Phase I clinical and pharmacokinetic trial of Brequinar sodium (DuP 785; NSC 368390)

Brequinar sodium is a 4-quinolinecarboxylic acid analogue that inhibits dihydroorotate dehydrogenase and subsequent de novo pyrimidine biosynthesis. It has shown dose-dependent antineoplastic activity against several mouse and human tumor models. This trial evaluated Brequinar given as a single daily i.v. bolus over a 5-day period repeated every 28 days. One hundred seven courses of treatment at dosages ranging from 36 to 300 mg/m2/day x 5 were administered to 45 patients (31 male and 14 female) with refractory solid tumors; median age was 58 years (range 30-74); median Southwest Oncology Group performance status was 1 (range, 0-3). Thirty patients had prior cytotoxic chemotherapy. Dose-limiting toxicities were thrombocytopenia and a severe desquamative maculopapular dermatitis. Two of 5 good risk patients at 300 mg/m2 and 3 of 6 poor risk patients at 170 mg/m2 developed a platelet count less than 25 x 10(3)/microliters. Two of 5 good risk patients at 300 mg/m2 and 1 of 6 poor risk patients at 170 mg/m2 developed a severe desquamative dermatitis. Moderate to severe mucositis was usually associated with the thrombocytopenia and/or the dermatitis. Nonhematological drug-related toxicities included nausea and vomiting, malaise, anorexia, diarrhea, phlebitis, reversible transaminase elevation, and mucositis. Other hematological toxicities were anemia, granulocytopenia, and leukopenia. There were no drug-related deaths. There were no objective tumor responses. Plasma and urine levels of Brequinar were quantified by high pressure liquid chromatography in 28 patients. Plasma levels and areas under the curve increased proportionally with increased dose. Brequinar had a harmonic mean terminal t1/2 of 8.1 +/- 3.6 h with a model-independent determined apparent volume of distribution at steady state of 9.0 +/- 2.9 liters/m2 and a total body clearance of 19.2 +/- 7.7 ml/min/m2. Renal excretion was a minor route of elimination for Brequinar. The maximally tolerated dose of Brequinar on a daily x 5 i.v. schedule was 250 mg/m2 for good risk patients. For the daily x 5 i.v. schedule, the recommended dose of Brequinar for phase II evaluation is 250 mg/m2 for good risk patients and 135 mg/m2 for poor risk patients.     

A phase I clinical and pharmacokinetic study of brequinar sodium,DUP 785 (NSC 368390), using a weekly and a biweekly schedule

Brequinar, DUP 785, is a substituted 4-quinoline carboxylic acid derivative which in preclinical studies has shown broad antitumor activity. It is a novel antimetabolite blocking pyrimidine nucleotide synthesis. In a clinical phase I study, 83 patients were treated on a weekly schedule and 18 patients on a biweekly schedule. The drug was given intravenously as a short infusion. Three patients were entered on each dose level from a starting dose of 6 mg/m² up to 2600 mg/m² weekly. The dose ranges on a biweekly schedule were 500–850 mg/m². There was no dose escalation in individual patients. Pharmacokinetic studies were performed in 19 patients on a weekly schedule and in two patients on a biweekly schedule. A biphasic decay in plasma was observed with a median half life of 10 h (5.1–23.4). The main dose-limiting toxicity was thrombocytopenia. Of non-hematologic side-effects, stomatitis/mucositis occurred frequently. Skin eruptions occurred rarely, but were a major problem when found. All side-effects were fully reversible; there were no signs of cumulative toxicity. Antitumor activity was observed in one patient with a lung metastasis from a bladder cancer and in a patient with an unknown primary tumor. The recommended doses for phase II trials with DUP 785 are: 1500–2000 mg/m² on a weekly schedule and 500–750 mg/m² on a biweekly schedule dependent on status before treatment.     

