Phase I and pharmacokinetic trial of carboplatin in refractory adult leukemia.

Sixteen patients [13 acute nonlymphocytic leukemia (ANLL), 2 acute lymphocytic leukemia, 1 chronic myelogenous leukemia in a blast crisis; median age, 40 yr; range, 25-78 yr; 9 male, 7 female] received 23 courses of carboplatin given as a bolus on a daily X 5 schedule. Six patients were given 7 courses of carboplatin at 200 mg/m2/day; 3 patients received 5 courses at 250 mg/m2; 9 patients received 11 courses at 300 mg/m2; 2 patients initially treated at 200 mg/m2 were given their 2nd course at 300 mg/m2. Significant hearing loss documented by audiometry occurred in five patients, including three of nine treated at 300 mg/m2. All five had prior or recent exposure to aminoglycoside antibiotics. Three patients developed cancer and acute leukemia group B grade 3 or 4 mucositis, and 18 of 23 courses were complicated by nausea and vomiting. Marrows were hypocellular or aplastic in all patients treated at the highest dose. No complete responses occurred, although two patients with ANLL treated at 300 mg/m2 achieved partial responses lasting 71 and 138 days. The t1/2 alpha [half-life (t1/2)], t1/2 beta, and total body clearance of ultrafilterable platinum were comparable to those previously described by us in patients receiving bolus doses of carboplatin of 22-77 mg/m2/day X 5. Carboplatin has activity in ANLL.

Phase I trial of granulocyte-macrophage colony-stimulating factor plus high-dose cyclophosphamide given every 2 weeks: a Cancer and Leukemia Group B study.

BACKGROUND: Chemotherapy-induced myelosuppression often limits escalation of cancer chemotherapy doses. Cyclophosphamide, an alkylating agent, is an ideal candidate for dose escalation: A log-linear relationship between cell kill and dose has been demonstrated, and the drug spares hematopoietic stem cells. In addition, studies suggest that granulocyte-macrophage colony-stimulating factor (GM-CSF) can enhance the ability to achieve optimal dose intensity as well as ameliorating chemotherapy-induced myelosuppression. PURPOSE: The purpose of this study was to determine the maximum tolerated dose and the toxic effects of cyclophosphamide administered every 2 weeks with GM-CSF support. METHODS: For this trial by the Cancer and Leukemia Group B (CALGB), cohorts of patients were treated with cyclophosphamide as a 1-hour intravenous infusion every 14 days; GM-CSF was given subcutaneously on days 3-10. Four dose levels of cyclophosphamide (1.5, 3.0, 4.5, and 6.0 g/m2) and three dose levels of GM-CSF (2.5, 5.0, and 10.0 micrograms/kg per day) were evaluated. There was no dose escalation in individual patients. Fifty-one patients with solid tumors who had CALGB performance status 0 or 1 and minimal prior radiotherapy were eligible for analysis. Drug clearance and area under the curve for plasma drug concentration x time (AUC) were estimated at completion of the infusion and at 4 and 24 hours after the start of the infusion. RESULTS: Ninety-five courses of therapy were analyzed. Treatment with cyclophosphamide at 3.0 g/m2 or more resulted in neutropenia (absolute neutrophil counts < 100/microL) in all cycles of therapy. At those doses, blood cell count recovery adequate for re-treatment occurred in 67%-85% of cycles (median, 16 days). Doses of 6.0 g/m2 were associated with the greatest degree of myelosuppression and frequent hospitalization (88% of cycles); requirements for blood transfusion prohibited further dose escalation. Nonhematologic toxic effects were tolerable, with two episodes of reversible cardiotoxicity and four episodes of hemorrhagic cystitis that precluded further therapy. Degree of myelosuppression was not correlated with cyclophosphamide AUC or clearance. CONCLUSIONS: The recommended phase II dose of cyclophosphamide is 4.5 g/m2 administered every 2 weeks with GM-CSF given at 5.0 micrograms/kg per day of GM-CSF. Our results suggest that, with GM-CSF support, high cumulative doses of cyclophosphamide can be given to achieve optimal dose intensity, with reproducible blood cell count recovery and without the need for autologous bone marrow transplantation. IMPLICATIONS: Phase II studies of this intensive regimen in malignant diseases sensitive to alkylating agents are currently being done in CALGB.

Phase I clinical and pharmacokinetic study of hexamethylene bisacetamide (NSC 95580) administered as a five-day continuous infusion.

