Phase 1 study of N1-N11-diethylnorspermine (DENSPM) administered TID for 6 days in patients with advanced malignancies.

UNLABELLED: This was a dose escalation Phase 1 trial designed to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of DENSPM. METHODS: Adult patients with refractory solid tumors were treated with DENSPM administered by intravenous infusion in 100 ml of normal saline over 30 minutes. The daily dose of DENSPM was divided into three equal doses administered approximately every eight hours for six days. Courses were repeated every 28 days. RESULTS: Twenty-eight patients were enrolled in the study. Dose levels of DENSPM explored were 25 mg/m2/day (3 patients), 50 mg/m2/day (9 patients), 60 mg/m2/day (5 patients), 75 mg/m2/day (6 patients), 94 mg/m2/day (3 patients) and 118 mg/m2/day (2 patients). The DLT for DENSPM was central nervous system toxicity characterized by aphasia, ataxia, dizziness, vertigo and slurred speech occurring at dose levels > or = 94 mg/m2/day, which was also the MTD. SAFETY: The most frequent drug-related adverse events were asthenia (9 patients), injection site reaction (6 patients) and anemia (6 patients). One patient was removed from the study due to CNS toxicity. There were no treatment-related deaths. No trends were observed regarding hematologic toxicities, biochemical changes or changes in vital signs. EFFICACY: Nineteen of the 28 patients enrolled in the study were assessed for response. No objective responses were observed. Five patients had stable disease as the best response to therapy. CONCLUSIONS: Because the DLT was CNS and because of the relatively low doses that could be safely administered on this schedule as compared with a once-a-day schedule, this regimen was not recommended for Phase 2.

Paromomycin: no more effective than placebo for treatment of cryptosporidiosis in patients with advanced human immunodeficiency virus infection. AIDS Clinical Trial Group.

To evaluate the efficacy of paromomycin for the treatment of symptomatic cryptosporidial enteritis in human immunodeficiency virus-infected adults, we conducted a prospective, randomized, double-blind, placebo-controlled trial before the widespread introduction of highly active antiretroviral therapy (HAART). Seven units under the auspices of the AIDS Clinical Trials Group enrolled 35 adults with CD4 cell counts of < or = 150/mm(3). Initially, 17 patients received paromomycin (500 mg 4 times daily) and 18 received matching placebo for 21 days. Then all patients received paromomycin (500 mg q.i.d.) for an additional 21 days. Clinical definitions of response were measured by an average number of bowel movements per day in association with concurrent need for antidiarrheal agents that was lower than that before study entry. There was no treatment response during the placebo-controlled phase of the study according to protocol-defined criteria (P=.88). Three paromomycin recipients (17.6%) versus 2 placebo recipients (14.3%) responded completely. Rates of combined partial and complete responses in the paromomycin arm (8 out of 17, 47.1%) and the placebo arm (5 out of 14, 35.7%) of the study were also similar (P=.72). The clinical course of cryptosporidiosis was quite variable. Paromomycin was not shown to be more effective than placebo for the treatment of symptomatic cryptosporidial enteritis. However, inadequate statistical power prevents definitive rejection of the usefulness of paromomycin as therapy for this infection.

Tinea pedis: diagnosis and treatment.

The authors review the common dermatophyte genera and the forms of tinea pedia they cause. They also provide a differential diagnosis, review diagnostic procedures, and outline the pathophysiology of this complex condition. A classification and treatment plan is provided, with an extensive review of recent clinical trials. The aim of the article is to expand practitioners' treatment options for individualizing treatment plans.

A phase II trial of diaziquone in patients with head and neck cancer.