Phase I and pharmacokinetic study of hepsulfam (NSC 329680)

Hepsulfam (NSC 329680), a bifunctional alkylating agent structurally related to busulfan, has entered clinical trial based on its broader preclinical antitumor activity compared with that of busulfan and its i.v. formulation which may circumvent the many problems arising from the p.o. administration of busulfan, such as significant individual differences in bioavailability. In this Phase I study, 53 patients received 95 courses of hepsulfam at doses ranging from 30 to 480 mg/m2 administered i.v. over 30 min every 28 days. Hematological toxicity was dose limiting. Leukopenia and thrombocytopenia were dose related, delayed in onset, and sustained for long durations. Toxicity was cumulative in most patients receiving more than one course. This pattern of myelosuppression suggests that hepsulfam is cytotoxic to hematopoietic stem cells. Although hematological toxicity was not particularly severe during most courses, its lengthly duration precluded the prompt administration of subsequent courses. Minimal nonhematological effects were observed. Pharmacokinetic studies revealed that the clearance rate of hepsulfam is linear over the dose range studied and that its plasma disposition is biphasic with mean alpha and beta half-lives of 19 +/- 18 (SE) min and 337 +/- 248 (SE) min, respectively. The area under the plasma clearance curve correlated with the percentage of change in WBC using a sigmoidal Emax model and with the duration of thrombocytopenia in patients with hematological toxicity. Based on the protracted duration of the toxicity of multiple doses that were greater than 210 mg/m2, the recommended starting dose for Phase II trials is 210 mg/m2. However, these trials should be pursued with caution because of the protracted nature of hepsulfam's myelosuppression. Because hepsulfam produced minimal nonhematological toxicity, substantial dose escalation above 480 mg/m2 may be possible with hematopoietic stem cell support.     

Pharmacokinetics of Brequinar sodium (NSC 368390) in patients with solid tumors during a phase I study

The pharmacokinetics of the novel antipyrimidine agent Brequinar sodium (NSC 368390; DUP 785) was studied in 23 patients with solid tumors during the phase I study of this compound. The drug was administered by short-term (10–60 min) intravenous infusion every 3 weeks. The doses ranged from 15 to 2250 mg/m².At doses higher than 1500 mg/m² the areas under the plasma concentration vs. time curve (AUC) increased non-proportionally, while the total body clearance (Cl₁) dropped substantially, indicating non-linear pharmacokinetics of the drug. Brequinar sodium showed a triphasic decay of plasma concentrations with half-life ranges of 11.1–36.6 min, 1.7–6.9 h and 12.5–25.0 h, respectively. The volume of distribution (Vd_ss) ranged from 4.4 to 10.6 l/m². The total body clearance (Cl₁) ranged from 6.9 to 22.1 ml/min with a small contribution of the renal clearance (0.04-0.4 ml/min). Up to 7 days, the cumulative urinary excretion (CUE) and the cumulative fecal excretion (CFE) ranged from 0.4 to 8.3% and from 7.7 to 18.3% of the dose, respectively. There was evidence for the presence of drug metabolites in urine and feces. There was no drug accumulation with repeated administration of Brequinar sodium by the above mentioned drug schedule. The ratio between the plasma AUC at the maximum tolerable dose (MTD) in mana nd that at the mouse ld₁₀ was 0.8, while the ratio between the respective doses was 5.7. The ratios between the AUC in patients and that at the mouse ld₁₀ were applied to guide dose escalation in the phase I study. The results of the above mentioned pharmacokinetic studies were useful for the choice of an optimal schedule for phase II trials of Brequinar sodium.     

In vivo inhibition of the pyrimidine de novo enzyme dihydroorotic acid dehydrogenase by brequinar sodium (DUP-785; NSC 368390) in mice and patients

Little is known about the in vivo effects of inhibition of the mitochondrial pyrimidine de novo synthesis enzyme dihydroorotic acid dehydrogenase (DHO-DH). In mice a new inhibitor of DHO-DH, Brequinar sodium (DUP-785, NSC 368390) depleted the plasma uridine concentration to 40% within 2 h, followed by a small rebound after 7-9 days. The drug was subsequently evaluated in a Phase I clinical trial, during which it was possible to follow its biochemical effects in 24 patients (27 courses). In addition to the measurement of plasma uridine concentrations, we also measured in lymphocytes of 9 patients (10 courses) the duration of DHO-DH inhibition. Brequinar sodium was administered every 3 weeks as an i.v. infusion at dose levels of 15-2250 mg/m2. The biochemical effects were studied following the first administration of the drug. In sonicated extracts of lymphocytes from 7 healthy volunteers the activity of DHO-DH varied from 2.0 to 3.9 nmol/h per 10(6) cells, while in the lymphocytes of 9 patients obtained immediately before treatment this value was between 0.5 and 4.8 nmol/h per 10(6) cells. Within 15 min of drug administration DHO-DH activity was not detectable and was still low up to 1 week later. Duration of the inhibition appeared to be related to the extent of clinical toxicity, e.g., myelosuppression, nausea, vomiting, diarrhea, and mucositis. Severe lymphopenia was observed in patients receiving Brequinar sodium at the maximum tolerated dose. At dose levels of greater than or equal to 600 mg/m2, uridine depletion (40-85%) was observed between 6 h and 4 days, followed by a rebound of 160-350% after 4-7 days. The extent of the depletion and of the accompanying rebound of uridine levels and the extent and duration of DHO-DH inhibition in the individual patients could be partially associated with drug toxicity in these patients. This is the first report describing biological effects of DHO-DH inhibition in humans in relation to the degree and duration of inhibition of this enzyme.     