Hexamethylene bisacetamide (HMBA), a potent differentiating agent, was tested in patients with refractory, solid tumors. Twenty patients received 25 evaluable courses. HMBA was given by continuous i.v. infusion for 5 consecutive days with courses repeated every 4 wk, provided there was acceptable, reversible toxicity. The starting dose was 4.8 g/m2/day for 5 days with escalations in subsequent cohorts of patients to 43.2 g/m2/day for 5 days. The patients included 12 females and eight males with median age of 56 yr (range 35 to 75 yr) and a median performance status of 80% (range, 60 to 100%). All except two patients had received prior chemotherapy, radiation therapy, or both. Metabolic acidosis and neurotoxicity, consisting of agitation, hallucinations, confusion, and alteration of consciousness, were dose dependent and dose limiting. The one patient treated with 43.2 m/m2/day became acidotic, agitated, and disoriented but recovered to his previous mental and electrolyte status by 8 days after the end of the HMBA infusion. One patient treated with 33.6 g/m2/day became severely acidotic (pH 7.07) and obtunded and also developed myocardial and cerebral infarctions during the HMBA infusion. The other two patients treated with 33.6 g/m2/day became mildly agitated during drug infusion. Six patients were treated at 24 g/m2/day without neurotoxicity. Transient renal insufficiency was seen in the two patients with severe neurotoxicity and in three other patients. Dose-related, mild to moderate nausea and vomiting were observed in ten patients. Four patients developed cutaneous herpes infections during treatment. White blood cell depression was not dose related, and at 24 g/m2/day, the median white blood cell nadir was 4,500/microliter (range, 2,000 to 7,900/microliter). Thrombocytopenia was dose related. At 24 g/m2/day, the median platelet count nadir was 207,000/microliter (range, 66,000 to 542,000/microliter). No objective tumor regressions were noted. HMBA pharmacokinetics was studied at all dosages. Plasma and urine samples from 20 patients were analyzed by gas-liquid chromatography for parent compound. HMBA plasma steady-state concentrations (Css) were achieved in all patients by 12 to 24 h into infusion. Once Css was achieved, daily variation was generally less than or equal to 10% from the mean Css. HMBA plasma Css increased linearly with dose, but there was variation in the Css achieved in individual patients at each dose. Doses of 24 to 33.6 g/m2/day consistently produced plasma HMBA Css of 1 to 2 mM matching concentrations required for differentiation in vitro.(ABSTRACT TRUNCATED AT 400 WORDS)

Phase I trial using adaptive control dosing of hexamethylene bisacetamide (NSC 95580).

Hexamethylene bisacetamide (HMBA), a potent differentiating agent, was administered to patients with refractory malignant tumors. Thirteen patients received 30 evaluable courses. HMBA was given by continuous i.v. infusion for 5 days. Therapy was repeated every 28 days, if patients had recovered from toxicity. The starting dose was 24 g/m2/day. Because our previous trial had shown wide interpatient variability in HMBA pharmacokinetics and excess toxicity at HMBA plasma concentrations greater than 2 mM (HMBA doses between 24 and 33.6 g/m2/day), we attempted to individualize each patient's dose based on a dosing scheme using an adaptive (feedback) control algorithm, which assumed linear clearance for HMBA. In all courses, a plasma sample was assayed daily and infusion rates were adjusted to achieve an HMBA plasma concentration of 1.5-2.0 mM (300-400 mg/liter). The patients included 12 men and 1 woman with a median age of 56 years (range, 34-76) and median Karnofsky performance status of 90% (range, 60-100). All patients had received prior chemotherapy and 9 patients had also received radiation therapy. The linear adaptive control algorithm was reasonably precise, with a mean absolute error of 0.28 (SE 0.04) mM. However, adjustments in infusion rate systematically overshot the desired change in steady state concentration, probably due to nonlinear clearance of HMBA. For levels within 24 h of a change in infusion rate, this resulted in significant bias, with a mean error of 0.24 (SE 0.09) mM. The mean absolute error was 0.40 (SE 0.06) mM. A second adaptive control algorithm, using a pharmacokinetic model with parallel first-order (renal) clearance and Michaelis-Menten (nonrenal) clearance and using Bayesian parameter estimation with a priori estimates based on our previous phase I trial, proved to be much more precise than the linear method and was unbiased when applied retrospectively to the same observations, with a mean error (within 24 h of a change in infusion rate) of 0.02 (SE 0.06) mM and a mean absolute error of 0.22 (SE 0.03) mM. Toxicity was reversible in all cases. Neurotoxicity, consisting of hallucinations, agitation, somnolence, or confusion, was seen in 2 patients. Four patients complained of insomnia or anxiety. Mild asymptomatic acidosis was seen in 3 patients. Other toxicity included grade 1-2 nausea and vomiting (10 patients), grade 2 diarrhea (2 patients), grade 3 thrombocytopenia (3 patients), grade 1-3 leukopenia (3 patients), and oral herpes simplex infection (4 patients). Mild reversible renal insufficiency (measured by creatinine clearance) was seen in 8 patients.(ABSTRACT TRUNCATED AT 400 WORDS)

Prospective validation of a pharmacologically based dosing scheme for the cis-diamminedichloroplatinum(II) analogue diamminecyclobutanedicarboxylatoplatinum.

