Pharmacokinetic and phase I studies of brequinar (DUP 785; NSC 368390) in combination with cisplatin in patients with advanced malignancies.

Brequinar (DUP 785; NSC 368390) is a quinoline carboxylic acid derivative that inhibits pyrimidine synthesis at the level of dihydro-orotate dehydrogenase and revealed synergy with cisplatin in preclinical models. In this study investigating the pharmacokinetic and toxicity of brequinar in combination with cisplatin, patients were initially treated with weekly brequinar, in combination with an every-three-week administration of cisplatin. Due to toxicity, the schedule was modified to a 28-day cycle with brequinar given on days 1, 8, 15, and cisplatin on day 1. A total of 24 patients (16 male, 8 female; median age 57; median performance status 1) received 69 courses of therapy. Six dose levels were explored, with cisplatin/ brequinar doses, respectively, of 50/500, 50/650, 50/860, 60/860, 75/650, and 75/860 mg/m2. The serum concentration versus time curves for brequinar were biphasic. A comparison of the pharmacokinetic results after the first and third doses of brequinar indicate that the presence of 50, 60, and 75 mg/m2cisplatin did not change the protein binding and the pharmacokinetics of brequinar in any of the three brequinar-dose groups. Total cisplatin plasma pharmacokinetic followed a triphasic-shape curve and unbound cisplatin decayed at a very rapid rate. Since pharmacokinetic parameters for total cisplatin in this study were similar to those reported in the literature, the presence of brequinar is unlikely to alter the pharmacokinetics of cisplatin. Main dose-limiting toxicities included myelosuppression (including neutropenia and thrombocytopenia) and mucositis. Cisplatin/brequinar doses of 50/500, 50/650, 50/860, 60/860, 75/650, and 75/860 mg/m2, were associated with dose limiting toxicity in 0/3, 1/3, 1/3, 1/3, 2/4, 2/5, and 4/6 patients, respectively. This study shows that co-administration of brequinar and cisplatin does not affect the pharmacokinetic properties of either drug and that the MTDs of cisplatin/brequinar combinations are 60/860 mg/m2 or 75/650 mg/m2. From this study, we conclude that full dose of 75 mg/m2 cisplatin (day 1) can be administered with 650 mg/m2 brequinar (days 1, 8 and 15) without significant modifications of individual drug pharmacokinetic parameters.

Phase II trial of paclitaxel by 24-hour continuous infusion for relapsed non-Hodgkin's lymphomas: Southwest Oncology Group trial 9246.

PURPOSE: The Southwest Oncology Group (SWOG) recently conducted a multiinstitutional phase II trial to determine the complete response (CR) and partial response (PR) rates, toxicities, and progression-free and overall survivals of patients with relapsed non-Hodgkin's lymphomas (NHLs) treated with a 24-hour continuous infusion of paclitaxel at a dose of 175 mg/m2. PATIENTS AND METHODS: Sixty-six patients with relapsed NHL who had received minimal prior therapy (one prior chemotherapy regimen for intermediate- to high-grade NHL [44 patients] or one or two prior regimens for low-grade NHL [22 patients]) were premedicated with dexamethasone, diphenhydramine, and cimetidine and then treated with continuous intravenous infusion paclitaxel over 24 hours every 21 days. RESULTS: Eleven of 66 patients (17%) achieved rigorously documented objective remissions, including two CRs (3%) and nine PRs (14%). In addition, another five patients (8%) achieved apparent PRs on a single computed tomographic (CT) scan. Responses were brief, lasting a median of 3 months (5 months for indolent lymphomas and 3 months for intermediate- to high-grade lymphomas). Grade 4 or 5 granulocytopenia was the only common serious toxicity, and occurred in 42 of 66 patients (64%). CONCLUSION: Paclitaxel is generally well tolerated when given as a continuous infusion of 175 mg/m2 over 24 hours, despite predictable granulocytopenia. However, single-agent paclitaxel has modest clinical efficacy compared with other available treatments for relapsed NHL.

Interobserver variability in prostate cancer specific survival.