Phase I and pharmacokinetic study of tiazofurin (NSC 286193) administered by 5-day continuous infusion

Summary A phase I and pharmacokinetic study of tiazofurin (NSC 286193), a C-nucleoside that inhibits IMP dehydrogenase, has been completed. The drug was administered by continuous infusion over 5 days. The maximum tolerated dose was 1650 mg/m² per day, neurological toxicity being the dose-limiting factor. Gastrointestinal and hematological toxicity were mild. A definite relationship exists between dosage and steady-state levels. The plasma clearance was 29.13 (±SD 4.05) ml/min per m². No complete or partial remissions were demonstrated among the 18 patients treated at five dose levels between 550 mg/m² and 2200 mg/m² per day.     

Phase I and pharmacokinetic study of 5-aza-2'-deoxycytidine (NSC 127716) in cancer patients

A phase I trial and pharmacokinetic study of 5-aza-2'-deoxycytidine (5-aza-dCyd) were conducted in 21 patients with advanced solid tumors. The drug was given as three 1-h infusions, separated by intervals of 7 h. Treatment was repeated every 3-6 weeks. Forty-six cycles of 5-aza-dCyd were administered at 7 dose levels ranging from 25 to 100 mg/m2 in three infusions. The dose-limiting toxicity was myelosuppression, with a delayed white blood cell nadir, occurring at Day 22. Other toxicities included a mild, reversible elevation of serum creatinine in three patients, minimal nausea and vomiting in six patients, and transient fatigue in three patients. In this study one partial response in a patient with an undifferentiated carcinoma of the ethmoid sinus was observed. Plasma and urinary concentrations of 5-aza-dCyd were measured using a bioassay based on growth inhibition of L1210 leukemia cells in vitro. For 75 and 100 mg/m2 given as 1-h infusions, mean peak plasma concentrations of 0.93 and 2.01 microM, respectively, were attained. In seven of nine courses at doses of 25-60 mg/m2, plasma 5-aza-dCyd concentration was less than 0.01 microM. In one case at 30 mg/m2 and another at 60 mg/m2, peak plasma drug concentrations were determined to be 0.244 and 0.409 microM, respectively. Following cessation of the infusion rapid disappearance of drug from plasma was observed with a t1/2 alpha and t1/2 beta of 7 and 35 min, respectively. High clearance values and a total urinary excretion of less than 1% of the administered dose suggest that 5-aza-dCyd is eliminated rapidly and largely by metabolic processes. For the present schedule studied, a dose of 75 mg/m2 in three infusions, every 5 weeks, is recommended for phase II trials in solid tumors.     

Phase I bioavailability and pharmacokinetic study of hexamethylene bisacetamide (NSC 95580) administered via nasogastric tube

A Phase I clinical trial and pharmacological study of nasogastrically administered hexamethylene bisacetamide, a polar-planar compound with in vitro differentiating activity, was conducted in 14 adult patients with refractory cancer. Hexamethylene bisacetamide was administered as a 5% (w/v) solution via a nasogastric or gastrostomy tube every 4 h for 5 days, followed in 21 days by a 5-day continuous i.v. infusion at the same daily dose. Parenteral drug administration was then continued at the same interval in the absence of disease progression or unacceptable toxicity. Three patients each were treated at doses of 12 and 24 g/m2/day, while eight patients received a dose of 30 g/m2/day. Toxicity was comparable for both routes of drug administration at the above doses. Nasogastrically administered hexamethylene bisacetamide was well tolerated at the lower doses, whereas neurotoxicity and nausea and vomiting were the major, but manageable, toxicities at 30 g/m2/day. Metabolic acidosis, renal dysfunction, mucositis, and thrombocytopenia were the other commonly observed drug toxicities at this dose. No objective tumor responses were observed. Hexamethylene bisacetamide was rapidly absorbed from the gastrointestinal tract with a mean measured bioavailability of 99 +/- 15%. Pharmacokinetic parameters for hexamethylene bisacetamide and plasma concentrations of the two major metabolites, N-acetyl-1,6-diaminohexane and 6-acetamidohexanoic acid, were similar for either route of administration in individual patients. Hexamethylene bisacetamide exhibited apparent monoexponential plasma elimination after either nasogastric or parenteral administration with 27 to 60% of the administered dose being excreted in the urine as parent compound. Based on its demonstrated complete bioavailability and tolerability, nasogastric administration of hexamethylene bisacetamide can be directly and safely substituted for the comparable i.v. dose.     

