Gy, and 15 Gy for tumors </= 20 mm, 21-30 mm, and 31-40 mm in maximum diameter. Unacceptable CNS toxicity was more likely in patients with larger tumors, whereas local tumor control was most dependent on the type of recurrent tumor and the treatment unit.

Adult↗

PubMed2004

Dose-dense regimen of temozolomide given every other week in patients with primary central nervous system tumors.

BACKGROUND: Temozolomide has shown activity and limited toxicity in patients with primary brain tumors at doses of 150-200 mg/m(2)/day on days 1-5 every 4 weeks. In this study, a new alternative dose-dense regimen of temozolomide was explored in patients with recurrent brain tumors. PATIENTS AND METHODS: In this study, we evaluated the safety, dose-limiting toxicity, maximum tolerated dose, recommended dose and activity of temozolomide given on days 1-3 and 14-16 every 28 days (one cycle). The starting daily dose was 200 mg/m(2) in a group of at least six patients, with subsequent increments of 50 mg/m(2) in groups of at least 12 patients until unacceptable toxicity was reached. Oral ondansetron (8 mg) was given 1 h prior to temozolomide administration. McDonald's criteria were used to evaluate antitumor activity. RESULTS: Seventy patients with brain tumors entered this study. The median number of prior chemotherapy treatments was two (range 1-3). Patients were assigned to one of four groups to receive temozolomide at daily doses of 200 (seven patients), 250 (13 patients), 300 (38 patients) and 350 mg/m(2)/day (12 patients). The absence of dose-limiting toxicity at cycle 1 led us to establish dose recommendations based on toxicity after repeated cycles. A total of 23, 72, 192 and 83 cycles were given at daily doses of 200, 250, 300 and 350 mg/m(2), respectively. Grade 3-4 thrombocytopenia was observed in 0/7, 1/13, 5/38 and 4/12 patients treated at doses of 200, 250, 300 and 350 mg/m(2)/day, respectively. Grade 3-4 neutropenia was observed in 1/7, 0/13, 3/38 and 4/12 patients treated with 200, 250, 300 and 350 mg/m(2)/day temozolomide, respectively. At a dose of 350 mg/m(2), sustained grade 2-3 thrombocytopenia did not allow treatment to be resumed at day 14 in >40% of patients, and this dose was considered to be the maximum tolerated dose. Thus, a dose of 300 mg/m(2)/day that was associated with <20% treatment delay due to sustained hematological toxicity was considered as the recommended dose. Objective responses were reported in 13 patients. CONCLUSIONS: Temozolomide can be given safely using a dose-dense regimen of 300 mg/m(2)/day for 3 consecutive days every 2 weeks in patients with recurrent brain tumors.

Adolescent↗

PubMed1983

Optimal design of the chronic animal bioassay.

Optimal experimental designs for carcinogenicity bioassays conducted for the assessment of risks associated with exposure to environmental chemicals are derived. For our purposes, an optimal experimental design is a design that minimizes the mean-squared error of the maximum likelihood estimate of the virtually safe dose from the Armitage-Doll multistage model and maintains a high power for the detection of increased carcinogenic response. Three- and four-dose designs (including control as one of the doses) are discussed for a variety of dose response patterns. Monte Carlo simulation techniques are used to estimate the power and mean-squared error for small samples sizes. Two forms of the multistage model are used to estimate the virtually safe dose: the linear model and the linear-quadratic model. The optimal designs for fitting the linear model used a control group and a group administered the maximum tolerated dose, with about 50% of the animals at each dose. The three- and four-dose optimal designs when fitting the linear-quadratic model were found to be equivalent. However, after considering several biological issues, including overt toxicity, the optimal four-dose designs would use between 150 and 300 animals, with 50 to 60 animals in the control group, and 40 to 60 animals in the group administered the maximum tolerated dose. One-third of the remaining animals would be administered a dose between 10 and 30% of the maximum tolerated dose, and two-thirds of the remaining animals would be administered 50% of the maximum tolerated dose.

Animals↗

PubMed1986

Angina pectoris-like pain provoked by intravenous adenosine in healthy volunteers.

