Biomedical subjects

John Murren

Publications and source records attributed to John Murren.

6 recordsLinked to original sources

PubMed2005

A phase I and pharmacokinetic study of VNP40101M, a new alkylating agent, in patients with advanced or metastatic cancer.

PURPOSE: VNP40101M is a new alkylating agent that demonstrated broad anti-tumor activity in murine tumor models. A phase I trial was initiated to determine the toxicities, maximum tolerated dose, and pharmacokinetics of VNP40101M by short IV infusion. STUDY DESIGN: The starting dose was 3 mg/m(2) every four weeks, and was escalated in successive cohorts as follows: 6, 12, 24, 40, 60, 80, and 100 mg/m(2). Beyond 100 mg/m(2), dose increments were 25%. Initially, 1-2 patients were assigned to a dose level. Intra-patient dose escalation was permitted. With the first instance of a drug-related > or = grade 2 adverse event, all dose levels required assessment of 3-6 patients. Pharmacokinetic parameters were assessed in the first cycle and any cycle with a change in dose. RESULTS: Twenty-six patients in 13 dose levels ranging from 3-305 mg/m(2) were evaluated. Dose-related thrombocytopenia was the major toxicity, with the nadir occurring at a median of day 27. At 305 mg/m(2), six of eight patients developed grade 3 thrombocytopenia, including one event that met the definition for DLT. Other dose-related toxicities included moderate granulocytopenia, anemia, and a mild infusion-related syndrome consisting of acute headache and facial flushing. The granulocyte nadir occurred at a median of day 34, and recovery of both thrombocytopenia and neutropenia to < grade 2 occurred at a median of day 43. VNP40101M peak plasma concentrations and AUC were linear with dose. The elimination half-life was short and estimated to be approximately 15 minutes. CONCLUSIONS: The MTD and recommended dose for phase II trials is 305 mg/m(2) every six weeks. Phase II trials in less heavily pre-treated patient populations are warranted.

Adult↗

PubMed2005

Comparison of health-related quality of life questionnaires in ambulatory oncology.

The purpose of this study is to compare three commonly used health-related quality of life (HR-QOL) questionnaires for their ease of use, accuracy, and patient preference; identify factors related to patient preference; identify differences in patient completion rates; and to identify factors associated with patient completion of these questionnaires. Three psychometrically sound measures, the Symptom Distress Scale (SDS), Medical Outcome Study Short Form-36 (SF-36), and Functional Assessment of Cancer Therapy (FACT), were tested. Seventy-nine patients completed questionnaires in the ambulatory oncology setting. No significant differences in patient ratings were found in ease of use and accuracy among the questionnaires. All of the questionnaires were rated as easy to use and accurate. Patient ratings on preference were marginally significant (p = 0.07). Forty-six percent of participants indicated that they preferred the SDS, whereas 27% and 39% preferred the SF-36 and the FACT. No significant differences in patient completion rates were found among the questionnaires. One hundred percent completion rates ranged from 88.6% for the SDS to 78.5% for the SF-36, and 80% completion rates ranged from 98.7% for the SDS to 94.9% for the SF-36. Administration of standardized HR-QOL questionnaires is feasible in the clinical setting.

Activities of Daily Living↗

PubMed2005

Severe irinotecan-induced toxicities in a patient with uridine diphosphate glucuronosyltransferase 1A1 polymorphism.

Irinotecan is an analogue of camptothecin, a topoisomerase I inhibitor, that has an important role in the management of advanced colorectal cancer. It is approved as first-line therapy in combination with 5-fluorouracil and leucovorin or as monotherapy in the second-line setting. Its clinical use has been associated with variability in terms of pharmacokinetic behavior and toxicities, especially myelosuppression and diarrhea. Irinotecan is metabolized to the active compound SN-38; it is now known that the metabolism of irinotecan and the inactivation of SN-38 by glucuronidation are mediated by genetic differences, which contributes to the variability. In this article, a case is presented that illustrates this, and there is a brief discussion of the clinical pharmacology of irinotecan and some of the genetic variations that affect its cellular metabolism.

Adenocarcinoma↗

PubMed2005

Oxaliplatin induces a delayed immune-mediated hemolytic anemia: a case report and review of the literature.