A phase I and pharmacokinetic study of diamminecyclobutane-dicarboxylatoplatinum (NSC 241240)

Carboplatin (CBDCA; NSC 241240) is a second-generation platinum coordination compound which in preclinical testing was found to be less nephrotoxic and emetogenic than cis-diamminedichloroplatinum (CDDP), while retaining a broad spectrum of antitumor activity. We have conducted a Phase I trial of CBDCA in 38 patients with advanced carcinoma. The drug was given without hydration as a 24-hr constant i.v. infusion on Day 1 of a 28-day cycle. Seventy-five cycles of CBDCA were administered in eight dose levels ranging from 20 to 320 mg/sq m. Dose-limiting toxicity was myelosuppression, primarily thrombocytopenia, occurring between Days 14 and 28 of the cycle. Myelosuppression was first observed at a dose of 240 mg/sq m and became dose-limiting at 320 mg/sq m, which is the recommended dose for Phase II trial. Other toxicities included nausea and vomiting and reversible renal failure seen in two patients with low normal pretreatment creatinine clearances. No consistent changes were seen on serial audiograms. Plasma concentrations of total and ultrafilterable platinum were measured by flameless atomic absorption spectrophotometry. Following cessation of the infusion, a half-life of 170 +/- 34 min (S.D.) was found for CBDCA-derived ultrafilterable platinum. In vitro clonogenic assay of a CDDP-sensitive human ovarian cancer cell line using clinically achievable drug concentrations suggests that prolonged infusions of CBDCA may be more cytotoxic than bolus administration. In this study, minimal responses were seen in two patients with ovarian carcinoma who had failed previous combination chemotherapy including CDDP. In addition, three patients with refractory metastatic breast cancer responded to CBDCA (two minimal responses and one partial response) with remission durations averaging 3 months. CBDCA behaves as predicted by preclinical studies with different toxicities from CDDP and apparent activity in breast cancer.     

Phase I and pharmacokinetic study of arabinofuranosyl-5-azacytosine (fazarabine, NSC 281272).

A Phase I clinical trial of 1-beta-D-arabinofuranosyl-5-azacytosine (ara-AC or fazarabine) given as a 72-h continuous infusion on a 21-day cycle was conducted in 27 adult patients with refractory cancer. The major toxicity was reversible granulocytopenia and thrombocytopenia. Dose-limiting toxicity was observed at a dose rate of 1.96 mg/m2/h in which Grade IV leukopenia (WBC less than 1,000/mm3) occurred in 4 of 11 patients and Grade IV thrombocytopenia (platelets less than 25,000/mm3) occurred in 3 of 11 patients. Plasma steady-state levels ranged from 0.13 to 0.6 microM for doses of 1.25 to 5.94 mg/m2/h. Mean total body clearance was 647 ml/min/m2. Minor clinical responses were seen in one patient with testicular cancer, one patient with colon cancer, one patient with breast cancer, and one patient with acute nonlymphocytic leukemia. Another patient with adenocarcinoma of unknown primary had stable disease during 13 cycles of therapy. Based on the results of this study, the recommended dose for Phase II studies of 1-beta-D-arabinofuranosyl-5-azacytosine administered as a 72-h continuous infusion is 2.0 mg/m2/h (48 mg/m2/day).     