We evaluated the reliability of disease-specific survival (DSS) as an outcome measure in patients with carcinoma of the prostate (CaP). The records of 50 patients had a diagnosis of CaP and had expired were selected from the hospital tumor registry. Records were reviewed by six individuals and each individual was asked to specify cause of death as due to CaP or some other cause. DSS curves were generated based on the determinations of each reviewer. Although the DSS curves were generally parallel, a high degree of variability was seen at various intervals, leading us to conclude that DSS is dependent upon the individual reviewer. Published by Elsevier Science Inc.

Expectations and experiences of patients with cancer participating in phase I clinical trials.

PURPOSE/OBJECTIVES: To describe the expectations and experiences of patients entering phase I clinical trials. DESIGN: Descriptive, exploratory, prospective. SETTING: A large military medical teaching center. SAMPLE: Thirty-seven adult patients completed the entry and exit interviews. Subjects had a good performance status, were middle aged, and had common tumor types. METHODS: Interviews using structured entry and exit questionnaires. MAIN RESEARCH VARIABLES: Expectations and experiences of patients in phase I clinical trials. FINDINGS: Patients expected slightly increased support from family members and received more support than expected. Patients' expectations for tumor response and increased communication with their physician were not met. Patients expected symptoms such as fatigue, nausea and vomiting, and weight loss to improve during therapy, yet their expectations were not met. CONCLUSIONS: One theme that emerged from the data was hope/optimism. An issue that needs further exploration is the extent to which patients accurately understand information in the consent form. Findings also support the importance of communication between the patient and family members and the healthcare team. IMPLICATIONS FOR NURSING PRACTICE: Oncology nurses can mediate the flow of information between physicians and patients. Oncology nurses can and should assess the patient's level of understanding of the clinical trial, the consent form, and potential side effects at the time of entry into the trial and intermittently during the course of therapy. Nurses must allow patients with cancer who are undergoing investigational therapy to maintain a level of hope, while realistically counseling them about their progress during phase I trial participation.

Acute myeloid leukemia evolving from essential thrombocythemia in two patients treated with hydroxyurea.

Essential thrombocythemia (ET) is an uncommon myeloproliferative disorder, which is thought to develop from a multipotent stem cell. Like other myeloproliferative diseases, ET is associated with an increased risk of development of acute leukemia (AL). However, the large majority of cases of leukemic transformation in ET are thought to be related to prior therapy, usually radioactive phosphorous or alkylating chemotherapy, and the development of AL in ET is extremely rare in the untreated patient. In this report, two cases of ET which evolved into AL without prior exposure to radiation or alkylating agents, and which were treated with long-term hydroxyurea therapy, are described. The first case had cytogenetic changes in the bone marrow suggestive of therapy-associated leukemia, and the second developed myelodysplastic syndrome on therapy which was likely chemotherapy-induced and led to acute leukemia. Prolonged used of hydroxyurea in patients with ET may lead to therapy-associated acute leukemia.

Phase I clinical trial of ormaplatin (tetraplatin, NSC 363812).

Ormaplatin is a platinum analog that was developed because of an altered toxicity profile and non-cross resistance to cisplatin in both in vitro and in vivo models. To determine the toxicities and maximum tolerated dose of ormaplatin on a daily times five schedule, patients with refractory solid tumors received ormaplatin on five consecutive days at nine dose levels ranging from 1.0 to 15.0 mg/m2/day. A total of 35 patients received 70 cycles of therapy. Nausea and vomiting and myelosuppression were moderate and not dose-limiting. Dose-limiting neurotoxicity, consisting of a sensory peripheral neuropathy, was seen in all five patients who received cumulative doses greater than or equal to 165 mg/m2. This neurotoxicity was symptomatic in all patients and caused significant functional impairment in four patients with inability to walk in two patients. A sensitive atomic absorption spectroscopy analysis performed for one patient at the 13.0 mg/m2/day dose level showed a Cpmax of 163 ng/ml and a t1/2 of 10.9 min for free platinum. A phase II dose could not be determined due to the onset of peripheral neuropathy at low cumulative doses and not at absolute dose levels.

Phase I trial of sulofenur (LY186641) given orally on a daily x 21 schedule.

