A phase I and pharmacologic study of 9-aminocamptothecin administered as a 120-h infusion weekly to adult cancer patients.

PURPOSE: To define the toxicity profile and the recommended phase II doses of 9-aminocamptothecin (9-AC) administered as a weekly 120-h infusion. METHODS: 9-AC was administered over 120 h weekly to 55 adult cancer patients with solid tumors over doses ranging from 0.41 to 0.77 mg/m2 per day in a phase I and pharmacologic study. 9-AC formulated in dimethylacetamide/polyethylene glycol (DMA) was administered on a 3 of 4-week schedule, and the newer colloidal dispersion (CD) formulation was given on a 2 of 3-week schedule. RESULTS: Overall, 193 courses of therapy were administered over 122 dose levels. On the 3 of 4-week schedule, 9-AC DMA infused at > or = 0.6 mg/m2 per day for 120 h weekly produced dose-limiting neutropenia, thrombocytopenia, and diarrhea, or resulted in 1-2-week treatment delays. Shortening treatments to 2 of 3 weeks resulted in dose-limiting neutropenia and fatigue at infusion rates > 0.72 mg/m2 per day. The ratio of 9-AC lactone to total (carboxylate + lactone) drug plasma concentrations at steady-state was 0.15 +/- 0.07. Clinical toxicities and drug pharmacokinetics were not substantially different between the DMA and CD formulations. One objective response was observed in a patient with bladder cancer and minor responses were observed in patients with lung and colon cancers. Plasma area under the concentration versus time curve for 9-AC lactone modestly correlated with the degree of thrombocytopenia (r=0.51) using a sigmoid Emax pharmacodynamic model. CONCLUSION: The recommended phase II dose for the 9-AC DMA formulation is 0.48 mg/m2 per h over 120 h for 3 of 4 weeks and for the 9-AC CD formulation is 0.6 mg/m2 per day over 120 h for 2 of 3 weeks. Both regimens were well tolerated and feasible to administer.

Pharmacokinetics and pharmacodynamic effects of 5-fluorouracil given as a one-hour intravenous infusion.

PURPOSE: Clinical toxicity associated with 5-fluorouracil (5-FU) is related to the area under the plasma concentration-time curve (AUC). Recently, short-term infusions of 5-FU given over 30 or 60 min have been substituted for conventional "bolus" 5-FU given over 3-5 min in randomized clinical trials, but there are only limited pharmacokinetic data for these altered infusion durations. We therefore wished to determine the pharmacokinetics and toxicity associated with 5-FU given as a 1-h intravenous (i.v.) infusion. METHODS: A group of 22 adults with advanced gastrointestinal tract cancers and no prior systemic chemotherapy for advanced disease received interferon alpha-2a (5 MU/m2 s.c., days 1-7), leucovorin (500 mg/m2 i.v. over 30 min, days 2-6) and 5-FU (370 mg/m2 i.v. over 1 h, days 2-6). The doses of 5-FU and interferon-alpha were adjusted according to individual tolerance. The pharmacokinetics and clinical toxicity were retrospectively compared with patients receiving the same regimen under the same treatment guidelines except that 5-FU was given over 5 min. RESULTS: The regimen was well tolerated, and 41% of the patients tolerated 5-FU dose escalations to 425-560 mg/m2 per day. Grade 3 or worse diarrhea and fatigue ultimately occurred in 14% of the patients each. Granulocytopenia, mucositis, and diarrhea appeared to be appreciably milder in the present trial compared with our prior phase II experience in colorectal cancer. The peak 5-FU plasma levels and AUC with 370 mg/m2 5-FU given over 1 h were 7.3-fold and 2.4-fold lower than previously measured in 31 patients who received 5-FU over 5 min. CONCLUSION: Increasing the length of 5-FU infusion to 1 h seemed to substantially reduce the clinical toxicity with this modulated 5-FU regimen, likely due to markedly lower peak 5-FU plasma levels and AUC. Changes in the duration of a short infusion of 5-FU clearly affects the clinical toxicity, but raises the concern of a potentially adverse impact on its antitumor activity. These results suggest the importance of including precise guidelines concerning the time over which 5-FU is given in clinical trials. Having a specified duration of 5-FU infusion is also important if 5-FU dose escalation is considered.

Phase I and pharmacokinetic trial of weekly oral fluorouracil given with eniluracil and low-dose leucovorin to patients with solid tumors.

