Erlotinib in combination with pemetrexed for patients with advanced non-small-cell lung cancer (NSCLC): a phase I dose-finding study.

BACKGROUND: Erlotinib and pemetrexed are approved single agents for second-line treatment of non-small-cell lung cancer (NSCLC) and, in combination, have shown synergistic antitumor activity in NSCLC cell lines. We investigated the safety, pharmacokinetics and preliminary efficacy of combined erlotinib-pemetrexed in patients with refractory advanced NSCLC. PATIENTS AND METHODS: A nonrandomized, open-label, phase IB study was performed in patients with advanced NSCLC whose disease had progressed on or following first-line chemotherapy with a platinum-containing regimen or for whom the erlotinib-pemetrexed combination was considered appropriate. Patients received i.v. pemetrexed 500-700 mg/m² every 3 weeks and oral erlotinib 100-150 mg/day. RESULTS: Twenty patients were recruited. The most common adverse events (AEs) were rash, diarrhea and fatigue. Serious AEs occurred in eight patients (three treatment related) and there were eight deaths (none treatment related). Dose-limiting toxic effects were not experienced up to erlotinib 150 mg/day plus pemetrexed 600 mg/m². Concurrent administration did not affect pharmacokinetic parameters. Two patients achieved partial responses and nine had stable disease. CONCLUSIONS: Erlotinib-pemetrexed combination is well tolerated at doses equal to the licensed single-agent doses (150 mg/day and 500 mg/m², respectively). The good tolerability profile and promising efficacy indicate that this combination warrants further investigation for patients with advanced NSCLC.

Phase Ib safety and pharmacokinetic evaluation of daily and twice daily oral enzastaurin in combination with pemetrexed in advanced/metastatic cancer.

BACKGROUND: This phase Ib study evaluated the safety, pharmacokinetics, and activity of enzastaurin either 500 mg once daily (QD) or 250 mg twice daily (b.i.d.) in combination with pemetrexed. PATIENTS AND METHODS: Pemetrexed 500 mg/m(2) with folic acid and vitamin B(12) was given on day 1 every 21 days with enzastaurin 500 mg orally QD starting on day 5 of cycle 1 after a loading dose of 400 mg thrice daily on day 4. To evaluate whether a b.i.d. regimen results in higher enzastaurin exposures, the study was amended. After amendment, in cycle 1, patients received 500 mg enzastaurin QD on days 1-15 without initial loading dose and 250 mg b.i.d. on days 16-30; in subsequent cycles, patients received pemetrexed on day 1 every 21 days with enzastaurin b.i.d. RESULTS: Sixty-eight patients (42 preamendment and 26 postamendment) were assessed. Pemetrexed toxicity and pharmacokinetics did not appear to be altered by enzastaurin. Enzastaurin average steady-state plasma concentration (C(av,ss)) decreased by approximately 25% in the presence of pemetrexed. Enzastaurin C(av,ss) were approximately 40% higher in the b.i.d. versus QD regimen. Three patients (4.4%) with thyroid cancer of follicular/papillary type had partial response as defined by RECIST. CONCLUSIONS: Pemetrexed plus enzastaurin is well tolerated with preliminary evidence of anticancer activity, particularly in thyroid cancer.

A clinical phase II study with sorafenib in patients with progressive hormone-refractory prostate cancer: a study of the CESAR Central European Society for Anticancer Drug Research-EWIV.

Sorafenib is a multi-kinase inhibitor with antiangiogenic and antiproliferative activity. The activity of sorafenib in progressive hormone-refractory prostate cancer (HRPC) patients was investigated in a phase II clinical study. Progressive HRPC patients received sorafenib 400 mg bid p.o. continuously. Only patients with no prior chemotherapy, and either one-unidimensional measurable lesion according to RECIST-criteria or increasing prostate-specific antigen (PSA) values reflecting a hormone-refractory situation, were eligible for study entry. The primary study objective was the rate of progression-free survival of >/=12 weeks (PFS12). Secondary end points were overall response, overall survival, and toxicity. Fifty-seven patients with PC were enrolled. Two patients had to be withdrawn from the set of eligible patients. According to RECIST criteria, 4 patients out of 55 evaluable patients showed stable disease (SD). According to PSA-response, we saw 11 patients with SD PSA and 2 patients were responders at 12 weeks (PFS12=17/55=31%). Among the 257 adverse events, 15 were considered drug related of maximum CTC-grade 3. Twenty-four serious adverse events occurred in 14 patients (14/55=26%). Seven of them were determined to be drug related. No treatment-related death was observed. Sorafenib has antitumour activity in HRPCP when evaluated for RECIST- and PSA-based response. Further investigation as a component of combination regimens is necessary to evaluate its definite or overall clinical benefit for HRPCP.

