Library

Notes: Abstract  A phase I trial of all-trans-retinoic acid (ATRA) was conducted to establish the maximum tolerable dose (MTD) of ATRA given once daily to patients with solid tumors. Cancer patients for whom no standard therapy was available were treated with ATRA once daily. Doses were escalated in cohorts of at least three patients. The pharmacokinetics of ATRA were assessed on day 1 for all patients and weekly for 31 patients who received doses of ≥110 mg/m2 per day. Patients were followed for toxicity and response. Correlations of toxicity frequency and grade with pharmacokinetic parameters were sought. In addition, correlation of changes in ATRA pharmacokinetics with the concentration of ATRA metabolites in plasma were sought. A total of 49 patients received ATRA at doses ranging from 45 to 309 mg/m2 per day. Hypertriglyceridemia was dose-limiting at 269 mg/m2 per day. Other frequent toxicities included mucocutaneous dryness and headache. With chronic dosing, plasma ATRA concentrations fell in 59% of patients. Stable, low, or variable [ATRA] were seen in 16%, 6%, and 16% of patients respectively. Age, gender, smoking, or concurrent medication did not correlate with the pharmacokinetic pattern. Severe toxicities tended to occur with initial peak [ATRA] of ≥0.5 μg/ml (1.7 μM), and the toxicity frequency did not change if [ATRA] decreased with continued dosing. No consistent change in 4-oxo-ATRA or retinoid glucuronide concentrations was observed with decreases in plasma [ATRA]. The recommended once-daily ATRA dose is 215 mg/m2, although significant interpatient variability is observed in toxicity and plasma retinoid concentrations. Although not statistically significant, more frequent and severe toxicity tended to occur in patients with higher plasma peak ATRA concentrations. Other factors, such as responses at target tissues, may be at least as important as the plasma ATRA concentration in predicting toxicity and/or response.

Notes: Summary A phase II study of intermittent high-dose 6-thioguanine (6-TG) was undertaken in 19 patients with metastatic colorectal carcinoma. Fourteen patients had received prior myelosuppressive therapy. 6-TG was administered as a single dose by IV bolus over 15–30 min, with retreatment every 3 weeks. The starting dose was 700 mg/m2 in ten patients, 900 mg/m2 in one patient, 1,000 mg/m2 in four patients, and 1,200 mg/m2 in two patients. Two patients received reduced doses (350 mg/m2) because of liver dysfunction. There was no regression of measurable disease after treatment with 6-TG in this study. Eight patients achieved stabilization of previously progressive disease for periods of 10–32 weeks. Toxicities were nausea and vomiting (19 patients), mucositis (3 patients), reversible renal dysfunction with creatinine〉2 mg/dl (4 patients), nasal congestion (3 patients), diarrhea (1 patient), and skin blistering at the infusion site (1 patient). Seven patients had white blood count nadirs below 3,000/μl (the lowest nadir was 900/μl). Only one patient had a platelet count nadir below 100.000/μl. There were no infections or hemorrhage. 6-TG, as administered in this study, has no antitumor activity against colorectal carcinoma. Concentrations of 6-TG and metabolites were assessed in the plasma of six patients by a reversed-phase HPLC system. 6-TG and metabolites were extracted from human plasma at 50%–100% efficiency by cold 2 N perchloric acid (1 : 1). Neutralized extracts were chromatographed on a μ-Bondapak C18 column by two separate isocratic conditions. 6-TG, 6-thiouric acid, 6-thioguanosine, and 6-thioxanthine were analyzed with 0.01 M Na acetate, pH 3.5/10% methanol as the mobile phase and were detected at 340 nm. 6-Methyl TG and three unknown metabolites were eluted with Na acetate/25% methanol and were detected at 310 nm. External standard calibration was used for quantitation. The 6-TG detection limit was 0.8 nmol/ml. In six patients who received 1–1.2 g 6-TG/m2 IV, 6-TG achieved peak plasma concentrations of 61–118 nmol/ml (95.6 ± 23.0, mean ± SD). Plasma 6-TG concentrations decayed bi-exponentially, with initial t1/2 of 3 h and terminal t1/2 of 5.9 h. 6-Thiouric acid, 6-methyl TG, 6-thioguanosine, 6-thioxanthine, and three major unidenitified metabolites were also observed in plasma. The three unknowns were extracted with ethyl acetate from alkalinized pooled plasma extracts and were purified by HPLC.