PURPOSE: Fluorouracil (5-FU) given as a weekly, high-dose 24-hour infusion is active and tolerable. We evaluated an oral regimen of eniluracil (which inactivates dihydropyrimidine dehydrogenase [DPD]), 5-FU, and leucovorin to simulate this schedule. PATIENTS AND METHODS: Patients received a single 24-hour infusion of 5-FU (2,300 mg/m(2) on day 2) with leucovorin (15 mg orally [PO] bid on days 1 through 3) to provide reference pharmacokinetic data. Two weeks later, patients began treatment with eniluracil (20 mg) and leucovorin (15 mg) (PO bid on days 1 through 3) and 5-FU (10 to 15 mg/m(2) PO bid on day 2). RESULTS: Dose-limiting toxicity (diarrhea, neutropenia, and fatigue) was seen with 5-FU 15 mg/m(2) PO bid on day 2 given weekly for either 6 of 8 weeks or 3 of 4 weeks, whereas five of seven patients tolerated 5-FU 10 mg/m(2) PO bid given weekly for 3 of 4 weeks. Eniluracil led to a 35-fold reduction in 5-FU clearance. Fluoro-beta-alanine, a 5-FU catabolite, was not detected in plasma during oral 5-FU-eniluracil therapy. DPD activity was markedly suppressed in all patients during eniluracil therapy; the inactivation persisted after the last eniluracil dose; percentages of baseline values were 1.8% on day 5, 4.5% on day 12, and 23.6% on day 19. CONCLUSION: The recommended oral dosage of 5-FU (10 mg/m(2) PO bid) given with eniluracil and leucovorin is approximately 115-fold lower than the reference dosage for 24-hour infusional 5-FU. This difference is greater than expected given the reduction in 5-FU clearance. DPD inactivation persisted for several weeks after completion of eniluracil therapy.

Phase I and pharmacologic study of irinotecan administered as a 96-hour infusion weekly to adult cancer patients.

PURPOSE: We conducted a phase I and pharmacologic study of a weekly 96-hour infusion of irinotecan to determine the maximum-tolerated dose, define the toxicity profile, and characterize the clinical pharmacology of irinotecan and its metabolites. PATIENTS AND METHODS: In 26 adult patients with solid tumors, the duration and dose rate of infusion were escalated in new patients until toxicity was observed. RESULTS: In 11 patients who were treated with irinotecan at 12.5 mg/m(2)/d for 4 days weekly for 2 of 3 weeks, dose-limiting grade 3 diarrhea occurred in three patients and grade 3 thrombocytopenia occurred in two patients. The recommended phase II dose is 10 mg/m(2)/d for 4 days given weekly for 2 of 3 weeks. At this dose, the steady-state plasma concentration (Css) of total SN-38 (the active metabolite of irinotecan) was 6.42 +/- 1.10 nmol/L, and the Css of total irinotecan was 28.60 +/- 17.78 nmol/L. No patient experienced grade 3 or 4 neutropenia during any cycle. All other toxicities were mild to moderate. The systemic exposure to SN-38 relative to irinotecan was greater than anticipated, with a molar ratio of the area under the concentration curve (AUC) of SN-38 to irinotecan of 0.24 +/- 0.08. One objective response lasting 12 months in duration was observed in a patient with metastatic colon cancer. CONCLUSION: The recommended phase II dose of irinotecan of 10 mg/m(2)/d for 4 days weekly for 2 of 3 weeks was extremely well tolerated. Further efficacy testing of this pharmacologic strategy of administering intermittent low doses of irinotecan is warranted.

Sequence-dependent antagonism between fluorouracil and paclitaxel in human breast cancer cells.

The effects of 24-hr exposures to 5-fluorouracil (FUra) and paclitaxel in various sequences were studied in MCF-7 breast cancer cells to determine an optimal schedule for possible clinical use. In clonogenic assays, pre-exposure to FUra followed by paclitaxel resulted in marked antagonism, while sequential paclitaxel followed by FUra was optimal. Concurrent or pre-exposure to paclitaxel did not affect [3H]FUra metabolism, [3H]FUra-RNA incorporation, or the extent of FUra-mediated thymidylate synthase inhibition. Paclitaxel led to G2/M phase accumulation that persisted for up to 24 hr after drug exposure, while a 24-hr FUra exposure produced S-phase accumulation. FUra pre-exposure diminished paclitaxel-associated G2/M phase block, whereas subsequent exposure to FUra after paclitaxel did not. FUra exposure resulted in transient induction of p53 and p21, which returned to basal levels 24 hr after drug removal. p53 and p21 protein content also increased markedly during paclitaxel exposure, accompanied by phosphorylation of Bcl-2. Double-stranded DNA fragmentation (approximately 50 kb) was seen at 48 hr when cells were exposed to paclitaxel for an initial 24-hr period. Paclitaxel-associated DNA fragmentation was not prevented by concurrent or subsequent exposure to FUra. Thus, paclitaxel-mediated G2/M phase arrest appeared to be a crucial step in induction of DNA fragmentation. Since an initial 24-hr paclitaxel exposure did not interfere with subsequent FUra metabolism or thymidylate synthase inhibition, and delayed exposure to FUra did not impede either paclitaxel-mediated induction of mitotic blockade or DNA fragmentation, the sequence of paclitaxel followed by FUra is recommended for clinical trials.

Rituximab therapy in hematologic malignancy patients with circulating blood tumor cells: association with increased infusion-related side effects and rapid blood tumor clearance.