In a study to characterise the chest pain induced by adenosine this agent was given as a bolus into a peripheral vein to six healthy volunteers (five men) aged 30-44. On the first day the maximum tolerable dose was determined in each case. On the second day three doses of adenosine (one third, two thirds, and the full maximum tolerable dose) and three doses of saline were given single blind in randomised order. Thereafter aminophylline 5 mg/kg was given and the procedure repeated in a different randomised order. On the third day between two thirds and the full maximum tolerable dose was given followed by 10 mg dipyridamole intravenously and a second injection of the same dose of adenosine. Heart rate and atrioventricular blocks were recorded by electrocardiography. One minute after each dose of adenosine the chest pain was scored. The maximum tolerable dose of adenosine ranged from 10.6 to 37.1 mg. All subjects experienced uneasy central chest pain provoking anxiety. The pain radiated to the shoulders, ulnar aspect of the arms, epigastric area, back, and into the throat. The pain began about 20 seconds after the injection and lasted 10-15 seconds. Increasing the dose of adenosine increased the intensity of the pain. Administration of aminophylline reduced the pain significantly. Second degree heart block was recorded in five of the six subjects during the time that the pain was experienced. After aminophylline no block was observed. Dipyridamole increased the intensity of pain. The duration of second degree heart block increased in four of the subjects, and in two of these third degree heart block occurred. These findings suggest that adenosine released from the myocardium during ischaemia induces angina pectoris by stimulating theophylline sensitive receptors.

Adenosine↗

PubMed1999

Paclitaxel, 5-fluorouracil, hydroxyurea, and concomitant radiation therapy for poor-prognosis head and neck cancer.

A series of phase I and phase II studies investigating multiagent concomitant chemoradiotherapy in patients with poor-prognosis head and neck cancer have been conducted at the University of Chicago. Drug combinations initially included 5-fluorouracil (5-FU) and hydroxyurea, with the more recent addition of cisplatin; in the most recent trial, paclitaxel was substituted for cisplatin. The primary end point of these trials was definition of maximum tolerated doses in combination with radiation therapy. All radiation therapy was given concomitantly with chemotherapy on an every-other-week schedule (total dose, </=75 Gy). Maximum tolerated doses of the two-drug combination of hydroxyurea and 5-FU were defined at 1 g given orally twice daily for a total of 11 doses and 800 mg/m2/d for 5 days (by continuous intravenous infusion), respectively. When cisplatin was added to this regimen, the observed myelosuppression necessitated the addition of granulocyte colony-stimulating factor. The recommended phase II doses for the three-drug combination were cisplatin 100 mg/m2 every 28 days, 5-FU 800 mg/m2/d for 5 days, and hydroxyurea 1 g orally twice daily for 11 doses. The feasibility of administering radiation at 1.5 Gy twice daily with chemotherapy was also established, which allowed the administration of 75 Gy over 5 cycles (10 weeks). The initial review of this trial suggested substantial toxicity, particularly mucositis and myelosuppression; however, local and regional control rates also were high. Most recently, paclitaxel has replaced cisplatin in this regimen. Recommended phase II doses were hydroxyurea 0.5 g orally twice daily for 11 doses, 5-FU 600 mg/m2/d for 5 days, and paclitaxel 20 mg/m2/d for 5 days, with radiation therapy administered twice daily in 1. 5-Gy fractions. A formal phase II study of this regimen in previously untreated patients with stage IV disease has recently completed accrual and is awaiting analysis. Evaluation of a simplified paclitaxel administration schedule (1-hour infusion on day 1 of chemoradiotherapy between the two radiation fractions) is under way. In addition, the feasibility of substituting gemcitabine for hydroxyurea is undergoing evaluation. Future trials in this disease should focus on developing new combinations that are less toxic and have similar efficacy.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1997

Influence of drug release characteristics on the therapeutic activity of liposomal mitoxantrone.

The influence of liposome drug release on the therapeutic activity of encapsulated mitoxantrone was investigated. Liposomes prepared from 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC)/cholesterol (Chol) (55:45, molar ratio) or 1,2 dimyristoyl-sn-glycero-3-phosphocholine (DMPC)/Chol (55:45, molar ratio) were loaded with mitoxantrone using the transmembrane pH gradient loading procedure. In vivo studies demonstrated that DMPC/Chol liposomes released drug faster (1.7 microg drug/microg lipid/hr) than did DSPC/Chol liposomes (<0.025 microg drug/microg lipid/hr). In BDF1 mice, the acute toxicities of DMPC/Chol and DSPC/Chol liposomal mitoxantrone were similar, with a maximum tolerated dose of approximately 30 mg drug/kg, in comparison with the maximum tolerated dose of free drug, which was approximately 10 mg/kg. Efficacy studies were conducted in BDF1 mice inoculated i.v. with murine P388 cells or L1210 tumor cells. These cells seed in the liver and spleen of animals after i.v. inoculation, and a single dose of DMPC/Chol liposomal mitoxantrone of 10 mg drug/kg resulted in 100% of the treated animals surviving for >60 days. In contrast, no long-term survivors were obtained in any other treatment group, even when drug doses were escalated to the maximum tolerated dose. Pharmacodynamic studies with DMPC/Chol liposomal mitoxantrone and DSPC/Chol liposomal mitoxantrone illustrate the importance of achieving a balance between drug release characteristics and drug delivery to the site of tumor progression.

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