Phase II study of MTX-HSA in combination with cisplatin as first line treatment in patients with advanced or metastatic transitional cell carcinoma.

PURPOSE: To assess the efficacy, tolerability and safety of MTX-HSA (methotrexate (MTX) covalently linked to human serum albumin (HSA)) combined with cisplatin as first line therapy for advanced bladder cancer. METHODS: Patients (pat) were treated with a loading dose of 110 mg/m(2) of MTX-HSA followed by a weekly dose of 40 mg/m(2) starting on day 8. Cisplatin was given on day 2 of each 28 day cycle at a dose of 75 mg/m(2). RESULTS: Tumor response evaluation was possible in 7 patients. Complete response (CR) and partial response (PR) was observed in 1 patient each (overall response rate: 29%). Key toxicities included CTC Grade (G) 3/4 stomatitis in 6 patients, vomiting G3 in 1 patient, fatigue G3 in 1 patient and thrombocytopenia G3 in 3 patients. CONCLUSION: The combination of MTX-HSA with cisplatin is feasible and shows antitumor activity against urothelial carcinomas combined with an acceptable toxicity profile.

BBR 3438, a novel 9-aza-anthrapyrazole, in patients with advanced gastric cancer: a phase II study group trial of the Central European Society of Anticancer-Drug Research (CESAR).

BBR 3438, a member of the 9-aza-anthrapyrazole family designed to decrease anthracycline dependent cardiotoxicity and to improve efficacy provided high in vivo activity in gastric carcinoma xenograft models. The present study was carried out to assess the efficacy and safety of BBR 3438 applied at a dose of 50 mg/m(2) four-weekly as an 1-hour infusion to pretreated patients with gastric cancer. Twenty-seven patients received at least one administration of BBR 3438. Lymph nodes and liver were the most common sites of metastases. A total of 94 cycles were administered (median 2, range 1-6). The main toxicity consisted of (worst per patient [%]; NCIC CTC grades 1/2/3/4) neutropenia 7/7/19/52 (one case of febrile neutropenia), stomatitis 15/19/4/-, nausea 22/26/7/-, vomiting 19/7/7/-, alopecia 15/33/-/-. Neutrophil nadir (520/mul) was reached after a median 15 days. The median time to recovery to < or = grade 1 neutropenia was 13.5 days. The median average cumulative dose of BBR 3438 was 166.8 mg, and the median dose intensity was 48.8 mg/m(2). Left ventricular ejection function (LVEF) was monitored with multiple-gated angiography (MUGA). Median LVEF values at baseline and at the end of cycle 2 were 67.5% and 65%, respectively, and no patient showed a relevant decrease of LVEF. In 25 patients evaluable for response no remission was observed. Four patients (16%) had stable disease. Median time to progression was 51 days, median overall survival was 64 days. In all, the feasibility and tolerability of BBR 3438 applied 4-weekly at a dose of 50 mg/m(2) was confirmed and neither relevant LVEF decreases nor hints of cardiac toxicity were observed. In terms of antitumor activity, BBR 3438 was found to be ineffective in the treatment of gastric cancer.

The role of protein kinase C-alpha (PKC-alpha) in cancer and its modulation by the novel PKC-alpha-specific inhibitor aprinocarsen.

As our understanding of tumorigenesis increases, interference with the various signaling pathways of tumor cells has become an attractive approach to arresting tumor cell growth and overcoming chemoresistance. Among many intracellular signaling proteins, protein kinase C (PKC) isoenzymes have been identified as possible targets to render tumor cells more susceptible to apoptosis and growth arrest. We review the known biology of the alpha-isoenzyme of PKC in different cancers to provide a rational approach for developing targeted therapies using PKC modulators, including aprinocarsen, an antisense oligonucleotide (ASO) against PKC-alpha.

A phase II trial of pemetrexed in patients with metastatic renal cancer.