Pediatric phase I trial and pharmacokinetic study of tiazofurin (NSC 286193)

Tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide), a new nucleoside antimetabolite, was evaluated in a phase I trial involving children with refractory cancers. The drug was administered i.v. as a 10-min infusion daily for 5 consecutive days repeated at 3-week intervals. The dose ranged from 550 to 3300 mg/sq m/day. Seventeen patients received 23 courses and were evaluable for toxicity. The maximally tolerated dose was 2200 mg/sq m/day. The major dose-limiting toxicities were nonhematological. Neurotoxicity, including headache, drowsiness, and irritability, was common and was the principal dose-limiting toxicity at the higher doses. Severe myalgias were also dose limiting in one patient. Other side effects were mild, reversible elevations in serum transaminases; nausea, vomiting, and diarrhea; mild hypertension; dysphagia; and exfoliative dermatitis of the hands and feet. Myelotoxicity was not significant. The pharmacokinetics of tiazofurin was studied in 16 patients. Plasma disappearance was triphasic with half-lives of 9.7 min, 1.6 h, and 5.5 h. Clearance was dose related, ranging from 120 ml/min/sq m at 550 mg/sq m/day to 70 ml/min/sq m at 3300 mg/sq m/day. The primary route of elimination was renal with 85% of the drug recoverable in the urine as the parent compound in the 24 h following administration.     

Distribution of the novel anticancer drug candidate brequinar sodium (DuP 785, NSC 368390) into normal and tumor tissues of nude mice bearing human colon carcinoma xenografts

Summary The distribution of the novel anticancer drug candidate Brequinar Sodium (DuP 785, NSC 368390) was studied in control mice and mice implanted subcutaneously with human colon carcinoma xenografts. Mice were given radiolabeled ¹⁴C-Brequinar Sodium intravenously. Brequinar concentrations in blood and various tissues were determined at 1, 6, and 24 h after drug administration. Within 1 h Brequinar distributed to the tumor and all other tissues studied. The tumor-to-blood drug concentration ratios ranged from 0.19 to 0.41. Radioactivity in the liver and small intestine at 1 h accounted for 17% and 13%, respectively, of the dose given. Elimination rates of Brequinar from all tissues were approximately equal to that from blood. Comparison of blood concentrations determined by both radioactivity and HPLC methods suggests that the intact drug is probably the only form in the blood.     

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)     

A phase I and pharmacokinetic study of dihydro-5-azacytidine (NSC 264880)

5,6-Dihydro-5-azacytidine (DHAC; NSC 264880) is an analogue of 5-azacytidine that does not possess the hydrolytically unstable 5,6-imino bond of the parent compound. Thus, unlike 5-azacytidine, DHAC is stable in aqueous solution and may be administered by prolonged i.v. infusion, potentially avoiding acute toxicities associated with bolus administration of 5-azacytidine. In this study, patients with advanced cancer were treated with DHAC administered as a 24-h constant i.v. infusion every 28 days. Treatment began at a dose of 1 g/sq m and was escalated to the maximum-tolerated dose of 7 g/sq m, where the limiting toxicity was pleuritic chest pain. Other toxicities included nausea and vomiting, which were not limiting. There was no evidence for myelosuppression, nephrotoxicity, or hepatotoxicity. DHAC was measured in plasma, urine, and ascites by a sensitive and specific reverse-phase high-performance liquid chromatography assay capable of detecting 50 ng of drug per ml. Steady-state plasma levels were achieved with 8 h and ranged from 10.0 to 20.5 micrograms of DHAC per ml at the maximum-tolerated dose. Total-body clearance of 311 +/- 76 ml/min/sq m and postinfusion half-lives between 1 and 2 h were observed. Between 8 and 20% of the administered dose was excreted unchanged in urine. While ascites DHAC levels in a patient with ovarian cancer were comparable to plasma levels, postinfusion elimination was slower from this compartment than from plasma. No correlation was observed between DHAC plasma levels and duration or intensity of dose-limiting pleuritic chest pain. One patient with progressive Hodgkin's lymphoma demonstrated stabilization of disease for seven treatment cycles, and two patients with aggressive lymphoma demonstrated dramatic, although transient, disease responses. A dose of 7 g/sq m is recommended for Phase II trials of DHAC using this schedule.     

Phase I clinical and pharmacokinetic study of oral penclomedine (NSC 338720) in adults with advanced solid malignancy.