Notes: Summary Twenty-nine patients with non-small cell lung cancer refractory to prior therapy were treated with either vindesine (VDS) alone (3 mg/m2 every week) or the combination of VDS plus cisplatin (DDP) (100 mg/m2 every 28 days). Serial blood and urine samples were colletected to assess the pharmacokinetics of VDS and DDP. All patients were evaluable for toxicity and 27 were evaluable for response. No objective antitumor responses were observed. Peripheral neuropathy manifested by paresthesias, muscle weakness, and constipation were observed in 20 treated patients, and hematologic toxicity consisting of thrombocytopenia and/or leukopenia occurred in 18 patients. The plasma and urinary pharmacokinetics of VDS and DDP measured in this study indicate that VDS and DDP do not interfere with each other and that the pharmacokinetics in previously treated and untreated patients are similar. The antitumor responses and degree of toxicity observed in this trial compare unfavorably with previously reported VDS and VDS-DDP trials in previously untreated patients with this disease and suggest that prior exposure to chemotherapy might both decrease antitumor activity and enhance toxicity of these chemotherapeutic agents.

Notes: Summary Three patients with advanced refractory malignancies were treated with whole-body hyperthermia (WBH: 42–42.3° C) for 2 h during which time they also received an infusion of 60 or 80 mg/m2 of cis-diamminedichloroplatinum II (DDP). Each patient developed an elevated serum creatinine (2.7–13.6 mg/dl), with maximum creatinine occurring between days 7 and 12 after treatment. WBH did not alter plasma or urinary pharmacokinetics of total or ultrafilterable platinum compared with pharmacokinetic data of the same or other patients given DDP euthermically. Although the mechanism of the renal damage is unclear, it appears that WBH can potentiate the nephrotoxic actions of DDP and that further study of this combination is not warranted.