We previously correlated both renal function and thrombocytopenia, the dose limiting toxicity of carboplatin, with the plasma pharmacokinetics of carboplatin. From these correlations, we developed equations to calculate carboplatin dosage for any patient based on that patient's creatinine clearance, body surface area, pretreatment platelet count, desired platelet nadir, and status of prior chemotherapy. We prospectively applied these equations in 44 courses of carboplatin given to 24 patients. There were 13 males and 11 females with median age 53 (range, 33-77), median Karnofsky performance status 80 (range, 50-100), and creatinine clearance 32 to 118 ml/min. Ten patients had creatinine clearances less than 60 ml/min. Precision of the equations used for dose calculation was evaluable in 38 courses administered to 23 patients. In 23 courses of carboplatin administered to 12 patients without extensive prior chemotherapy, the observed change in platelets = 1.04 X predicted change -48,000 (r = 0.96). In the 15 courses of carboplatin administered to 11 heavily pretreated patients, the observed change in platelets = 1.13 X predicted change +6,600 (r = 0.97). For the overall combined population, the observed change in platelets = 0.96 X predicted change -7,000 (r = 0.94). These relationships which nearly define the line of identity (observed = expected) validate our initial observations. Only 2 patients developed WBC less than 2,000, but 12 patients developed hematocrit less than or equal to 29% and 8 required RBC transfusions. Fifteen patients had nausea and vomiting greater than or equal to grade 2. There were no other nonhematological toxicities observed. In view of continuing documentation of the antitumor activity of carboplatin, these equations allow safe and rational drug dosing of patients with potentially platinum-responsive tumors but with renal function too poor to receive cisplatin. Among the 9 patients in this study evaluable for response, there was 1 partial response in a patient with malignant melanoma and 1 objective response (less than partial response) in a patient with adenocarcinoma of the cervix.

Phase I study and pharmacokinetics of menogaril (NSC 269148) in patients with hepatic dysfunction.

We performed a phase I study of menogaril to determine if dosage reduction was required in patients with hepatic dysfunction and if the relationship between pharmacokinetics and leukopenia, previously defined in patients with normal hepatic and renal function, was altered. Eighteen patients received 27 courses of menogaril, of which 26 were evaluable for toxicity. Patient characteristics were median age, 63 years (range, 28-80 years), 14 male/4 female, and median Karnofsky performance status 80% (range, 60-100%). Prior therapy included none, five; chemotherapy only, seven; radiotherapy only, two; and chemotherapy and radiotherapy, four. Menogaril was administered as a 2-h.i.v. infusion every 28 days at 62.5 (one patient), 125 (eight patients), 187.5 (seven patients), and 250 mg/m2 (six patients), based on pretreatment serum bilirubin, aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase. Patients also had indocyanine green and antipyrine clearances measured before menogaril treatment. Menogaril and metabolites were assayed by high performance liquid chromatography. Dose-limiting toxicity was leukopenia. WBC nadirs occurred between days 8 and 20 (median, 15). Three patients developed platelet nadirs below 100,000/microliters. Other toxicities included grade I nausea and vomiting in three patients and phlebitis at the site of drug infusion in six patients. Correlations were defined between pretreatment indocyanine green clearance and serum concentrations of alkaline phosphatase and total bilirubin. There were no correlations between pretreatment serum concentrations of bilirubin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, indocyanine green clearance or antipyrine and menogaril clearances. Menogaril pharmacokinetics in patients with elevated liver function tests was indistinguishable from that described in patients with normal liver function tests. There were excellent correlations between plasma area under the curve of menogaril and the percentage decreases in WBC and neutrophils. These were well described by two models previously used to study the same relationships in patients with normal hepatic and renal function. When compared to previous studies, patients with hepatic and renal dysfunction had a greater percentage decrease in WBC for any given area under the curve than did patients with normal hepatic and renal function. On the other hand, there was no difference in the relationship between percentage decrease in neutrophils and menogaril area under the curve in these two groups of patients.(ABSTRACT TRUNCATED AT 400 WORDS)

Plasma pharmacokinetics and urinary excretion of hexamethylene bisacetamide metabolites.