BACKGROUND: Metastatic renal cell carcinoma (RCC) is rising in incidence but remains difficult to treat. This clinical trial evaluated the effects of pemetrexed (multitargeted antifolate, ALIMTAR) for the treatment of metastatic RCC. PATIENTS AND METHODS: Patients were required to have histological diagnosis of metastatic RCC with measurable disease and no prior chemotherapy. In addition, patients were required to have a World Health Organization (WHO) performance status of 0-2 and adequate bone marrow reserve. Patients received pemetrexed at a dose of 600 mg/m2 as a 10 min infusion every 3 weeks. Patients did not receive folic acid or vitamin B12 supplementation. RESULTS: Thirty-nine patients were enrolled and thirty two were evaluable for response. Three patients had a partial response for a response rate of 9% (95% CI 2-25%). The median time to progressive disease was 10.5 months. Of the nonresponders, twenty two had stable disease (median duration was 5.8 months; range 1.5-27.7) and seven had progressive disease (median time to progression was 5.4 months). Median time to progression for all qualified patients was 5.7 months. Common toxicities experienced were diarrhea and infection. Fatigue, stomatitis, and rash were also reported. The most common hematologic toxicity was grade 3/4 lymphopenia in 76% of patients. Leukopenia, granulocytopenia, and thrombocytopenia were also frequently reported. CONCLUSION: Single-agent pemetrexed has moderate activity in the treatment of metastatic RCC and should be investigated in combination with other potential active agents, as first-line treatment.

An EORTC-ECSG phase I study of LU 79553 administered every 21 or 42 days in patients with solid tumours.

A single-agent dose-escalating phase I and pharmacokinetic study on the naphthalamide agent, LU 79553, was performed to determine its safety profile, maximum tolerated dose (MTD) and recommended dose for phase II studies. LU 79553 was given intravenously (i.v.) every 3 weeks to patients with advanced solid cancers (an extended cohort of patients also received the drug every 6 weeks). 59 patients were enrolled into the study (50 patients in the 3-weekly schedule and 9 patients in the 6-weekly schedule). Dose levels studied ranged from 10 mg/m(2) to 160 mg/m(2). Neuro-muscular toxicity was identified as the dose-limiting toxicity (DLT). This muscular toxicity was observed after administrating total doses of 160-450 mg/m(2) (median 330 mg/m(2)). Non-DLTs consisted of diarrhoea, nausea and vomiting, fatigue and local venous phlebitis. The major haematological toxicities observed were anaemia and neutropenia (and were mainly observed at the two highest dose levels). The proposed dose for phase II studies using the 3-weekly regimen is 100 mg/m(2)/course (60 min infusion in 500 ml normal saline), but a close clinical follow-up of the patients for neuromuscular toxicity is mandatory. Prolongation of the treatment interval to 6 weeks, based upon the long half-life of the drug in the plasma and tissue, observed during this study, seemed not to be feasible in this heavily pretreated group of patients.

Population pharmacokinetic and dynamic analysis of the topoisomerase I inhibitor lurtotecan in phase II studies.

Population pharmacokinetic-dynamic analysis was prospectively integrated in a broad phase II program of lurtotecan (GI147211), a novel camptothecin derived topoisomerase I inhibitor, to determine the population pharmacokinetic profile in a larger population, to estimate individual pharmacokinetic parameters and to investigate relationships with clinical outcome. A sparse sampling method was applied during course one, which involved two sampling time-points. A Bayesian algorithm was used to estimate individual pharmacokinetic parameters, in particular total plasma clearance (CL) and volume of distribution. In total, samples were collected of 109 (63%) of 173 patients. Pharmacokinetic-dynamic evaluation could be carried out successfully in 85 (78%) of the sampled patients. CL of lurtotecan showed substantial variability (mean 87 +/- 28 L/h) and was of the same magnitude as in the phase I studies where full pharmacokinetic curves were used. Residual variability in the population estimate of CL was 9.9%. No significant relationships were observed between exposure parameters and toxicity nor likelihood of tumor response, however the latter relationship may well have been obscured by the heterogeneity of the studied population. Prospective implementation of large scale population pharmacokinetic-dynamic analysis is feasible and important to establish whether interpatient variability in drug exposure is a major determinant of toxicity or activity.

In vitro activity of liposomal N4octadecyl-1-beta-D-arabinofuranosylcytosine (NOAC), a new lipophilic derivative of 1-beta-D-arabinofuranocylcytosine on biopsized clonogenic human tumor cells and hematopoietic precursor cells.

