Phase I clinical and pharmacogenetic study of weekly TAS-103 in patients with advanced cancer.

PURPOSE: TAS-103 is an inhibitor of both topoisomerase I and II enzymes with broad antitumor activity. It is metabolized to TAS-103-glucuronide (TAS-103-G) predominantly by uridine diphosphate glucuronosyltransferase isoform 1A1 (UGT1A1). We conducted a phase I study to determine the maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT) of TAS-103 when administered on a weekly schedule to patients with advanced cancer. In addition, we evaluated the influence of UGT1A1 genotype on the pharmacokinetics and toxicity of TAS-103. PATIENTS AND METHODS: Thirty-two patients were treated with escalating doses (50 to 200 mg/m(2)) of TAS-103, administered intravenously over 1 hour each week for 3 weeks. Pharmacokinetic analysis was performed at the 130-, 160-, and 200-mg/m(2) dose levels. UGT1A1 genotypes were determined using reverse-transcription polymerase chain reaction techniques. RESULTS: DLT (grade 3 neutropenia) was observed in 5 of 12 patients at 160 mg/m(2) and in 3 of 6 patients at 200 mg/m(2). At 160 mg/m(2), there was a significant correlation between areas under the curve (AUCs) for TAS-103 and TAS-103-G (r = 0.76, P <.05) and an apparent relationship between TAS-103 AUC and D 15 absolute neutrophil count (r = -0.63, P <.05, n = 11, one outlier excluded). UGT1A1 genotype did not influence clearance of TAS-103. CONCLUSION: We recommend a dose of 130 to 160 mg/m(2), or 250 to 300 mg administered using the above weekly schedule for phase II studies. Further studies to characterize the pharmacodynamics and pharmacogenetics of TAS-103 are warranted.

A randomized, double-blind trial of fluorouracil plus placebo versus fluorouracil plus oral leucovorin in patients with metastatic colorectal cancer.

PURPOSE: A prospectively randomized trial was performed to determine whether the combination of fluorouracil (FU) plus leucovorin (FU-LV) administered orally is more effective than equitoxic FU for patients with metastatic colorectal cancer. PATIENTS AND METHODS: A double-blind, placebo-controlled trial design was used to eliminate observer bias. An escalating FU dosing schedule was used to achieve equal toxicity. End points were response, time to treatment failure (TTF), and eight quality-of-life (QL) parameters. A crossover arm allowed FU-treated patients to receive FU-LV combination treatment after treatment failure. RESULTS: Response rate was 32% for FU-LV versus 23% for FU (P = .15). Median TTF was 22 versus 16 weeks (P = .27). Median survival time was 44 versus 54 weeks (P = .26). QL was the same for both treatments, except for days of hospitalization, which was greater for FU-LV (P < .001). Toxicities were similar to those previously reported for FU-LV and FU alone. CONCLUSION: Oral LV-FU produces the same efficacy and toxicity pattern as has been reported for intravenous LV-FU. When FU-LV is compared with equitoxic doses of FU, there is no difference in patient outcome. These results suggest that patients with advanced disease should receive FU at doses adequate to produce toxicity.

Clinical experience with leucovorin and 5-fluorouracil.

Two trials of leucovorin (LV) and 5-fluorouracil (5-FU) in patients with metastatic colorectal cancer were done, both using a 3-day loading dose and then weekly doses to minimize toxicity. The first trial used LV administered by intravenous infusion with a constant dose of 5-FU 400 mg/m2, and the second trail used oral LV with increasing doses of 5-FU. In the first trail, 45 eligible patients (20 with and 25 without previous therapy) were treated. Toxicity usually consisted of diarrhea or weakness and was controlled by delaying or decreasing the 5-FU dose. Subjective responses occurred in 75% of patients but did not correlate with antineoplastic effect. Objective responses were seen in 36% and stabilization of disease in 31% of patients; these correlated with prolonged survival. Median survival was 8 months for patients with previous treatment and 10 for those without. Twelve-month survival was 32% and 40%, respectively. There was no correlation between the development of toxicity and response or survival. The second trial was conducted recently in cooperation with Duke University to determine toxicity and efficacy of oral LV with intravenous 5-FU before a randomized trial of this combination versus placebo with intravenous 5-FU. Eighteen patients were treated, and serum levels of folates were obtained on ten. First toxicity occurred at 5-FU doses ranging from 375 to 850 mg/m2, and consisted of diarrhea in nine, lethargy in seven, nausea/vomiting in four, dermatitis in four, conjunctivitis in two, hypersalivation in two, stomatitis in one, and profound granulocytopenia in one. Response rate was 35%, and stabilization was 35% with median survival of 14 months. Twelve-month survival was 56%.

Use of polyethylene glycol-modified uricase (PEG-uricase) to treat hyperuricemia in a patient with non-Hodgkin lymphoma.

