Biomedical subjects

Brigitte C Widemann

Publications and source records attributed to Brigitte C Widemann.

9 recordsLinked to original sources

PubMed2006

A phase 1 study of ABT-751, an orally bioavailable tubulin inhibitor, administered daily for 7 days every 21 days in pediatric patients with solid tumors.

PURPOSE: To determine the toxicity profile, dose-limiting toxicities, and maximum tolerated dose of ABT-751 administered orally once daily for 7 days, repeated every 21 days. EXPERIMENTAL DESIGN: Patients who were </=18 years of age, with relapsed or refractory solid tumors, and who were able to swallow capsules were eligible. The starting dose was 100 mg/m(2)/d (n = 3) and was escalated to 130 mg/m(2)/d (n = 6), 165 mg/m(2)/d (n = 6), 200 mg/m(2)/d (n = 6), and 250 mg/m(2)/d (n = 2) in cohorts of three to six patients. The maximum tolerated dose was determined from dose-limiting toxicities occurring during the first treatment cycle. RESULTS: Twenty-four children (median age, 13 years; range, 4-18 years) were enrolled; 23 were evaluable for toxicity. Diagnoses included neuroblastoma (n = 8), sarcomas (n = 8), primary brain tumors (n = 2), Wilms' tumor (n = 2), and other solid tumors (n = 3). Dose-limiting toxicities (grade 3 sensory and motor neuropathy, grade 3 hypertension, and grade 3 fatigue) were observed in patients enrolled at the 250 mg/m(2)/d dose level. The maximum tolerated dose of ABT-751 administered daily for 7 days every 21 days was 200 mg/m(2)/d. Non-dose-limiting toxicities at the maximum tolerated dose included anemia, fatigue, peripheral sensory neuropathy, abdominal pain, nausea, constipation, anorexia, fever, and weight loss. Myelosuppression was minimal at the maximum tolerated dose. The median number of cycles administered is 2 (range, 1-50). No significant ABT-751-related cumulative toxicities were observed. CONCLUSION: ABT-751 is well tolerated in children. The recommended dose for phase 2 trials in solid tumors is 200 mg/m(2)/d administered orally, daily for 7 days every 21 days. This dose is >40% higher than the maximum tolerated dose in adults receiving the same dosing schedule.

Administration, Oral↗

PubMed2006

Phase I trial and pharmacokinetic study of the farnesyltransferase inhibitor tipifarnib in children with refractory solid tumors or neurofibromatosis type I and plexiform neurofibromas.

PURPOSE: This pediatric phase I trial of tipifarnib determined the maximum-tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of tipifarnib in children with refractory solid tumors and neurofibromatosis type 1 (NF1) -related plexiform neurofibromas. PATIENTS AND METHODS: Tipifarnib was administered twice daily for 21 days, repeated every 28 days starting at 150 mg/m2/dose (n = 4), with escalations to 200 (n = 12), 275 (n = 12), and 375 (n = 6) mg/m2/dose. The MTD was also evaluated on a chronic continuous dosing schedule (n = 6). Pharmacokinetic sampling was performed for 36 hours after the first dose and peripheral-blood mononuclear cells (PBMCs) were collected at baseline and steady state for determination of farnesyl protein transferase (FTase) activity and HDJ-2 farnesylation. RESULTS: Twenty-three solid tumor and 17 NF1 patients were assessable for toxicity. The MTD was 200 mg/m2/dose, and dose-limiting toxicities on cycle 1 were myelosuppression, rash, nausea, vomiting, and diarrhea. The 200 mg/m2/dose was also tolerable on the continuous dosing schedule. Cumulative toxicity was not observed in the 17 NF1 patients who received a median of 10 cycles (range, 1 to 32 cycles). The plasma pharmacokinetics of tipifarnib were highly variable but not age dependent. At steady state on 200 mg/m2/dose, FTase activity was 30% compared with baseline, and farnesylation of HDJ-2 was inhibited in PBMCs. CONCLUSION: Oral tipifarnib is well tolerated in children receiving the drug twice daily for 21 days and a continuous dosing schedule at 200 mg/m2/dose, which is equivalent to the MTD in adults. The pharmacokinetic profile of tipifarnib in children is similar to that in adults, and at the MTD, FTase is inhibited in PBMC in vivo.

Adolescent↗

PubMed2006

Understanding and managing methotrexate nephrotoxicity.