N4-octadecyl-1-beta-D-arabinofuranosylcytosine (NOAC) is a new lipophilic derivative of 1-beta-D-arabinofuranosylcytosine (ara-C) with potent antitumor activity against leukemias and solid tumors. In this study the activity of NOAC against freshly explanted clonogenic cells from human tumors was determined and compared with conventional antitumor agents. NOAC was used in two liposomal preparations, a stable lyophilized and a freshly prepared liquid formulation. Both formulations inhibited tumor colony formation equally in a concentration-dependent fashion in both short- (1 h) and long-term (21-28 d) exposure experiments. NOAC (100 microM, long-term exposure) had a significantly better activity compared to the clinically used drugs cisplatin, doxorubicin, 5-fluorouracil, gemcitabine, mitomycin C and etoposide. The comparison of NOAC with ara-C in the long-term exposure experiment showed that ara-C was more effective at 4 and 10 microM, whereas at 1 and 100 microM there was no difference between the two drugs. NOAC was less toxic in a hematopoietic stem cell assay than ara-C and doxorubicin by factors ranging from 2.5 to 200, indicating that this drug is well tolerated at high doses. The antitumor activity of NOAC (NSC 685096) was confirmed by the NCI in vitro drug screening program where the drug was found to be active against several types of human tumors. Further development of NOAC in phase II studies is warranted.

Pemetrexed disodium: a novel antifolate clinically active against multiple solid tumors.

Pemetrexed disodium (ALIMTA), "pemetrexed") is a novel, multi-targeted antifolate that has demonstrated promising clinical activity in a wide variety of solid tumors, including non-small cell lung, breast, mesothelioma, colorectal, pancreatic, gastric, bladder, cervix, and head and neck. Pemetrexed inhibits multiple folate-dependent enzymes involved in both purine and pyrimidine synthesis including thymidylate synthase, dihydrofolate reductase, glycinamide ribonucleotide formyltransferase, and aminoimidazole carboxamide ribonucleotide formyltransferase. As a single agent, pemetrexed exhibits a moderate toxicity profile at a dose of 500 mg/m(2) by 10-minute infusion once every 21 days with myelosuppression being the dose-limiting toxicity. Folic acid added to the diet in preclinical studies reduced toxicities while maintaining antitumor activity. Based on this observation and clinical toxicities, folic acid and vitamin B(12) dietary supplementation has been recently introduced into all ongoing trials. Studies combining pemetrexed with other active chemotherapeutic agents demonstrate that these combination therapies may become important treatment regimens in a variety of cancer types. Currently, pemetrexed phase III trials are ongoing in mesothelioma and non-small cell lung cancer with future trials planned to explore this unique multitargeted antifolate.

UFT and leucovorin in first-line chemotherapy for patients with metastatic gastric cancer. An Early Clinical Studies Group (ECSG)/European Organization for Research Treatment of Cancer (EORTC) phase II trial.

A phase II study was performed to evaluate 1-(2-tetrahydrofuryl)-5-fluorouracil and uracil (UFT) and leucovorin as first-line chemotherapy in European patients with advanced gastric cancer. From 38 patients, 25 were evaluable for response and 36 for toxicity. Patients received UFT at 300 mg/m(2)/day for 28 days, every 35 days and leucovorin at 90 mg/day on an identical schedule. Overall response rate was 10.5% (95% confidence interval (CI): 3.7-22.5%) in intent-to-treat analysis and 16% (95% CI: 5.7-33%) in evaluable patients. Grade 3-4 common toxicity criteria (CTC) toxicities were diarrhoea (28%; 10/36), nausea (11%; 4/36), vomiting (8%; 3/36) and asthenia (11%; 4/36). 23 patients in 44% (42/96) of the courses had to skip days of treatment due to toxicity or to non-compliance. In conclusion, UFT+leucovorin has a definitive, but low, efficacy in advanced gastric cancer patients. Toxicities were mainly gastrointestinal and treatment needs to be withheld if grade 2 diarrhoea occurs.

Population pharmacokinetics and dynamics in phase II studies of the novel bioreductive alkylating cytotoxic indoloquinone EO9.

Population pharmacokinetic-dynamic analysis was prospectively integrated in the clinical phase II programme of EO9 to determine the population pharmacokinetic profile in a larger population of patients, to estimate individual patient pharmacokinetic parameters, and to investigate relationships between drug exposure and clinical outcome. A sparse sampling method was developed, which involved three sampling times, and was implemented during course 1. A Bayesian algorithm was used to estimate individual pharmacokinetic parameters, in particular total plasma clearance (CL) of EO9 and area under the curve (AUC). In total, samples were collected of 85 (65%) of the patients. Pharmacokinetic evaluation was successful in 61 (72%) of the sampled patients. CL of EO9 showed substantial variability (median 5.08 l/min; range 2.67-6.42) and was of the same magnitude as in the phase I study where full pharmacokinetic profiles were used. No significant relationships were noticed between exposure parameters and safety, but overall limited toxicity was observed. No tumor responses were documented. Prospective implementation of large-scale population pharmacokinetic-dynamic analysis is feasible and may generate important findings, in particular when tumor responses and relevant toxicity are observed.