Modification by covalent attachment of monomethoxypolyethylene glycol (PEG) can reduce the immunogenicity and prolong the circulating life of injected enzymes, making their use as therapeutic agents feasible. We report the first clinical use of PEG-modified Arthrobacter protoformiae uricase (PEG-uricase) to treat hyperuricemia in a patient with non-Hodgkin lymphoma and renal insufficiency who was allergic to allopurinol. Two intramuscular injections totaling 3 U/kg body weight during the first 30 hours of treatment lowered the plasma urate level from 910 to 190 mumol/L (15.3 to 3.2 mg/dL), after which a dose of 2 U/kg every 5 to 6 days maintained the plasma urate level at 540 mumol/L (9 mg/dL) or lower. After the injection of PEG-uricase, uricase activity appeared in plasma rapidly, peaking within 24 hours and persisting for approximately 5 days; an inverse relation between plasma uricase activity and plasma urate concentration was noted. The agent was nontoxic and well tolerated. No antibody to either PEG-uricase or unmodified uricase developed over a 3-week period, during which four doses of PEG-uricase were administered. Because of its long circulating life, PEG-uricase is probably a more effective hypouricemic agent than unmodified uricase, which has previously had limited use. As an adjunct to cytolytic therapy for hematologic malignancies when protection from hyperuricemia is needed rapidly, PEG-uricase deserves further study.

Clinical experience with CF-FUra.

Two trials of CF-FUra in patients with metastatic colorectal cancer were performed, both using a 3 day loading dose and then weekly maintenance doses to minimize toxicity. The first trial used CF by IV infusion with constant dose of FUra 400 mg/m2, and the second trial used oral CF with escalating doses of FUra. In the first trial, 45 eligible patients (20 with and 25 without prior therapy) were treated. Toxicity usually consisted of diarrhea or weakness and was controlled by delaying or decreasing 5FU dose. Subjective responses occurred in 75% of patients but did not correlate with antineoplastic effect. Objective responses were seen in 36% and stabilization of disease in 31% of patients, and correlated with prolonged survival. Median survival was 8 months for patients with prior treatment and 10 for those without, and 12 month survival was 32% and 40%, respectively. There was no correlation between the development of toxicity and response or survival. The second trial was recently conducted in cooperation with Duke University to determine toxicity and efficacy of oral CP with IV FUra prior to a randomized trial of this combination versus placebo with IV FUra. Eighteen patients were treated and serum levels of folates were obtained on 10. First toxicity occurred at FUra doses ranging from 375 to 850 mg/m2, and consisted of diarrhea in 9, lethargy in 7, nausea/vomiting in 4, dermatitis in 4, conjunctivitis in 2, hypersalivation in 2, stomatitis in 1, and profound granulocytopenia in 1. Response rate was 35% and stabilization was 35% with median survival of 14 months and 12 month survival of 56%.

Evidence for the involvement of platelet glycoproteins other than GP Ib in heparin-associated thrombocytopenia and thrombosis.

Heparin-associated thrombocytopenia and thrombosis (HATT) is a potentially fatal complication of heparin therapy which is characterized by a progressive fall in the platelet count associated with arterial or venous thrombosis. The etiology is consistent with the development an antibody which, in the presence of heparin, induces intravascular platelet aggregation. Biochemical analysis has demonstrated that the platelet membrane glycoprotein (GP) Ib binds heparin. Recent studies have shown that polyclonal antisera or monoclonal antibodies to GP Ib can inhibit platelet aggregation induced by HATT plasma in the presence of heparin implicating GP Ib as the site of heparin-antibody interaction. The Bernard-Soulier syndrome (BSS) is an inherited bleeding disorder in which the platelets fail to adhere to exposed subendothelium due to a deficiency of GP Ib. We have used the platelets from a patient with documented BSS to further investigate the role of GP Ib in the heparin- dependent platelet aggregation induced by the plasma of three patients with HATT. We have shown that platelet aggregation by HATT plasma in the presence of heparin occurred as readily with BSS platelets as with normal donor platelets. These results indicate that glycoprotein Ib cannot be the only site of platelet-heparin-antibody interactions.

Initial clinical studies of piritrexim.

Piritrexim (PTX) is a second-generation, lipid-soluble inhibitor of dihydrofolate reductase (DHFR). Metabolic inhibition occurs within seconds after rapid diffusion into human cancer cells. We describe the initial phase I studies with iv and oral forms of this drug given on a daily basis for 5 days to patients with cancer. The dose-limiting toxicity is primarily hematologic (leukopenia, granulocytopenia, thrombocytopenia), but phlebitis is also encountered with iv administration and gastrointestinal problems (nausea, vomiting) with oral administration. Oral toxicity can be reduced by giving the daily dose in 2 divided doses. The maximum tolerated dose (MTD) for the iv route is 170 mg/m2 per day for 5 days; for the oral route it is 480 mg/m2 per day for 5 days. Unlike an earlier lipid-soluble folate antagonist, piritrexim did not cause neurologic or histamine-like disorders.