Diaziquone (AZQ) is a lipophilic alkylating agent which crosses the blood-brain barrier and has marked antitumor activity in a broad spectrum of murine tumor systems. Myelosuppression has been the dose-limiting toxicity in phase I trials. In this study 36 patients with head and neck cancer received diaziquone. Thirty-one of these patients (28 male, 3 female) were evaluable for efficacy. The initial starting dose was 7 mg/m2/day X 5 days i.v. repeated every 28 days. Because of the severe myelosuppression encountered in the first four patients, the starting dose was decreased by 20% to 5.5 mg/m2/day X 5 days repeated every 28 days. The majority of patients were considered to be good-risk patients as evidenced by performance status (80% 0-1 Zubrod) and prior therapy. Even with this dosage reduction, myelosuppression (especially thrombocytopenia) was again the dose-limiting toxicity with 25% of patients experiencing granulocyte and platelet nadirs below 1000/mm3 and 50,000/mm3 respectively. Thirty-five percent of patients required a subsequent dosage reduction of 20% prior to receiving a second course of therapy. There was one complete (CR), four partial (PR) and three minor (MR) responses. All but the CR were of relatively short duration (mean of 30 days). The patient with a CR has remained disease-free for nearly 3 years. In this group of patients the activity of diaziquone as a single agent at this dose and schedule (CR + PR + MR = 26%; CR + PR = 16%) is less than that of methotrexate, bleomycin, and cis-platinum but is encouraging. Further trials utilizing combinations are warranted.

Pharmacokinetics of ametantrone acetate (NSC-287513).

Ametantrone is the second anthracene derivative to enter clinical trials. The pharmacokinetic parameters for ametantrone acetate (CI-881) were characterized in six patients concurrently with the phase I clinical trial. Biological samples were assayed by a specific and sensitive high-performance liquid chromatography procedure. Plasma levels of ametantrone declined in a triexponential fashion, with a mean terminal half-life (t 1/2 gamma) of 25 h. The estimated mean total-body plasma clearance was 25.9 +/- 14.7 1 h-1 m-2. The steady-state volume of distribution (Vdss) was large, averaging 568 +/- 630 l/m2. Excretion of unchanged ametantrone in the urine over 48 h averaged 5.7% of the total dose, indicating that there is another major route of elimination.

Phase I-II evaluation of intra-arterial diaziquone for recurrent malignant astrocytomas.

Diaziquone (AZQ) is a lypophilic alkylating agent that crosses the blood-brain barrier and has shown broad activity in animal tumor models. Five of 12 patients with malignant astrocytoma treated with iv AZQ had clinical and/or radiographic improvement (Schold, Neurology 34:615, 1984). Intra-arterial administration of AZQ to patients with brain tumors should produce higher peak levels of drug in the tumor and should reduce systemic toxicity. Twenty-one patients with astrocytoma (grade II, four; grade III, 11; and grade IV, six), in all of whom irradiation and intra-arterial carmustine chemotherapy failed, received intra-arterial AZQ as a single dose every 28 days. Two of 20 evaluable patients experienced partial responses of 5 and 8+ months, respectively. Four patients had disease stabilization of 3, 4, 5, and 8 months' duration, respectively, and one of these patients had tumor shrinkage (partial response) after seven courses of AZQ. The initial dose in the first three patients was 10 mg/m2, and doses in subsequent groups of three patients were begun at increases of 5 mg/m2. The within-group dose escalation was 5 mg/m2 per course if there was no hematologic toxicity. Dose-limiting toxicity was myelosuppression, which occurred at doses greater than 15 mg/m2. The maximum tolerated dose was 25 mg/m2. Intra-arterial AZQ appears to be of marginal effectiveness in patients refractory to carmustine and offers no advantage over iv AZQ in efficacy or toxicity.

Phase II trial of diaziquone in patients with colon cancer.

Seventeen patients with metastatic colon cancer received diaziquone iv daily for 5 days repeated every 28 days. Based on recommended starting doses for phase II trials (6-8 mg/m2 daily X 5), the first six patients received 7 mg/m2/day X 5. Two of these patients were heavily pretreated with chemotherapy, two had received prior 5-FU alone, and two had received no prior chemotherapy. There were no responses and three septic deaths (both of the heavily pretreated patients and one 5-FU-only patient who received concurrent radiotherapy). Eleven subsequent patients received 5.5 mg/m2/day X 5. Nine had no prior therapy; two had received prior 5-FU. No antitumor responses were observed. Myelosuppression was again the major toxic effect. No further septic deaths occurred. Diaziquone in this dose and schedule had no antitumor activity in this group of patients.