Phase I and pharmacokinetic study of the oral farnesyl transferase inhibitor SCH 66336 given twice daily to patients with advanced solid tumors.

PURPOSE: A single-agent dose-escalating phase I and pharmacokinetic study on the farnesyl transferase inhibitor SCH 66336 was performed to determine the safety profile, maximum-tolerated dose, and recommended dose for phase II studies. Plasma and urine pharmacokinetics were determined. PATIENTS AND METHODS: SCH 66336 was given orally bid without interruption to patients with histologically or cytologically confirmed solid tumors. Routine antiemetics were not prescribed. RESULTS: Twenty-four patients were enrolled onto the study. Dose levels studied were 25, 50, 100, 200, 400, and 300 mg bid. Pharmacokinetic sampling was performed on days 1 and 15. At 400 mg bid, the dose-limiting toxicity (DLT) consisted of grade 4 vomiting, grade 4 neutropenia and thrombocytopenia, and the combination of grade 3 anorexia and diarrhea with reversible grade 3 plasma creatinine elevation. After dose reduction, at 300 mg bid, the DLTs consisted of grade 4 neutropenia, grade 3 neurocortical toxicity, and the combination of grade 3 fatigue with grade 2 nausea and diarrhea. The recommended dose for phase II studies is 200 mg bid, which was found feasible for prolonged periods of time. Pharmacokinetic analysis showed a greater than dose-proportional increase in drug exposure and peak plasma concentrations, with increased parameters at day 15 compared with day 1, indicating some accumulation on multiple dosing. Plasma half-life ranged from 4 to 11 hours and seemed to increase with increasing doses. Steady-state plasma concentrations were attained at days 7 through 14. A large volume of distribution at steady-state indicated extensive distribution outside the plasma compartment. CONCLUSION: SCH 66336 can be administered safely using a continuous oral bid dosing regimen. The recommended dose for phase II studies using this regimen is 200 mg bid.

Pharmacokinetics of MEN-10755, a novel anthracycline disaccharide analogue, in two phase I studies in adults with advanced solid tumours.

The doxorubicin analogue MEN-10755 has been identified as a compound with promising antitumour activity based on structure-activity studies of a new series of anthracycline disaccharides. The high antitumour activity of MEN-10755 in human tumour xenografts, including doxorubicin-resistant xenografts, and its unique pharmacological and biological properties made this novel disaccharide analogue an interesting candidate for clinical evaluation. Two pharmacokinetic phase I studies with different dosing schedules were performed in adults with solid refractory malignancies. The pharmacokinetics of MEN-10755 were studied after a 15-min i.v. infusion given once every 3 weeks or once every week for 3 weeks followed by 1 week rest. Plasma and urine levels of MEN-10755 were measured by HPLC with fluorescent detection. It was possible to combine the pharmacokinetic results of the two studies because there was no accumulation of MEN-10755 before the next infusion of MEN-10755 in the weekly study with 1 week rest. The administered dose levels on day 1 in this study were all in the lower range from the 3-weekly study. The postinfusion plasma kinetics of MEN-10755 were best described by a triexponential model. The plasma peak levels (Cmax) of MEN-10755 showed a linear relationship with the administered dose. Peak plasma MEN-10755 levels ranged between 474 and 21,587 microg/l. The mean elimination half-life (T(1/2gamma)) was 20.7+/-9.0 h. The AUC(0-infinity) was proportional to the administered dose. The mean plasma clearance of MEN-10755 was 6.0+/-2.2 l/h per m2 with a mean volume of distribution (Vss) of 95.6+/-43.4 l/m2. The mean renal excretion of unchanged drug within 24 h was 4.3+/-1.8%. Compared to epirubicin and doxorubicin, the pharmacokinetics of MEN-10755 were characterized by an approximately twofold shorter terminal half-life, a much lower total plasma clearance and a much smaller volume of distribution.

Carzelesin phase II study in advanced breast, ovarian, colorectal, gastric, head and neck cancer, non-Hodgkin's lymphoma and malignant melanoma: a study of the EORTC early clinical studies group (ECSG).