In order to further understand the clinical toxicities of hexamethylene bisacetamide (HMBA) and to allow appropriate in vitro studies, we developed a suitable gas chromatographic assay and quantified plasma concentrations and urinary excretion of four metabolites which we had previously identified in urine of patients receiving 5-day HMBA infusions at 4.8-43.2 g/m2/day. 6-Acetamidohexanoic acid (AcHA) was the major plasma metabolite and reached steady state concentration (Css) by 24 h. AcHA Css increased from 0.12 +/- 0.02 (SD) mM at 4.8 g/m2/day to 0.72 mM at 43.2 g/m2/day. The Css AcHA:Css HMBA ratio decreased with increasing HMBA dosage. At dosages below 24 g/m2/day plasma Css of N-acetyl-1,6-diaminohexane (NADAH), the initial metabolite of HMBA, were below the limit of detection of our assay. With HMBA infusions of 24, 33.6, and 43.2 g/m2/day, Css of NADAH were 0.16 +/- 0.05, 0.14 +/- 0.06, and 0.19 +/- 0.04 mM, respectively. Css NADAH:Css HMBA ratios at 24, 33.6, and 43.2 g/m2/day were 0.18 +/- 0.06, 0.08 +/- 0.02, and 0.31 +/- 0.05, respectively. Plasma Css of 1,6-diaminohexane and 6-aminohexanoic acid were below the limit of detection of our assay. Each patient's urinary excretion of NADAH, AcHA, and 1,6-diaminohexane was consistent from day to day. The fraction of dose excreted in urine as AcHA was not affected by HMBA dosage and accounted for 12.7 +/- 3.9% of the daily dose. The percentage of daily HMBA dose accounted for by excretion of NADAH decreased with increasing HMBA dosage (10.8 +/- 6.0% at 4.8 g/m2/day to 4.2 +/- 1.2% at 33.6 g/m2/day). Urinary excretion of 1,6-diaminohexane always accounted for less than 3% of the daily dose. Our results indicate that: (a) plasma concentrations of AcHA alone cannot explain the degree of acidosis observed with toxic doses of HMBA; (b) NADAH is present in plasma at concentrations that we have found to cause differentiation in vitro; and (c) the probable rate-limiting step in HMBA metabolism is the initial deacetylation.

A limited sampling strategy for cyclophosphamide pharmacokinetics.

A limited sampling strategy was developed to estimate the total area under the curve of plasma cyclophosphamide concentrations versus time (AUC). The strategy was developed with a training set consisting of 29 pharmacokinetic studies in 16 patients who received 1-h i.v. infusions of cyclophosphamide at a dosage of 1000 mg/m2. The strategy was developed by applying stepwise forward multiple regression analysis to cyclophosphamide concentrations observed at each time in the training set (independent variables) versus the AUC (dependent variable). It was confirmed by applying stepwise backward elimination regression analysis to the same data set. The final sampling strategy, which utilized three time points, was: AUC = 40.18C24 + 8.79C4 + 0.83C1 - 28 (dosage/1000), where C24, C4, and C1 represent plasma cyclophosphamide concentrations at 24, 4, and 1 h, respectively, and the dosage is in mg/m2 (r = 0.98). The strategy was validated prospectively with a test data set consisting of 14 pharmacokinetic studies in 11 patients who received 1-h i.v. infusions of cyclophosphamide at dosages of 300, 600, or 1200 mg/m2. The strategy proved highly predictive, with correlation coefficient between predicted and actual AUC of 0.94. The strategy also proved unbiased, with mean percentage of error (+/- SE) of 3.3 +/- 3.6%, and precise, with mean absolute percentage of error of 9.3 +/- 2.7%. The sampling strategy developed is being used in a multiinstitution trial of cyclophosphamide in an effort to relate cyclophosphamide pharmacokinetics, as expressed by AUC, with the toxic or therapeutic pharmacodynamic responses of the drug.