Sulofenur (LY186641), a diarylsulfonylurea, was evaluated clinically utilizing either a daily x 21 schedule or a daily x 5 (with 2 days off) for 3 weeks schedule. Eighteen patients with refractory solid tumors received 47 evaluable courses of sulofenur given p.o. daily x 21 every 28 days at five dose levels while 14 received 29 courses of sulofenur given daily x 5 for 3 weeks every 28 days at three dose levels. Toxicities included anemia, methemoglobinemia and hemolysis. One patient experienced a fatal subendocardial infarction on the daily x 21 schedule. One partial response was observed in a patient with a sertoli cell tumor on the daily x 5 for 3 weeks schedule. Daily x 5 for 3 weeks is the schedule recommended for phase II trials.

Testicular relapse in adult acute myelogenous leukemia.

Testicular relapse (TR) in adult acute myelogenous leukemia (AML) is uncommon, occurring in only 1-2% of patients with bone marrow relapse. TR in the absence of systemic relapse has been reported previously in 2 adults and 12 children, of which 67% were monocytic variants of AML. This article presents the case of a 29-year-old man with AML that relapsed in his testicle without evidence of bone marrow relapse. This patient and the two previously mentioned adults experienced bone marrow relapse within 2 months and died within 7 months of their TR. TR in adult myelogenous leukemia should be considered a harbinger of systemic relapse and suggests a need for aggressive local and systemic therapy.

Hemophagocytic syndrome: a cause of pancytopenia in human ehrlichiosis.

A 67-year-old white man with human ehrlichiosis infection complicated by pancytopenia, hemophagocytic syndrome, disseminated intravascular coagulopathy and septic shock is presented. The patient had been on a three-week camping trip to California, Colorado, Utah, and New Mexico. The diagnosis of human ehrlichiosis was confirmed by sixteen-fold rise in antibody titer to Ehrlichia canis, and supported by the characteristic cytoplasmic inclusions. Human ehrlichiosis should be considered in the differential diagnosis in patients with fever and cytopenia associated with hemophagocytosis. Pancytopenia associated with ehrlichiosis is transient; however, it may be severe, and appears to be associated with destruction of normal blood elements.

Phase I clinical and pharmacokinetic trial of Brequinar sodium (DuP 785; NSC 368390).

Brequinar sodium is a 4-quinolinecarboxylic acid analogue that inhibits dihydroorotate dehydrogenase and subsequent de novo pyrimidine biosynthesis. It has shown dose-dependent antineoplastic activity against several mouse and human tumor models. This trial evaluated Brequinar given as a single daily i.v. bolus over a 5-day period repeated every 28 days. One hundred seven courses of treatment at dosages ranging from 36 to 300 mg/m2/day x 5 were administered to 45 patients (31 male and 14 female) with refractory solid tumors; median age was 58 years (range 30-74); median Southwest Oncology Group performance status was 1 (range, 0-3). Thirty patients had prior cytotoxic chemotherapy. Dose-limiting toxicities were thrombocytopenia and a severe desquamative maculopapular dermatitis. Two of 5 good risk patients at 300 mg/m2 and 3 of 6 poor risk patients at 170 mg/m2 developed a platelet count less than 25 x 10(3)/microliters. Two of 5 good risk patients at 300 mg/m2 and 1 of 6 poor risk patients at 170 mg/m2 developed a severe desquamative dermatitis. Moderate to severe mucositis was usually associated with the thrombocytopenia and/or the dermatitis. Nonhematological drug-related toxicities included nausea and vomiting, malaise, anorexia, diarrhea, phlebitis, reversible transaminase elevation, and mucositis. Other hematological toxicities were anemia, granulocytopenia, and leukopenia. There were no drug-related deaths. There were no objective tumor responses. Plasma and urine levels of Brequinar were quantified by high pressure liquid chromatography in 28 patients. Plasma levels and areas under the curve increased proportionally with increased dose. Brequinar had a harmonic mean terminal t1/2 of 8.1 +/- 3.6 h with a model-independent determined apparent volume of distribution at steady state of 9.0 +/- 2.9 liters/m2 and a total body clearance of 19.2 +/- 7.7 ml/min/m2. Renal excretion was a minor route of elimination for Brequinar. The maximally tolerated dose of Brequinar on a daily x 5 i.v. schedule was 250 mg/m2 for good risk patients. For the daily x 5 i.v. schedule, the recommended dose of Brequinar for phase II evaluation is 250 mg/m2 for good risk patients and 135 mg/m2 for poor risk patients.