PURPOSE: Rituximab was recently approved for use in relapsed, low-grade non-Hodgkin's lymphoma; however, few data exist regarding the safety of this agent in patients with a high number of tumor cells in the blood. METHODS AND RESULTS: After the observation at our institution of a rapid reduction of peripheral-blood tumor cells with associated severe pulmonary infusion-related toxicity in two patients with refractory hematologic malignancies, data on three additional cases were collected from physician-submitted reports of adverse events related to rituximab treatment. Five patients with hematologic malignancies possessing a high number of blood tumor cells were treated with rituximab and developed rapid tumor clearance. The median age was 68 years (range, 26 to 78 years). Patients were diagnosed with B-cell prolymphocytic leukemia (n = 2), chronic lymphocytic leukemia (n = 2), or transformed non-Hodgkin's lymphoma (n = 1). All of these patients had bulky adenopathy or organomegaly. All five patients developed a unique syndrome of severe infusion-related reactions, thrombocytopenia, rapid decrement in circulating tumor cell load, and mild electrolyte evidence of tumor lysis, and all required hospitalization. In addition, one patient developed ascites. These events resolved, and four patients were subsequently treated with rituximab without significant complications. CONCLUSION: Rituximab administration in patients who have a high number of tumor cells in the blood may have an increased likelihood of severe initial infusion-related reactions. These data also suggest that rituximab may have activity in a variety of other lymphoid neoplasms, such as chronic lymphocytic leukemia and B-cell prolymphocytic leukemia.

Clinical significance of the FV:Q506 mutation in unselected oncology patients.

PURPOSE: A common germline mutation in the factor V gene (FV:Q506) has been associated with hypercoagulability in families with heritable predisposition to thrombosis. We examined the prevalence and clinical significance of the FV:Q506 mutation in cancer patients. PATIENTS AND METHODS: We performed a retrospective cohort study by examining 353 consecutive, unselected patients in a general hematology/oncology clinic. We ascertained risk factors, obtained the clinical clotting history, and determined the heterozygous or homozygous presence of the FV:Q506 allele for each patient. RESULTS: We detected a germline mutation in 5.4% (19 of 353) of patients, of whom 18 were heterozygous and 1 was homozygous for the FV:Q506 mutant allele. In 17 of 18 heterozygous patients, there was no history of venous thrombosis or catheter-associated thrombosis. These asymptomatic patients included 13 patients who had been diagnosed with cancer or leukemia for a mean of 66.2 months (median 69) and had received a variety of local and systemic treatments. In contrast, 1 of 18 heterozygous and 1 of 1 homozygous patients had developed deep vein thrombosis that was associated, respectively, with either recurrent thrombotic events or a strong family history for pulmonary embolus. CONCLUSIONS: Routine screening for the FV:Q506 mutation in cancer patients without a personal or family history for venous thrombosis is not helpful in guiding management. In contrast, an episode of venous thrombosis in a patient with a mutant germline FV:Q506 allele was associated with recurrent thrombotic events. These findings suggest that patients heterozygous for the FV:Q506 allele may require an independent "susceptibility" element to manifest a venous hypercoagulable state. In addition, only 2 of 25 clinic patients with a venous clot carried the FV:Q506 allele suggesting this genetic defect plays a minor role in the hypercoagulable state of cancer.

Clinical aspects of expression of inversion 16 chromosomal fusion transcript CBFB/MYH11 in acute myelogenous leukemia subtype M1 with abnormal bone marrow eosinophilia.

The pericentric inversion of chromosome 16 (inv(16)(p12q22)) is a characteristic karyotypic abnormality associated with acute myeloid leukemia, most commonly of the M4Eo subtype. It is increasingly appreciated as both a favorable prognostic factor and important guide to therapy. The breakpoints of the inversion have been cloned and a fusion transcript can be identified by RT-PCR. We expand upon our prior abstract of a case of AML subtype M1 with abnormal eosinophils that expressed the inversion 16 fusion transcript CBFB/MYH11. During remission, the transcript could not be detected. The patient relapsed twice during the first year after attaining a complete remission. Morphologically, the relapsed specimens were identical to the appearance of his diagnostic specimen. However, the CBFB/MYH11 fusion transcript was not detected in the relapsed specimen. We conclude that CBFB/MYH11 fusion transcript detection, as a surrogate for the favorable prognosis and treatment planning implied by inv(16) in AML M4Eo, should not be exclusively relied upon in AML M1 in the absence of prospective study of this specific (M1) category of AML. RT-PCR analysis should be correlated with cytogenetics when available and if used alone should be interpreted cautiously in cases of AML with atypical morphological features.

Torsades de pointes occurring in association with terfenadine use.

Torsades de pointes is a form of polymorphic ventricular tachycardia that is associated with prolongation of the QT interval. Although found in many clinical settings, torsades de pointes is most often drug induced. This report describes the first association (exclusive of drug overdose) of symptomatic torsades de pointes occurring with the use of terfenadine in a patient who was taking the recommended prescribed dose of this drug in addition to cefaclor, ketoconazole, and medroxyprogesterone. Measured serum concentrations of terfenadine and its main metabolite showed excessive levels of parent terfenadine and proportionately reduced concentrations of metabolite, suggesting inhibition of terfenadine metabolism. We believe that a drug interaction between terfenadine and ketoconazole resulted in the elevated terfenadine levels in plasma and in the cardiotoxicity previously seen only in cases of terfenadine overdose.