Penclomedine is a synthetic alpha-picoline derivative that has shown antitumor activity both in preclinical development and in Phase I work using an i.v. preparation. The main toxicities seen in those studies were dose dependent and mainly neurocerebellar, with hematological toxicity being far less severe. This Phase I trial of p.o. penclomedine was conducted to potentially alter the toxicity profile and to avoid the neurological side effects seen with i.v. penclomedine. Eligibility criteria included microscopic confirmation of a solid malignancy or lymphoma with a lack of effective anticancer therapy. Twenty patients were enrolled. The median age was 60.5 years, and the median performance status was one. All but one patient had received prior systemic therapy. The starting dose of penclomedine was 200 mg/m(2) p.o. for 5 days, and was escalated according to a traditional Fibonacci sequence until the maximum tolerated dose (MTD) was observed. No treatment-related deaths were observed during the study. The MTD was determined to be 800 mg/m(2) p.o. for 5 days. Dose-limiting toxicities included mainly neurocerebellar symptoms such as ataxia and dysmetria, but neurocortical symptoms, such as confusion, were seen as well. Myelosuppression was less common and resulted in the discontinuation of therapy in only two patients. Pharmacokinetics show that the observed MTD is consistent with the i.v. preparations, and that the bioavailability of p.o. penclomedine is 49 +/- 18%. This regimen can be considered for additional studies in patients with intracranial neoplasms, because good central nervous system penetration is evident. Further development of penclomedine metabolites, such as 4-O-demethylpenclomedine, should be considered to minimize dose-limiting neurotoxicity.     

Phase I clinical study with pharmacokinetic analysis of 2-beta-D-ribofuranosylthiazole-4-carboxamide (NSC 286193) administered as a five-day infusion

A Phase I trial of 2-beta-D-ribofuranosylthiazole-4-carboxamide (NSC 286193, tiazofurin) was conducted using a 5-day continuous infusion schedule. Twenty-four patients with advanced cancer were entered on this trial. Dose levels ranged from 360 to 2350 mg/sq m/day for 5 days. Neurotoxicity was dose limiting and occurred in six patients. Neurotoxicity was expressed as confusion, lethargy, or obtundation and was associated with focal neurological deficits in four of six patients: hemiparesis, three; cortical blindness and bilateral upper extremity weakness, one. Neurotoxicity was not clearly dose related, occurring at 900 mg/sq m/day for 5 days (two patients), 1100 mg/sq m/day for 5 days (two patients), 1850 mg/sq m/day for 5 days, and 2350 mg/sq m/day for 5 days (one patient each). Other toxicities seen were myelosuppression, desquamation of palms and soles, malar erythema, and hyperpigmentation, stomatitis, chest pain, drug fever, and increased serum creatine phosphokinase. Administered drug [71.5 +/- 11.2% (SE)] was recovered intact in the urine within 24 h of administration. Terminal-phase mean harmonic half-life was 8.0 h. The unpredictable neurotoxicity seen following continuous infusion therapy with tiazofurin suggests that Phase II trials of this schedule are not indicated until better understanding of the biochemical effects of tiazofurin is achieved.     

Phase I pharmacokinetic trial of perillyl alcohol (NSC 641066) in patients with refractory solid malignancies.

Perillyl alcohol (POH) is a monoterpene with anticarcinogenic and antitumor activity in murine tumor models. Putative mechanisms of action include activation of the transforming growth factor beta pathway and/or inhibition of p21ras signaling, leading to differentiation or apoptosis. In this Phase I trial, 17 patients took POH p.o. three times daily for 14 days of each 28-day cycle. The starting dose of POH was 1600 mg/m2/dose, with escalations to 2100 and 2800 mg/m2/dose in subsequent cohorts. Chronic nausea and fatigue were dose-limiting toxic effects at 2800 mg/m2. Grade 1-2 hypokalemia was common at 2100 and 2800 mg/m2. Although POH could not be detected in plasma, two of its metabolites, dihydroperillic acid (DHPA) and perillic acid (PA), were measured in plasma and urine on days 1 and 15 after the first and last doses of POH, respectively. Both area under the concentration versus time curve and peak plasma concentration (Cmax) values increased with dose and exhibited high intersubject variability. Day 15 DHPA Cmax values ranged from a mean +/- SD of 22.6+/-12 microM at 1600 mg/m2/dose to 42.4+/-15.24 microM at 2800 mg/m2/dose. Corresponding mean +/- SD Cmax values for PA were 433.2+/-245.8 and 774.1+/-439.6 microM. One patient treated at the 2800 mg/m2/dose had markedly prolonged plasma levels of both PA and DHPA and developed grade 3 mucositis. POH treatment did not consistently alter the expression of p21ras, rap1, or rhoA in peripheral blood mononuclear cells obtained from patients treated at the highest dose level. The metabolites PA and DHPA did not change expression or isoprenylation of p21ras in MCF-7 breast or DU145 prostate carcinoma cells at concentrations that exceeded those achieved in patient plasma after POH treatment. We conclude that POH at 1600-2100 mg/m2 p.o. three times daily is well tolerated on a 14-day on/14-day off dosing schedule. Inhibition of p21ras function in humans is not likely to occur after POH administration at safe doses of the present oral formulation.     