PURPOSE: In a phase II trial, the activity of carzelesin, a cyclopropylpyrroloindole prodrug analog, was assessed. PATIENTS AND METHODS: Carzelesin was used as second- or third-line chemotherapy in patients with breast, ovarian, head and neck cancer and non-Hodgkin's lymphoma, and as first-line chemotherapy in patients with colorectal and gastric cancer and melanoma. The drug was given as a bolus infusion at a 4-weekly dose of 150 microg/m2. A total of 140 patients were entered and a total of 285 courses were administered. RESULTS: In general, the compound was well tolerated. Myelotoxicity was the most common toxicity. Grade 3 and 4 leukopenia was observed in 18.6% of the courses, neutropenia in 20.3%, thrombocytopenia in 16.2% and anemia in 8.7%. Double nadirs were seen in a total of 41 courses for neutrophils, in 40 for leukocytes and in 3 for platelets. Non-hematological toxicity was very mild. Only one partial response in a patient with melanoma was seen. CONCLUSIONS: At this dose and schedule carzelesin did not yield activity in the types of tumors studied.

Phase I clinical and pharmacokinetic study of oral S-1 in patients with advanced solid tumors.

PURPOSE: To investigate the side effects, determine the maximum-tolerated dose (MTD), and study the pharmacokinetics of S-1, an oral fluoropyrimidine-based antineoplastic agent consisting of the fluorouracil (5-FU) prodrug tegafur combined with two modulators, 5-chloro-2,4-dihydroxypyridine and potassium oxonate. PATIENTS AND METHODS: Patients with advanced solid tumors received S-1 bid for 28 days, followed by 1 week of rest. 5-FU pharmacokinetics were investigated after a single initial dose of S-1 during the first 24 hours and weekly thereafter. RESULTS: Twenty-eight patients received S-1 at the four consecutive dose levels of 25, 45, 35, and 40 mg/m(2). The MTD was initially found at 45 mg/m(2), with diarrhea as the dose-limiting toxicity (DLT). Diarrhea was also the DLT at the dose of 40 mg/m(2), which was the MTD for patients exposed to extensive prior chemotherapy. Other toxicities were generally mild. Two patients had a reduction of more than 50% in tumor dimension. Plasma pharmacokinetics of 5-FU were linear; at the highest S-1 dose level, 5-FU plasma peak concentrations reached 1 to 2 micromol/L, and the half-life of 5-FU was 3 to 4 hours. A statistically significant relationship was observed between the severity of diarrhea and pharmacokinetic parameters of 5-FU. CONCLUSION: The recommended dose of S-1 in chemotherapy-naive or minimally chemotherapy-exposed patients is 40 mg/m(2) bid on 28 consecutive days, every 5 weeks. In heavily pretreated patients, the recommended dose is 35 mg/m(2) bid. Phase II trials are warranted in tumors known to be responsive to 5-FU treatment.

Phase I and pharmacological study of weekly administration of the polyamine synthesis inhibitor SAM 486A (CGP 48 664) in patients with solid tumors. European Organization for Research and Treatment of Cancer Early Clinical Studies Group.

A single-agent dose-escalating Phase I and pharmacological study of the polyamine synthesis inhibitor SAM 486A was performed. A dosing regimen of four weekly infusions followed by 2 weeks off therapy was studied. Fifty patients were entered into the study. Dose levels studied were 1.25, 2.5, 5, 8, 16, 32, 48, 70, 110, 170, 270, and 325 mg/m2/week. Pharmacokinetic sampling was done on day 1, and trough samples were taken weekly during the first treatment cycle. Pharmacodynamic sampling was done on days 1 and 22. At 325 mg/m2/week, dose-limiting toxicity was seen (one patient each with grade 4 febrile neutropenia, grade 3 neurotoxicity, and grade 3 hypotension with syncope and T-wave inversions on electrocardiogram). The recommended dose for further testing was set at 270 mg/m2/week. Infusion time was increased from 10 to 180 min due to facial paresthesias and flushing and somnolence. Drug exposure increased linearly with dose. Mean +/- SD t1,2 at 70-325 mg/m2 doses was 61.4+/-26.2 h, with a large volume of distribution at steady state. In peripheral blood leukocytes, a clear relationship between dose and inhibitory effect on S-adenosylmethionine decarboxylase or changes in intracellular polyamine pools was not recorded. SAM 486A can be administered safely using a dosing regimen of four weekly infusions followed by 2 weeks off therapy. The recommended dose for Phase II studies using this regimen is 270 mg/m2/week.