Pharmacokinetics and dosage reduction of cis-diammine(1,1-cyclobutanedicarboxylato)platinum in patients with impaired renal function.

cis-Diammine(1,1-cyclobutanedicarboxylato)platinum (CBDCA) is a nonnephrotoxic but myelosuppressive analogue of cisplatin (DDP) with greatly reduced protein binding and greatly increased renal excretion. Thus, CBDCA might produce undue toxicity in patients with decreased renal function. Twenty-two patients [14 females and 8 males; median age, 66 (range, 35 to 83); median Karnofsky performance status, 70 (range, 40 to 90)] with refractory tumors and renal dysfunction [creatinine clearance (CCr) 6 to 83 ml/min] were treated with 31 courses of i.v. bolus CBDCA every 4 to 5 weeks. Dosages were determined by pretreatment CCr. Patients with CCr greater than or equal to 40 ml/min received 400 mg/sq m; patients with CCr 20 to 39 ml/min received 250 mg/sq m; and patients with CCr 0 to 19 ml/min received 150 mg/sq m. Toxicities were assessed by weekly clinical and laboratory assessment. Responses were assessed in patients with measurable disease. Plasma pharmacokinetics and urinary excretion of total and ultrafilterable platinum were measured with flameless atomic absorption spectrometry. Observed toxicities were similar to those in patients with normal renal function. Myelosuppression, especially thrombocytopenia, was the major toxicity. Nausea and vomiting were mild to moderate. There was no ototoxicity, neurotoxicity, or nephrotoxicity or reduction in CCr due to CBDCA. Total body clearance of ultrafilterable platinum correlated highly with CCr. The percentage of reduction in platelet count correlated highly and linearly with the area under the curve (AUC) of plasma-ultrafilterable platinum. However, for any AUC, there was 17% greater platelet reduction in patients who had previously received extensive myelosuppressive chemotherapy than in nonpretreated patients. Since total body clearance is proportional to CCr, platelet reduction is proportional to AUC, and total body clearance = dosage/AUC, we have derived an equation to calculate a dosage that will produce a desired reduction in platelet count. Calculations for theoretical patients (both pretreated and nonpretreated) with CCr of 100 ml/min produce dosages very close to maximum tolerated dosages derived in actual Phase I trials. The actual clinical utility of these predictive equations must await validation in prospective studies with larger numbers of patients.

Phase I clinical and pharmacological study of 4'-(9-acridinylamino)-methanesulfon-m-anisidide using an intermittent biweekly schedule.

4'-(9-Acridinylamino)methanesulfon-m-anisidide (m-AMSA, NSC 249992), an acridine derivative, was given to 28 patients with solid tumors and one patient with Hodgkin's disease in a Phase I clinical trial. The dose schedule used was a single dose given every 14 days for three doses. The amount given ranged from 10 to 120 mg/sq m/dose. Dose-limiting toxicity was moderate to severe leukopenia which occurred at and above 70 mg/sq m. Thrombocytopenia was infrequent and did not require transfusion. Nonhematological side effects were mild and included nausea, vomiting, local irritation, and fever. Antineoplastic activity was noted in liposarcoma, adenocarcinoma of unknown primary origin, and squamous carcinoma of unknown primary origin (one patient each). Pharmacokinetics studies were done in 19 patients. Total m-AMSA and free m-AMSA concentrations showed a biphasic distribution with an initial rapid phase of t1/2 = 10 to 15 min for both, and a second slow phase of t1/2 = 8 to 9 hr for total m-AMSA and 3 hr for free m-AMSA. Phase II studies with m-AMSA, in hematological cancers are warranted, since its most consistent effect is on leukocytes. The recommended dosages for solid-tumor Phase II studies are 70 mg/sq m for good-risk patients and 50 mg/sq m for poor-risk patients, given as a single dose every other week, or 120 mg/sq m for poor-risk patients for the single-dose every-3-week schedule.

Human pharmacokinetics, excretion, and metabolism of the anthracycline antibiotic menogaril (7-OMEN, NSC 269148) and their correlation with clinical toxicities.

In a Phase I study, menogaril (7-OMEN) was administered daily for 5 days/course, every 21-28 days. Dosages of 3.5, 7, 11.5, 17, and 31.5 mg/m2 were infused over 1 h, and dosages of 42, 50, and 56 mg/m2 were infused over 2 h. Pharmacokinetics was studied at all dosages. Plasma and urine samples were collected from 24 patients, and bile samples were also collected from 2 patients. 7-OMEN and metabolites were measured by high performance liquid chromatography. 7-OMEN was the major plasma fluorescent species at all times, with only trace amounts of N-demethyl menogaril observed. 7-OMEN disappeared from plasma biexponentially with t1/2 alpha 0.19 +/- 0.04 (mean +/- SE) h and t1/2 beta 13.22 +/- 1.54 h. Plasma pharmacokinetics of 7-OMEN was linear from 3.5-56 mg/m2; area under the curve increased proportionally with dosage. Total body clearance of 7-OMEN was 28.18 +/- 3.33 liter/m2/h, Vc was 224 +/- 30.8 liter/m2, and Vss was 370 +/- 25.7 liter/m2. Plasma pharmacokinetics of 7-OMEN studied on multiple days of a given course were similar. Urinary excretion of 7-OMEN and fluorescent metabolites accounted for 5.4 +/- 0.4% of the daily dose. Parent compound still represented greater than or equal to 80% of urinary drug fluorescence after 24 h. N-demethyl menogaril was the only other fluorescent drug species detected in urine. In two patients with biliary tract drains, biliary excretion of drug fluorescence accounted for 2.2-4.2% of the daily dose. Only 7-OMEN and N-demethyl menogaril were detected in bile by high performance liquid chromatography and thin layer chromatography. 7-OMEN was the major fluorescent biliary species, but, by 24 h, N-demethyl menogaril accounted for approximately 40% of biliary drug fluorescence. When considered in light of each patient's observed toxicities, excellent relationships were observed between the plasma area under the curve of 7-OMEN and the percentage of decreases in WBC and absolute neutrophil count. These latter findings should be useful in developing more precise and intelligent dosing schemes for 7-OMEN.