Notes: Summary HMBA is a potent differentiating agent capable of causing〉95% morphological differentiation in cell lines in vitro. The induction of differentiation is dependent on both the concentration of and the duration of exposure to HMBA. However, acute toxicities (neurotoxicity and acidosis) have limited the maximal HMBAc ss value to 〈2mm, which is at the lower limit of effective in vitro concentrations. When HMBAc ss values have been maintained at 1–2mm, thrombocytopenia has limited the duration of HMBA infusion to ≤10 days. The present studies were performed to determine whether exposure to HMBA could be individualized and maximized without resulting in intolerable toxicity to patients and to determine which factors would predispose a patient to the development of acute toxicity during treatment with HMBA. For these investigations, patients were given HMBA at a targetc ss using an adaptive-feedback-control method rather than at a set dose. Because HMBA administration produces large anion gaps, a simple maneuver such as alkalinization might enable the escalation of plasma HMBAc ss values to 〉2mm. HMBA was given as a 5-day CI to 14 patients (26 courses) at 2 target HMBAc ss levels near the maximal tolerated value in the presence or absence of concurrent alkalinization with sodium bicarbonate. Symptomatic acidosis occurred in one patient who did not receive bicarbonate. Neurotoxicity proved to be dose-limiting at the target HMBAc ss value of 1.5–2.0mm in the absence of concurrent alkalinization and at ac ss level of 〉2mm, regardless of alkalinization. No neurotoxicity was seen at target HMBAc ss values of 1.5–2.0mm in patients who did receive concurrent alkalinization. Alkalinization was not associated with any detectable changes in plasma HMBA metabolites. With the maximal tolerable 5-day HMBAc ss having thus been defined at 1.5–2.0mm, we attempted to maximize exposure to HMBA by defining a tolerable duration of infusion. Individualization of the duration of HMBA infusion to a target nadir PLT was performed in patients who had received an initial 5-day CI of HMBA at ac ss 1.5–2.0mm along with concurrent alkalinization. The AUC achieved and the thrombocytopenia produced during this first course were used to predict the duration of infusion that each patient would subsequently tolerate (at an HMBAc ss of 1–2mm) to achieve a nadir PLT of 75,000–100,000/μl. The observed percentage changes in PLT matched the predicted percentage change in PLT, with the mean error (ME) being −8.9%. For a better determination as to which factors may contribute to neurotoxicity or acidosis in patients receiving HMBA, 98 courses of HMBA given as 5- to 10-day CIs to 56 patients were analyzed (multifactorial logistic regression). An HMBA AUC value of 〉7.5mm x day, the use of any concomitant narcotic analgesics, and a mean plasma HMBA level of 〉1.5mm or a peak plasma concentration of ≥1.75mm correlated significantly with grade 3 neurotoxicity (P〈0.001), whereas concomitant alkalinization and a mean plasma HMBA concentration of 〈1.5mm were associated with a lack of neurotoxicity (P〈0.001). An AUC value of 〉7.5mm x day, a mean or peak plasma HMBA level of 〉1.5mm, and an age of 〉70 years correlated with the likelihood of a large anion gap (P〈0.03). With the above factors being accounted for, neither the duration of infusion nor theC cr value showed any correlation with these toxicities in this patient population. These results imply that HMBA may be given for individualized durations at ac ss of 1.5mm in the presence or absence of concomitant alkalinization and that narcotic analgesics should not be given to patients receiving this agent. However, due to the resultant acute neurotoxicity, it is unlikely that AUCs of 〉7.5mm x day will be tolerated during simultaneous maintenance of ac ss value of 〉1.0mm.

Notes: Abstract A total of 21 patients with advanced cancer were entered into a phase I study to determine the maximum tolerable dose (MTD) of liposome-encapsulated doxorubicin (LED) given weekly for 3 consecutive weeks at doses of 20, 30, or 37.5 mg/m2 per week. For a comparison of the pharmacokinetic behavior of LED with that of standard-formulation doxorubicin, 13 patients received a dose of standard-formulation doxorubicin 2 weeks prior to the first dose of LED. All doses were given by 1-h infusion through a central vein. Toxicity was evaluated in 22 courses delivered to 17 patients. The MTD with this schedule was 30 mg/m2 per week×3. The single patient treated at 37.5 mg/m2 weekly could not complete the entire course due to myelosuppression. At the dose of 30 mg/m2 per week, three of eight patients had grade ≥3 leukopenia. Other toxicities included mild to moderate thrombocytopenia, nausea, vomiting, fever, alopecia, diarrhea, fatigue, stomatitis, and infection. At the dose of 30 mg/m2 per week, the total doxorubicin AUC and peak total doxorubicin concentrations in plasma were 8.75±8.80 μM h (mean±SD) and 3.07±1.45 μM, respectively, after LED administration. The total doxorubicin AUC and peak total doxorubicin concentrations in plasma were 3.92±2.47 μM h and 2.75±2.70 μM, respectively, after the infusion of standard-formulation doxorubicin. The total body clearance of doxorubicin was 18.42±11.23 l/h after the infusion of LED and 31.21±15.48 l/h after the infusion of standard-formulation doxorubicin. The mean elimination half-lives of doxorubicin were similar: 8.65±5.16 h for LED and 7.46±5.16 h for standard-formulation doxorubicin. Interpatient variability in pharmacokinetic parameters as demonstrated by the percentage of coefficients of variation was 33%–105%. There was no relationship between the percentage of WBC decrease or the duration of WBC suppression and the total doxorubicin or doxorubicinol AUC. There was no correlation between the duration of leukopenia and drug exposure as reflected by the AUC of liposome-associated doxorubicin. LED can be given in doses similar to those of standard-formulation doxorubicin and produces acute toxicities similar to those caused by standard doxorubicin.