Methotrexate (MTX) is one of the most widely used anti-cancer agents, and administration of high-dose methotrexate (HDMTX) followed by leucovorin (LV) rescue is an important component in the treatment of a variety of childhood and adult cancers. HDMTX can be safely administered to patients with normal renal function by the use of alkalinization, hydration, and pharmacokinetically guided LV rescue. Despite these measures, HDMTX-induced renal dysfunction continues to occur in approximately 1.8% of patients with osteosarcoma treated on clinical trials. Prompt recognition and treatment of MTX-induced renal dysfunction are essential to prevent potentially life-threatening MTX-associated toxicities, especially myelosuppression, mucositis, and dermatitis. In addition to conventional treatment approaches, dialysis-based methods have been used to remove MTX with limited effectiveness. More recently carboxypeptidase-G(2) (CPDG(2)), a recombinant bacterial enzyme that rapidly hydrolyzes MTX to inactive metabolites, has become available for the treatment of HDMTX-induced renal dysfunction. CPDG(2) administration has been well tolerated and resulted in consistent and rapid reductions in plasma MTX concentrations by a median of 98.7% (range, 84%-99.5%). The early administration of CPDG(2) in addition to LV may be beneficial for patients with MTX-induced renal dysfunction and significantly elevated plasma MTX concentrations.

Antimetabolites, Antineoplastic↗

PubMed2005

Phase I study of O6-benzylguanine and temozolomide administered daily for 5 days to pediatric patients with solid tumors.

PURPOSE: This pediatric phase I trial of O6-benzylguanine (O6BG) and temozolomide (TMZ) on a daily schedule for 5 days, every 28 days was performed to determine the maximum-tolerated dose of TMZ when given with a biologically active dose of O6BG and to define the toxicity profile of the combination in children with solid tumors. PATIENTS AND METHODS: Patients < or = 21 years old with refractory solid tumors were eligible. O6BG was administered intravenously over 60 minutes daily for 5 days. TMZ was administered orally 30 minutes after completion of each O6BG infusion. Starting doses of O6BG and TMZ were 60 mg/m2/d and 28 mg/m2/d, respectively. O6BG was escalated to 90 and 120 mg/m2/d; TMZ was subsequently escalated to 40, 55, 75, and 100 mg/m2/d. Cycles were repeated every 28 days. RESULTS: Forty-one patients were enrolled; 32 patients were assessable for toxicity. The combination of O6BG and TMZ was tolerable at TMZ doses less than half of the conventional dose of 200 mg/m2/d. Myelosuppression occurred sporadically at all dose levels and was the dose-limiting toxicity (DLT) at 100 mg/m2/d of TMZ combined with 120 mg/m2/d O6BG. Nonhematologic toxicities were generally mild. Evidence of antitumor activity was observed at 120 mg/m2/d O6BG combined with TMZ doses of 55 mg/m2/d and above. CONCLUSION: The recommended doses of O6BG administered with TMZ on a 5-day schedule in children are 120 mg/m2/d of O6BG and 75 mg/m2/d of TMZ. Evidence of activity was observed at these doses. Myelosuppression was the DLT.

Adolescent↗

PubMed2005

A phase I trial and pharmacokinetic study of tipifarnib, a farnesyltransferase inhibitor, and tamoxifen in metastatic breast cancer.

PURPOSE: Farnesyltransferase (FTase) inhibitors, which were designed to inhibit oncogenic Ras, act synergistically with tamoxifen in preclinical breast cancer models. We studied the safety and toxicity of tipifarnib in combination with tamoxifen in metastatic breast cancer. The pharmacokinetics and pharmacodynamics of tipifarnib were also assessed. PATIENTS AND METHODS: Patients with metastatic, hormone receptor-positive breast cancer were enrolled. Two cohorts of patients were treated with tipifarnib at either 200 or 300 mg p.o. twice daily for 21 of 28 days. Tamoxifen (20 mg once daily) was started after 1 week of tipifarnib monotherapy to perform pharmacokinetics and FTase inhibition levels in peripheral blood mononuclear cells with tipifarnib alone and with tipifarnib and tamoxifen. RESULTS: A total of 12 heavily pretreated patients with prior progression on hormonal therapy were enrolled. Minimal toxicity was observed at the 200-mg dose level of tipifarnib. At the 300-mg dose, all six patients required dose reduction of tipifarnib due to toxicities that included grade 2 nausea, rash, and fatigue and grade 3 diarrhea and neutropenia. Tipifarnib pharmacokinetic and pharmacodynamic variables were similar in the presence and absence of tamoxifen. Average FTase inhibition was 42% at 200 mg and 54% at 300 mg in peripheral blood mononuclear cells. Of the 12 patients treated, there were two partial responses and one stable disease for >6 months. CONCLUSIONS: Tipifarnib (200 mg twice daily for 21 of 28 days) and tamoxifen (20 mg once daily) can be given safely with minimal toxicity. Tamoxifen does not have a significant effect on tipifarnib pharmacokinetics.

Adult↗

PubMed2004

Treatment of accidental intrathecal methotrexate overdose with intrathecal carboxypeptidase G2.