A novel pharmacodynamically based approach to dose optimization of carboplatin when used in combination with etoposide.

Thrombocytopenia, the dose-limiting toxicity of carboplatin, is manageable and predictable with the dosing equation: Dose (mg/m2) = (0.091) (creatinine clearance)/(body surface area) (desired percentage change in platelet count) + 86. We used this equation to dose patients receiving carboplatin (day 1) and etoposide (80 mg/m2 days 1 to 3). An initial cohort of 14 patients with non-small-cell lung cancer (NSCLC) were treated with 75% of the calculated dose of carboplatin (29 evaluable courses) as a precaution against added myelosuppression from combination chemotherapy. The observed reduction in platelets was essentially equal to the reduction in platelets predicted if patients had received carboplatin alone. Subsequently, a second cohort of 20 evaluable patients with NSCLC received the full calculated dose of carboplatin and etoposide (51 evaluable courses). There was a linear relationship between observed (o) and predicted (p) reductions in platelets. With full-dose carboplatin in combination with etoposide, there was a significantly greater carboplatin dosage administered, greater reduction in platelets, and lower platelet nadir. Among 34 evaluable patients (80 courses) there was one complete response (CR) and four partial responses (PRs) for an overall response rate of 15% (90% confidence +/- 9%). The median duration of survival for responders was 336+ days and for nonresponders was 204+ days. Therapy was well tolerated. This study, in addition, supports our concept of individualized dosing of carboplatin and the underlying pharmacokinetic/pharmacodynamic relationships and represents an interesting pharmacodynamic and quantitative approach to studying potential drug-drug interactions and defining appropriate dosages for combination chemotherapy.

Phase I trial of N-methylformamide (NMF, NSC 3051).

N-methylformamide (NMF) is a polar-planar solvent with both cytotoxic and differentiating activity in preclinical models; it also acts as a radiosensitizer. We treated 17 patients with 18 courses of NMF on a schedule of six weekly doses, administered on a rapid intravenous infusion, which were escalated from 875 to 2,000 mg/m2/wk. The predominant toxicity was a dose-related syndrome of fatigue, malaise, nausea, and anorexia, which was reflected by a decrease in performance status (Karnofsky) of greater than or equal to 20% in six of ten patients who received doses greater than or equal to 1,500 mg/m2/wk. Other gastrointestinal toxicities included moderate vomiting and mild diarrhea. Reversible increase of liver enzymes occurred in six of ten patients at doses greater than or equal to 1,500 mg/m2/wk. The maximum tolerated dose on this schedule is 1,500 mg/m2/wk; the dose recommended for phase II studies is 1,125 mg/m2/wk. Future studies of this regimen in a combined modality setting are planned.

Population pharmacodynamic study of amonafide: a Cancer and Leukemia Group B study.

PURPOSE: To determine if variability in toxicity of amonafide during phase II trials could be correlated with pharmacokinetic variability. PATIENTS AND METHODS: Seventy-three patients enrolled onto three Cancer and Leukemia Group B (CALGB) phase II trials of amonafide (300 mg/m2 daily for 5 days) were studied, using a limited sampling strategy (45 minutes and 24 hours) to estimate the amonafide area under the plasma concentration-time curve (AUC). Concentrations of N-acetyl-amonafide, an active metabolite, were also determined. RESULTS: The primary determinant of toxicity at a fixed dose of amonafide was the extent of N-acetylation. Fast acetylators (36% of patients) had significantly greater toxicity than slow acetylators (64% of patients), with median WBC nadirs of 500/microL and 3,400/microL, respectively (P < or = .001). In a multivariate analysis, lower pretreatment WBC count, lower albumin level, and nonwhite race were also independently associated with toxicity. Further analysis of interracial differences demonstrated that minority women had slower clearance of amonafide (P = .026) and a higher incidence of grade 4 leukopenia (P = .042). CONCLUSION: The highly variable toxicity of amonafide is primarily due to genetic differences in N-acetylation. Other genetic (race) and acquired factors (baseline WBC count and albumin level) also appear to influence the extent of toxicity observed following administration of this agent.