Notes: Abstract The pharmacokinetics of cytarabine (ara-C) were determined in 265 patients with acute myeloid leukemia (AML) receiving ara-C (200 mg/m2 per day for 7 days as a continuous infusion) and daunorubicin during induction therapy. The mean (standard deviation) ara-C concentration at steady-state (Css) and systemic clearance (Cl) were 0.30 (0.13) μM and 134 (71) l/h per m2 respectively. Males had a significantly faster ara-C Cl (139 vs 131 l/h per m2,P=0.025) than females. Significant correlations were noted between ara-C Cl and the pretreatment, peripheral white blood cell count (P=0.005) and pretreatment blast count (P=0.020). No significant differences in ara-C Css or Cl were noted in patients achieving complete remission compared with those failing therapy (P=0.315,P=0.344, respectively). No significant correlations were observed between ara-C pharmacokinetic parameters and several indices of patient toxicity. Our findings indicate that variability in ara-C disposition in plasma at this dosage level does not correlate with remission status or toxicity in patients with AML receiving initial induction therapy with ara-C and daunorubicin.

Notes: Abstract  The pharmacokinetics of cytarabine (ara-C) were determined in 265 patients with acute myeloid leukemia (AML) receiving ara-C (200 mg/m2 per day for 7 days as a continuous infusion) and daunorubicin during induction therapy. The mean (standard deviation) ara-C concentration at steady-state (Css) and systemic clearance (Cl) were 0.30 (0.13) μM and 134 (71) l/h per m2 respectively. Males had a significantly faster ara-C Cl (139 vs 131 l/h per m2, P=0.025) than females. Significant correlations were noted between ara-C Cl and the pretreatment, peripheral white blood cell count (P=0.005) and pretreatment blast count (P=0.020). No significant differences in ara-C Css or Cl were noted in patients achieving complete remission compared with those failing therapy (P=0.315, P=0.344, respectively). No significant correlations were observed between ara-C pharmacokinetic parameters and several indices of patient toxicity. Our findings indicate that variability in ara-C disposition in plasma at this dosage level does not correlate with remission status or toxicity in patients with AML receiving initial induction therapy with ara-C and daunorubicin.