A phase I trial of ametantrone acetate (NSC-287513).

Ametantrone acetate is an intensely blue anthracenedione undergoing clinical trials in man. In this Phase I study, 20 patients received 39 courses of drug as a single IV dose given daily for five days and repeated every three weeks (21 days). Dosage escalations proceeded from 15 mg/m2 to 35 mg/m2. Predictable and reversible leukopenia was the dose limiting toxicity. One previously untreated patient with renal cell carcinoma metastatic to the lungs and right arm experienced a partial response of 51 days duration. Nine patients had pharmacokinetic studies performed during the study. Ametantrone was extensively distributed (apparent volume of distribution, 26.3 l/m2) and demonstrated a short half-life (harmonic mean half-life, 0.38 hour). The maximum tolerated dose in this study was 35 mg/m2. Recommended doses for Phase II trials are 30 mg/m2 in good risk patients and 25 mg/m2 in poor risk patients. Because of the partial response seen in one patient with renal cell carcinoma, Phase II trials should include this tumor category in order to better define the activity of ametantrone in this disease. In addition, since the total amount of drug that could be given to patients receiving the five day schedule (125-150 mg/m2) was approximately the same amount that could be administered as a single dose (140 mg/m2), it would appear that the only advantage of the daily times five day dosage schedule would be in the lower incidence of bluish skin discoloration.

Phase I investigation of ametantrone.

Ametantrone is the third of a family of anthracene derivatives to undergo a phase I trial in man. Sixteen patients received 33 courses of drug as a single iv dose given every 3 weeks. Escalations proceeded from 120 to 180 mg/m2. Predictable and reversible leukopenia was the dose-limiting toxic effect. Four patients developed thrombocytopenia. Nonhematologic toxic effects included a marked cumulative blue discoloration of the skin seen in all patients receiving more than three courses of the drug. This cumulative cosmetic effect may also be dose-limiting. Other nonhematologic toxic effects included: blue urine (all patients), nausea (two), vomiting (one), a blue stool (one), and reversible elevations of either SGOT or alkaline phosphatase (two). No objective responses were seen in this study. A dose of 140-160 mg/m2 is recommended as the starting dose for phase II trials in patients who have received prior chemotherapy or radiotherapy.

Diaziquone (AZQ).

Diaziquone is an aziridinylbenzoquinone with properties suggestive of an alkylating agent. The drug has shown broad antitumor activity against numerous transplantable murine tumors including curative activity against several intracerebrally implanted tumors. Parent diaziquone appears to have a t1/2 beta of approximately 30 min. The drug is rapidly and widely distributed to tissues as evidenced by a t1/2 alpha of approximately 1-3 min and a volume of distribution exceeding that of total body water. In addition, it rapidly penetrates the central nervous system, reaching peak concentrations (30-50%) of corresponding plasma levels) in approximately one hour. Diaziquone is rapidly and extensively metabolized by the liver. Diaziquone is a potent marrow suppressive agent inducing significant degrees of leukopenia, granulocytopenia, and thrombocytopenia in humans. Thrombocytopenia is often severe. Although myelosuppression is for the most part dose related, many patients had significant toxicity even at lower doses. Most investigators have attributed this to the extent of prior therapy. Diaziquone demonstrates a very steep dose-response relationship. Myelosuppression was the dose-limiting toxicity in all phase I trials. No nonhematologic dose-limiting toxicity has been identified to date. In phase I and preliminary phase II trials, diaziquone has demonstrated activity against primary brain tumors. Little activity has been seen in other tumor categories. It should be noted, however, that all studies to date have been carried out in heavily pretreated patients. Because of the broad spectrum of antitumor activity in experimental murine tumors, the lack of nonhematologic dose-limiting toxicity, the ability of this drug to attain significant levels in the central nervous system, and the activity of the drug in primary brain tumors, further studies examining its role in the management of patients with cancer are warranted. These studies should be conducted in patients who have had little or no prior therapy in order to better evaluate the efficacy of the drug.