We report a case of a 59-year-old woman with metastatic carcinoma of the ileocecal region who received FOLFOX(oxaliplatin/leucovorin/5-fluorouracil) and bevacizumab therapy and exhibited a partial remission with minimal side effects. She developed a mild self-limited episode of immune-mediated hemolytic anemia during her 16th cycle of chemotherapy, which precluded her from receiving further oxaliplatin. We review the literature on oxaliplatin-induced immune-mediated hemolysis, including its mechanism, presenting symptoms, laboratory features, management, and implications for future therapy.

Anemia, Hemolytic↗

PubMed2004

AN-9 (Titan).

Titan is developing AN-9 for the potential treatment of various cancers. AN-9 is a histone deacetylase inhibitor analog of butyric acid that causes apoptosis of cancer cells through signaling cellular differentiation. In March 2001, a phase I/II study involving patients with liver tumors was initiated. By November 2001, enrollment had been completed in a second phase II study of refractory non-small-cell lung cancer (NSCLC). In June 2003, Titan began enrollment for a phase IIb trial of AN-9 in combination with docetaxel in patients with NSCLC.

Animals↗

PubMed2003

Phase I and pharmacokinetic study of triapine, a potent ribonucleotide reductase inhibitor, administered daily for five days in patients with advanced solid tumors.

PURPOSE: A Phase I study in patients with advanced cancer was conducted to determine the safety, pharmacokinetics, and maximum tolerated dose of Triapine, a new, potent small-molecule inhibitor of ribonucleotide reductase. EXPERIMENTAL DESIGN: Triapine was administered by 2-h i.v. infusion daily for 5 days. Courses were repeated every 4 weeks. The starting dose was 5 mg/m(2)/day, but was reduced to 2 mg/m(2)/day after the first patient developed a hepatic adverse event. The dose was subsequently escalated using a modified Fibonacci scheme in cohorts of 3-6 patients. After the 12 mg/m(2)/day dose level, the study design was amended to permit 100% dose escalation in single-patient cohorts until the first episode of a drug-related grade 2 adverse event or dose-limiting toxicity (DLT). On reaching a dose of 96 mg/m(2)/day, the study was amended to determine the safety and tolerability of the 96-mg/m(2) dose administered daily for 5 days every 2 weeks in an expanded cohort of patients. RESULTS: A total of 32 patients received treatment. During the dose escalation phase of the study, grade 2-4 drug-related adverse events were first observed at a dose of 96 mg/m(2)/day. Grade 3-4 leukopenia was the primary toxicity observed among four patients treated at this dose, which occurred in the week after treatment and resolved to grade 1 or lower by day 15. Fifteen patients were subsequently treated at the 96-mg/m(2) dose, daily for 5 days, with courses repeated every 2 weeks. The most common nonhematological toxicities for the latter schedule were asthenia, fever, nausea and vomiting, mucositis, decreased serum bicarbonate, and hyperbilirubinemia, and were predominantly grade 1-2 in severity and rapidly reversible. Hematological toxicity on the every-other-week schedule consisted of leukopenia (grade 4 in 93% in at least one course) and anemia (grade 2 in 71%, grade 3 in 22%). Thrombocytopenia was less common and was grade 3-4 in severity in only 22%. Triapine showed linear pharmacokinetic behavior although interpatient variability was relatively high. Peak concentrations at the 96-mg/m(2)/day dose averaged 8 microM, and the mean elimination T(1/2) ranged from 35 min to 3 h, with a median value of approximately 1 h. Cumulative urinary recovery averaged 1-3% of the administered dose, suggesting that the elimination of Triapine was primarily through metabolism. No partial or complete responses were observed. CONCLUSIONS: Triapine administered at a dose of 96 mg/m(2) by 2-h i.v. infusion daily for 5 days on an every-other-week schedule demonstrates an acceptable safety profile. Serum concentrations that surpass in vitro tumor growth-inhibitory concentrations are achieved for brief periods of time each day and are sufficient to produce myelosuppression, the expected consequence of ribonucleotide reductase inhibition. Phase II trials are indicated but will proceed with a daily-for-4-days schedule to reduce the incidence of grade 4 leukopenia. The safety profile also supports the initiation of Phase I combination trials with other anticancer agents.

Adult↗