Randomized study of cyclophosphamide, doxorubicin, and etoposide (VP16-213) with or without cisplatinum in non-small cell lung cancer.

Sixty-eight patients with non-small cell lung cancer were treated in a prospectively randomized study with cyclophosphamide, doxorubicin (Adriamycin), and etoposide (VP16-213) with cisplatinum (CAE +/- P). Response rate, time to progression, and survival of CAE-P treated patients were each superior compared to those of patients who received CAE therapy. Of 36 patients, 10 (4 complete remissions, 6 partial remissions) responded to CAE-P and of 29 patients 3 (1 complete remission, 2 partial remissions) responded to CAE (p = 0.073). The median time to treatment failure was 22.9 wk for the CAE-P regimen and 15.0 wk for CAE (p = 0.032). The median survival for patients treated on the regimen with and without cisplatinum was 34.5 and 22.5 wk, respectively (p = 0.04). There were two CAE-P and one CAE drug-related deaths. Toxic effects were more severe in the CAE-P regimen. The addition of cisplatinum to the CAE combination produced an increase in response rate with significant prolongation in both time to progression and survival, but did add morbidity. These results suggest that the combined use of cisplatinum with at least one of the chemotherapeutic agents in the CAE regimen is synergistic.

Hypersensitivity reactions from taxol.

Taxol is an antitumor agent in clinical trial that has been shown to have activity against advanced ovarian carcinoma and melanoma. Hypersensitivity reactions (HSRs) have been one of the toxicities observed with administration of this drug. Of 301 patients treated, 32 patients have had definite (27 patients) or possible (five patients) hypersensitivity reactions to taxol. All but one patient had the reaction from the first or second exposure to this agent. Reactions occurred at a variety of doses and were characterized most frequently by dyspnea, hypotension, bronchospasm, urticaria, and erythematous rashes. Thirteen (41%) patients had received premedication designed to prevent such toxicity; nevertheless, they sustained HSRs. Prolonging the drug infusion appears to have somewhat reduced, but not obviated, the risk of HSRs. The cause (taxol itself or its excipient Cremophor EL; Badische Anilin und Soda-Fabrik AG [BASF], Ludwigshafen, Federal Republic of Germany) and the mechanism of these reactions to taxol are unknown. We provide guidelines to prevent or minimize such toxicity and treat reactions if they still occur.

Interleukin-2 therapy in patients with metastatic malignant melanoma: a phase II study.

Forty-seven patients with metastatic malignant melanoma were treated with two 5-day cycles of 100,000 U/kg recombinant interleukin-2 (IL-2) intravenously (IV) every 4 hours separated by 1 week. This dose and schedule of IL-2 were identical to those used in a previous combined IL-2 and lymphokine-activated killer (LAK) cell phase II clinical trial of the IL-2/LAK Working Group. Patient eligibility criteria, and clinical management guidelines were similar to those used in the previous trial. Forty-six patients were assessable for response. Objective responses were observed in 10 of 46 patients (two complete responses [CRs], eight partial responses [PRs]) or 22% with responses occurring in lung and liver as well as lymph nodes and subcutaneous sites. The median response duration was 8 months. Toxicity was significant; three patients developed myocardial infarction, and one patient died during therapy. Overall the toxicity and response rate for single-agent IL-2 are similar to that observed with IL-2 administered in combination with LAK cells in the previous trial. These results suggest that single-agent therapy with IL-2 when administered in this schedule has significant antimelanoma activity in humans, and that LAK cells generated from peripheral blood add little to the antimelanoma activity of this dose and schedule of IL-2.

Pharmacokinetic and pharmacodynamic study of the combination of docetaxel and topotecan in patients with solid tumors.