Comparative auditory toxicity of aminoglycoside antibiotics in leukopenic patients.

The incidence of auditory toxicity resulting from therapy with ticarcillin (T) (12 g/sq m/day) in combination with gentamicin (G) (200 mg/sq m/day), amikacin (A) (600 mg/dq m/day), or netilmicin (N) (280 mg/sq m/day) was compared. Before administration of these antibiotic combinations to febrile, granulocytopenic patients, baseline audiograms were determined by a pharmacist using a portable audiometer. The before-therapy audiograms for 32 patients receiving T and G, 29 receiving T and A, and 29 receiving T and N were compared with the audiograms after the completion of therapy. The mean length of therapy was seven days. Two patients (6.2%) receiving T and G, one (3.4%) receiving T and N, and one (3.4%) receiving T and A developed auditory toxicity with bilateral decreases of at least 20 decibels at one or more frequencies. The incidence of auditory toxicity secondary to aminoglycoside exposure was low, and the relative auditory toxicity among the three aminoglycosides appeared to be similar.

Randomized trial of empiric antibiotic therapy with ticarcillin in combination with gentamicin, amikacin or netilmicin in febrile patients with granulocytopenia and cancer.

A randomized trial of ticarcillin plus gentamicin (group 1), ticarcillin plus amikacin (group 2) and ticarcillin plus netilmicin (group 3) as empiric antibiotic therapy in patients with granulocytopenia and cancer was carried out at the Baltimore Cancer Research Center. The response rate for all infections was 97 per cent in group 1, 91 per cent in group 2 and 95 per cent in group 3. Patients with bacteremias showed improvement in 93 per cent (group 1), 78 per cent (group 2) and 82 per cent (group 3) of cases. All failures were among patients with gram-negative bacteremias. Both antibiotic susceptibility of the bacteremic organism and granulocyte recovery correlated with patient improvement. Nephrotoxicity and ototoxicity were rare and were not significantly different in three groups of patients. Therefore, ticarcillin plus gentamicin, ticarcillin plus amikacin and ticarcillin plus netilmicin appear to be equally efficacious and minimally toxic in this patient population. Excellent over-all results can be expected with these combinations provided the etiologic agent is susceptible.

Role of vancomycin as a component of oral nonabsorbable antibiotics for microbial suppression in leukemic patients.

A total of 38 adult patients with acute leukemia who were undergoing remission induction chemotherapy in regular patient rooms were randomly allocated to one of two oral nonabsorbable antibiotic regimens for infection prophylaxis (gentamicin, vancomycin, and nystatin [GVN] or gentamicin and nystatin [GN]) to evaluate whether vancomycin was a necessary component. The patient population in both groups were comparable. Tolerance to GVN was less than GN but compliance was approximately equal (>85% in both groups). Patients receiving vancomycin demonstrated greater overall alimentary tract microbial suppression; however, acquisition of potential pathogens was approximately equal in both groups. The incidence of bacteremia, as well as the overall incidence of infection as related to the number of days at various granulocyte levels, was also approximately equal in both groups. Group D Streptococcus species were poorly suppressed by GN compared with GVN, although no patient developed an infection with these organisms. Colonization by newly acquired gram-negative bacilli was significantly less in the GN group (GN, 3 colonizations; GVN, 13 colonizations; P < 0.01). It is concluded that vancomycin may be safely eliminated from the GVN regimen provided microbiological data is monitored to detect resistant organisms.

High-dose methotrexate with folinic acid rescue.

A brief review of the pharmacology of methotrexate is presented, and the rationale for the administration of high-dose methotrexate and the necessity of a folinic acid rescue to prevent methotrexate toxicity are discussed. Critical factors concenrning the use of this therapy, as well as unusual toxicities associated with the use of high-dose methotrexate, are presented. Several drug-and patient-related variables which may affect the toxicity of this dual drug administration are discussed to better enable pharmacists to monitor patients receiving this form of therapy. High-dose methotrexate with folinic acid rescue has improved the therapeutic index of methotrexate. The optimal dosage and duration of the two agents are yet to be determined.