Notes: Abstract To define a maximum tolerable dose, chloroquinoxaline sulfonamide (CQS) was given as a 1-h infusion every 28 days to cancer patients for whom no effective standard therapy was available. Doses were escalated in cohorts of at least three patients each. Plasma for characterization of the pharmacokinetics of free and total CQS was obtained during and after the initial infusion and, when possible, during and after subsequent infusions of CQS if the dose had been reduced. A total of 101 courses of CQS in 55 patients were evaluated. Dose levels ranged from 18 to 3,700 mg/m2. The dose-limiting toxicity was hypoglycemia, first recognized at the 3,700-mg/m2 dose. When dose-limiting hypoglycemia was recognized, patients were entered at successively lower doses, with close monitoring of plasma glucose and insulin concentrations being done in 26 patients. grade 1–3 hypoglycemia occurred within 4 h of the termination of CQS infusion and cleared by 24 h. Symptomatic hypoglycemia was more frequent at doses of CQS above 1,000 mg/m2 Concomitant administration of 5% gyciosion being done in 26 patients. Grade 1–3 hypoglycemia close monitoring of plasma glucose and insulin concentrations being done in 26 patients. Grade 1–3 hypoglycemia occurred within 4 h of the termination of CQS infusion and cleared by 24 h. Symptomatic hypoglycemia was more frequent at doses of CQS above 1,000 mg/m2. Concomitant administration of 5% glucose did not ameliorate the hypoglycemia associated with CQS doses of 〉1,000 mg/m2. The total calorie intake, percentage of ideal body weight, or percentage of weight lost did not explain the incidence or severity of hypoglycemia in 12 patients in whom these data were obtained. Cardiac tachyarrhythmias occured in 7 patients who received CQS at doses of ≥1,000 mg/m2, and tachyarrhythmia was associated with hypoglycemia in 3 patients. Other toxicities were sporadic, but the frequency of toxicity was higher at CQS doses of ≥1,000 mg/m2. These toxicities included fever, rash, lightheadedness, leukopenia, thrombocytopenia, alopecia, diarrhea, nausea, and vomiting. All toxicities were reversible. Mean peak plasma [CQS] and AUC increased with dose, with a suggestion that peak plasma [CQS] plateaued at higher doses. The decline in plasma [CQS] was fitted to a three-compartment, open linear model. The terminal half-life ranged from 28 to 206 h. Total body clearance ranged from 44 to 881 ml/h with no evidence of saturation. Urinary excretion of the parent compound in 24 h averaged 〈5%. CQS not bound to plasma protein (free CQS) comprised 1%–17% of total plasma CQS and was not related to dose. A relationship was defined between the magnitude of hypoglycemia and CQS pharmacokinetic parameters. The percentage of decrease in plasma [glucose], i.e., (predose [glucose]-nadir [glucose]/predose [glucose])×100, correlated with both free and total peak plasma [CQS]. The relationship was described by the Hill equation:Effect=(Emax) (peak) H/(peak 50)H+(peak)H, where the maximal effect (Emax) equals the maximal possible percentage of decrease in plasma [glucose] equals 100%,peak 50 is the peak total [CQS] at whichE is half-maximal (326 mg/l), andH is the Hill constant, a measure of the sigmoidicity of the relationship (1.06). The relationship fit the data precisely with a mean absolute error (MAE) of 10.42 and was unbiased with a mean error (ME) of −0.06. The recommended phase II dose of CQS is 1,000 mg/m2. Because the magnitude of hypoglycemia after CQS administration is related to peak plasma [CQS], repetitive CQS doses of ≤1,000 mg/m2 would probably be tolerated better than single large doses of equivalent intensity.

Notes: Summary Because of potential synergistic interactions, we added 25 mg/m2 i. v. cisplatin (P) 25 given on days 1–5 to the combination of 45 mg/m2 i. v. doxorubicin (A) given on day 1, 800 mg/m2 i. v. cyclophosphamide (C) given on day 1, and 50 mg/m2 i. v. etoposide (E) given on days 1–5. The resulting PACE regimen was given every 21 days for the first three courses and then every 28 days for the next five courses. PACE was used in two trials: the first, for both limited and extensive disease, was conducted at the University of Maryland Cancer Center and North Shore University Hospital; and the second, for extensive disease, was carried out as a Cancer and Leukemia Group B pilot study. Chest irradiation was not used. Prophylactic cranial irradiation at a dose of 3,000 cGy was given to all patients achieving a complete response (CR). A total of 33 subjects were entered in the first study; 8 of the 15 (53%) presenting with limited disease and 7 of the 18 (39%) exhibiting extensive disease achieved a CR. A partial response (PR) was obtained in 27% and 33% of cases, respectively. Of the 34 patients entered in the second study, 25 were cligible; 8 (32%) achieved a CR and 6 (24%) showed a PR. Toxicity was severe in both studies, including 〉90% severe or life-threatening leukopenia and thrombocytopenia. Serial creatinine-clearance evaluations in the first study indicated progressive deterioration, which required discontinuation of the cisplatin before the planned completion of treatment in most cases. Since the response rate was no higher than the historic data reported for the three-drug ACE combination and because the toxicity was severe, the studies were stopped and patients were followed for survival. After a follow-up period of 〈6 years, the median survival was 24 months for limited disease, with 33% and 27% of the patients being alive at 3 and 6.5 years, respectively. The median survival for extensive disease was 15 and 11 months in the first and second studies, respectively. These pilot studies suggest that the addition of cisplatin may augment the activity of the ACE regimen, but at the cost of severe toxicity. Further studies seem warranted if the myelotoxicity can be better controlled.