PURPOSE: The sequence in which chemotherapeutic agents are administered can alter their pharmacokinetics, therapeutic effect, and toxicity. We evaluated the pharmacokinetics and pharmacodynamics of docetaxel and topotecan when coadministered on two different sequences of administration. PATIENTS AND METHODS: On cycle 1, docetaxel was administered as a 1-hour infusion at 60 mg/m(2) without filgrastim and at 60, 70, and 80 mg/m(2) with filgrastim on day 1, and topotecan was administered at 0.75 mg/m(2) as a 0.5-hour infusion on days 1 to 4. On cycle 2, topotecan was administered on days 1 to 4, and docetaxel was administered on day 4. Cycles were repeated every 21 days. Blood samples for high-performance liquid chromatography measurement of docetaxel (CL(DOC)) and topotecan (CL(TPT)) total clearance were obtained on day 1 of cycle 1 and day 4 of cycle 2. CL(DOC) and CL(TPT) were calculated using compartmental methods. RESULTS: Mean +/- SD CL(DOC) in cycles 1 and 2 were 75.9 +/- 79.6 L/h/m(2) and 29.2 +/- 17.3 L/h/m(2), respectively (P: <.046). Mean +/- SD CL(TPT) in cycles 1 and 2 were 8.5 +/- 4.4 L/h/m(2) and 9.3 +/- 3.4 L/h/m(2), respectively (P: >. 05). Mean +/- SD neutrophil nadir in cycles 1 and 2 were 4,857 +/- 6, 738/microL and 2,808 +/- 4,518/microL, respectively (P: =.02). CONCLUSION: Administration of topotecan on days 1 to 4 and docetaxel on day 4 resulted in an approximately 50% decrease in docetaxel clearance and was associated with increased neutropenia.

Phase I study of the orally administered butyrate prodrug, tributyrin, in patients with solid tumors.

Butyrates have been studied as cancer differentiation agents in vitro and as a treatment for hemoglobinopathies. Tributyrin, a triglyceride with butyrate molecules esterified at the 1, 2, and 3 positions, induces differentiation and/or growth inhibition of a number of cell lines in vitro. When given p.o. to rodents, tributyrin produces substantial plasma butyrate concentrations. We treated 13 patients with escalating doses of tributyrin from 50 to 400 mg/kg/day. Doses were administered p.o. after an overnight fast, once daily for 3 weeks, followed by a 1-week rest. Intrapatient dose escalation occurred after two courses without toxicity greater than grade 2. The time course of butyrate in plasma was assessed on days 1 and 15 and after any dose escalation. Grade 3 toxicities consisted of nausea, vomiting, and myalgia. Grades 1 and 2 toxicities included diarrhea, headache, abdominal cramping, nausea, anemia, constipation, azotemia, lightheadedness, fatigue, rash, alopecia, odor, dysphoria, and clumsiness. There was no consistent increase in hemoglobin F with tributyrin treatment. Peak plasma butyrate concentrations occurred between 0.25 and 3 h after dose, increased with dose, and ranged from 0 to 0.45 mM. Peak concentrations did not increase in three patients who had dose escalation. Butyrate pharmacokinetics were not different on days 1 and 15. Because peak plasma concentrations near those effective in vitro (0.5-1 mM) were achieved, but butyrate disappeared from plasma by 5 h after dose, we are now pursuing dose escalation with dosing three times daily, beginning at a dose of 450 mg/kg/day.

Phase I trial of all-trans retinoic acid in patients with treated head and neck squamous carcinoma.

Although retinoids show promise for prevention of second primary upper aerodigestive tract tumors, the optimum retinoid, dose, and schedule are unknown. All-trans retinoic acid (ATRA) has greater affinity for retinoic acid receptors and may be more active than other retinoids but has a shorter plasma half life and may up-regulate its own metabolism. We defined the maximum long-term tolerable dose, dosing frequency, pharmacokinetics, and toxicity of ATRA in patients with treated squamous cell carcinoma of the head and neck (SCCHN). Twenty-one patients were randomized to 45, 90, or 150 mg/m2 ATRA either once daily, or as divided doses every 8 h, for 1 year. Pharmacokinetics were assessed periodically. Fourteen men and seven women with previous SCCHN of initial stage I-IV were treated. Grade > or =3 toxicities (reversible) included headache and hypertriglyceridemia in 5 and 6 patients each, mucositis in 2 patients, and hyperbilirubinemia, elevated alkaline phosphatase, colitis, lipasemia, xerostomia, eczema, and arthritis in 1 patient each. The 150-mg/m2 dose was not tolerable. Doses were reduced for grade > or =3 toxicity in seven of eight patients at 90 mg/m2 daily. Three of nine patients at 45 mg/m2/day required dose reduction, two at the once-daily dose. Day 1 ATRA area under the plasma concentration versus time curve (AUC) increased with dose, and after 1-2 months of continued dosing, the AUC declined in 7 of 13 patients (54%) studied. ATRA AUC did not correlate with toxicity severity or frequency. Fifteen mg/m2/day every 8 h is a tolerable dose for 1 year in patients with treated SCCHN. ATRA pharmacokinetics did not correlate with toxicity.