The bacterial enzyme carboxypeptidase G2 (CPDG2) rapidly hydrolyzes methotrexate to inactive metabolites. We administered recombinant CPDG2 (2000 U) intrathecally to seven cancer patients 3 to 9 hours after they had received an accidental overdose of intrathecal methotrexate (median dose = 364 mg; range = 155-600 mg). Four of the seven patients had cerebrospinal fluid (CSF) exchange to remove methotrexate before CPDG2 administration. Immediate symptoms of the methotrexate overdoses included seizures (n = 5), coma (n = 2), and cardiopulmonary compromise (n = 2). Before CPDG2 administration, the median concentrations of methotrexate in CSF were 264 microM (range = 97-510 microM) among patients who had CSF exchange and 8050 microM (range = 2439-16 500 microM) among patients who did not. After intrathecal CPDG2 administration, methotrexate concentrations in CSF declined by more than 98%. All patients recovered completely from the intrathecal methotrexate overdose except for two patients who had memory impairments. Antibodies to CPDG2 were not detected in plasma after treatment with intrathecal CPDG2. Intrathecal CPDG2 is well tolerated, rapidly decreases CSF methotrexate concentrations, and appears to be efficacious for treating accidental intrathecal methotrexate overdoses.

Adult↗

PubMed2004

High-dose methotrexate-induced nephrotoxicity in patients with osteosarcoma.

BACKGROUND: High-dose methotrexate (HDMTX)-induced renal dysfunction can be life threatening, because it delays methotrexate (MTX) excretion, thereby exacerbating the other toxicities of MTX. HDMTX-induced nephrotoxicity has been managed with high-dose leucovorin, dialysis-based methods of MTX removal, thymidine, and with the recombinant enzyme, carboxypeptidase-G2 (CPDG2), which cleaves MTX to inactive metabolites. The objectives of the current study were to estimate the current incidence of HDMTX-induced renal dysfunction in patients with osteosarcoma and to compare the efficacy and recovery of renal function for dialysis-based methods of MTX removal with treatment using CPDG2. METHODS: The literature was reviewed for osteosarcoma trials, use of dialysis-based methods for MTX removal, and reports of MTX-induced nephrotoxicity, including information regarding recovery of renal function. Clinical trial databases of select osteosarcoma studies were reviewed. The efficacy of CPDG2 and renal recovery after CPDG2 rescue was obtained from the database of a compassionate-release trial. RESULTS: Approximately 1.8% of patients with osteosarcoma (68 of 3887 patients) who received HDMTX developed nephrotoxicity Grade >/= 2. The mortality rate among those patients was 4.4% (3 of 68 patients). Dialysis-based methods of MTX removal were used frequently but had limited effectiveness in removing MTX compared with the rapid reductions > 98% in plasma MTX concentrations achieved with CPDG2. CPDG2 did not appear to increase the time to recovery of renal function compared with supportive treatment that included dialysis-based methods. CONCLUSIONS: HDMTX-induced renal dysfunction continues to occur in approximately 1.8% of patients with osteosarcoma who are treated on clinical protocols with optimal supportive care. For patients with delayed MTX excretion and high plasma MTX concentrations, CPDG2 should be considered over hemodialysis to lower plasma MTX concentrations rapidly and efficiently.

Acute Kidney Injury↗

PubMed2003

Evaluation and treatment of fever in the non-neutropenic child with cancer.

PURPOSE: To document the current approach to the evaluation and treatment of febrile non-neutropenic children with cancer by surveying American Society of Pediatric Hematology/Oncology (ASPHO) members. METHODS: Five hundred ninety-five ASPHO members were sent questionnaires polling their current practices in the evaluation and treatment of clinically stable, febrile (oral temperature of 38 degrees C x2, or >or=38.3 degrees C), non-neutropenic (absolute neutrophil count > 500/microL) pediatric cancer patients who have no identifiable bacterial infection. Patients were assigned to one of four groups based on the presence or absence of a central venous catheter (CVC) and no source (NS) or presumed viral source (VS) for fever. RESULTS: Three hundred sixteen ASPHO members (53%) responded and 300 questionnaires were evaluable. If a CVC was present, respondents universally drew blood cultures (99% NS, 96% VS) from the CVC, but only one third drew peripheral blood cultures (33% NS, 29% VS). If a CVC was not present, the majority of respondents (80% NS, 61% VS) drew peripheral cultures. ASPHO members started empiric antibiotics more frequently in patients with a CVC (69% NS, 55% VS) than in patients without a CVC (33% NS, 23% VS). Most did not admit these patients to the hospital (40% CVC and NS, 33% CVC and VS, 22% no CVC and NS, 19% no CVC and VS). ASPHO members with more years of experience were more likely to obtain peripheral blood cultures if a CVC was present and to admit a patient without a CVC. CONCLUSIONS: Nearly all respondents obtained a blood culture from the CVC in the initial assessment of the febrile, non-neutropenic patient with a CVC, but other evaluation and management practices varied considerably.

Anti-Bacterial Agents↗

PubMedDate not supplied

Merlin PAKs a punch.

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Animals↗