Phase I and pharmacokinetic study of NSC 655649, a rebeccamycin analog with topoisomerase inhibitory properties.

PURPOSE: To assess the feasibility of administering NSC 655649, a water-soluble, rebeccamycin analog with topoisomerase inhibitory properties, as a brief intravenous (IV) infusion once every 3 weeks and to determine the maximum-tolerated dose (MTD) of NSC 655649, characterize its pharmacokinetic behavior, and seek preliminary evidence of antitumor activity. PATIENTS AND METHODS: Patients with advanced solid malignancies were treated with escalating doses of NSC 655649 administered over 30 to 60 minutes IV once every 3 weeks. An accelerated dose-escalation method was used to guide dose escalation. After three patients were treated at the first dose level, doses were escalated in increments that ranged up to 150% using single patient cohorts until moderate toxicity was observed, when a more conservative dose-escalation scheme was invoked. MTD was defined as the highest dose level at which the incidence of dose-limiting toxicity did not exceed 20%. MTD was determined for both minimally pretreated (MP) and heavily pretreated (HP) patients. Plasma and urine were sampled to characterize the pharmacokinetic and excretory behavior of NSC 655649. RESULTS: Forty-five patients were treated with 130 courses of NSC 655649 at doses ranging from 20 mg/m(2) to 744 mg/m(2). Myelosuppression was the principal toxicity. Severe neutropenia, which was often associated with thrombocytopenia, was unacceptably high in HP and MP patients treated at 572 mg/m(2) and 744 mg/m(2), respectively. Nausea, vomiting, and diarrhea were common but rarely severe. The pharmacokinetics of NSC 655649 were dose dependent and fit a three-compartment model. The clearance and terminal elimination half-lives for NSC 655649 averaged 7.57 (SD = 4.2) L/h/m(2) and 48.85 (SD = 23.65) hours, respectively. Despite a heterogeneous population of MP and HP patients, the magnitude of drug exposure correlated well with the severity of myelosuppression. Antitumor activity was observed in two HP ovarian cancer patients and one patient with a soft tissue sarcoma refractory to etoposide and doxorubicin. CONCLUSION: Recommended phase II doses are 500 mg/m(2) and 572 mg/m(2) IV once every 3 weeks for HP and MP patients, respectively. The absence of severe nonhematologic toxicities, the encouraging antitumor activity in HP patients, and the unique mechanism of antineoplastic activity of NSC 655649 warrant further clinical development.     

Phase I and clinical pharmacology study of intravenous flavone acetic acid (NSC 347512)

We have conducted a Phase I and pharmacological study of flavone acetic acid, one of a series of novel flavonoids. The drug was administered i.v. weekly for 4 weeks, with a 2-week rest and then repeated. Flavone acetic acid was given initially in a 1-h infusion, but at the 3900-mg/m2 dose level, the infusion time was lengthened to 3 h. A total of 31 patients were treated with 9 different dose levels, ranging from 330 to 6400 mg/m2. Dose-limiting toxicity was acute hypotension that began after about one-third of each drug dose had been infused and rarely lasted more than a few minutes after the infusion was discontinued. In addition, subjective fatigue and asthenia causing unacceptable patient discomfort was dose limiting. A significant side effect noted that was not dose limiting was diarrhea during the infusion. This drug exhibited nonlinear pharmacokinetic behavior. Plasma levels exceeded 300 micrograms/ml during the infusion at the maximally tolerated dose. After the infusion ended the principal half-life was about 2 h. In 24-h urine collections 27% of the flavone acetic acid dose was recovered as intact drug and an additional 37% was recovered as a metabolite. The maximally tolerated dose determined in this study is 6400 mg/m2 given i.v. over 3 h.