Acute lymphoblastic leukemia of Burkitt's type (L3 ALL) with 8;22 and 14;18 translocations and absent surface immunoglobulins.

A 57-year-old woman presented with L3 acute lymphoblastic leukemia demonstrating typical Burkitt's type morphology. Cytogenetic analysis revealed one of the variant translocations seen in Burkitt's lymphoma [t(8;22)] and a 14;18 translocation. Surface marker data at presentation and at autopsy demonstrated several B-cell markers, but absent surface immunoglobulins. The case presented here reveals a possible cytogenetic link between Burkitt's lymphoma and follicular center-cell lymphoma, and illustrates a variant surface marker profile for Burkitt's lymphoma.

Phase I study of pharmacological and immunological effects of human lymphoblastoid interferon given to patients with cancer.

An extensive Phase I evaluation of human lymphoblastoid interferon has been completed which, in addition to describing its clinical and pharmacological effects, emphasized a broad-scale evaluation of the immune response as a function of interferon dosage. Dose-limiting toxicity was generally due to constitutional symptoms which are remarkably similar to those produced by influenza, although transient peripheral and central neurotoxicity (including deterioration in cognitive and behavioral functions) is observed at higher doses. It is difficult to establish "clean" dose-response effects except for fever and bone marrow suppression, neither of which is a major dose limitation. Enhancement of the immune system was limited to natural killer cells which had a complex dose-response relationship, whereby low interferon concentrations were less stimulatory (than were high doses) following a single dose but gave more sustained stimulation over a 5-week course of 3 times per week i.m. administration. The effects on various measures of monocyte function and of nonspecific immunity (hypersensitivity, immunoglobulins, complement) were negative. We suspect that in practice it may be difficult to exploit the narrow dosage window of immunostimulation, but it is important to note that the nontoxic lower doses were more stimulatory than were the very high doses which are being used in numerous clinical trials.

Unpredictable fluctuations in serum acid phosphatase activity in prostatic cancer.

Repeated determinations of the elevated serum acid phosphatase activities in five patients with advanced prostatic cancer were found to be highly variable during 24 to 48 hours of observation. Samples collected every three hours had fluctuations of 44% to 97% around the 24- to 48-hour mean values. These fluctuations appeared to be random, had no apparent circadian rhythm, and were unrelated to concurrent medications or activity. These spontaneous variations indicate the need for caution when using serial serum acid phosphatase determinations as an indicator of the response of prostate cancer to therapy. Elevated serum alkaline phosphatase activities did not show these extreme fluctuations.

Lipid-soluble inhibitors of dihydrofolate reductase. I. Kinetics, tissue distribution, and extent of metabolism of pyrimethamine, metoprine, and etoprine in the rat, dog, and man.

With the aim of developing anticancer compounds which overcome some of the clinical limitations of the polar dihydrofolate reductase inhibitor, methotrexate, the physicochemical properties, kinetics, and metabolism of a series of lipid-soluble 2,4-diamino-5-phenylpyrimidine folate antagonists have been studied. Metoprine and etoprine, potent inhibitors of mammalian dihydrofolate reductase, were compared with pyrimethamine, a widely used antimalarial drug. The development of assay procedures in our laboratory and the synthesis of radiolabeled compounds have enabled a comparison of the kinetic characteristics and tissue distribution of these compounds in several species. The relative lipophilicities as indicated by the octanol/water partition coefficient are: etoprine (log P = 3.19) greater than metoprine (log P = 2.82) greater than pyrimethamine (log P = 2.69). Etoprine has the greatest affinity for plasma proteins, but all three compounds are bound to human plasma protein by 87% or more at therapeutic concentrations. Pharmacokinetic studies in the mouse, rat, dog, and man indicate that metoprine has the longest plasma half-life in all four species. The mean plasma half-lives in man are: pyrimethamine, 85 hr; metoprine, 216 hr; etoprine, 176 hr.

Fragmentation haemolysis in patients with severe diabetic angiopathy.

Haemolytic anaemia associated with prominent red cell fragmentation is described in seven patients with long-standing diabetes mellitus. A common freature in the patients was severe microangiopathy as detected by retinal examination and microscopic examination of the kidneys. Renal or pancreatic islet malfunction per se is not involved in the haemolytic syndrome, since red cell abnormalities persisted in one patient for over a year following successful renal and pancreatic transplantation--this, despite the maintenance of normal renal and carbohydrate homeostasis. The kinetics of fragmentation was sutdied by tranfusing snormal type O cells into this type A patient. With reisolation of these cells by the Ashby-technique, rapid and porgressive red cell fragmentation was demonstrated by: (a) membrane lipid loss; (b) osmotic fragility increase; and (c) increase in mean cell haemoblobin concentration. This studies indicate that a red-cell-fragmentation haemolytic anaemia may occur in long-standing diabetes mellitus, related to the angiopathy of this disease and not to insulin deficiency or renal malfunction.