Phase I/pharmacokinetic trial of the novel thioxanthone SR233377 (WIN33377) on a 5-day schedule.

PURPOSE: SR233377 (WIN33377) is a novel 4-aminomethyl thioxanthone derivative with promising preclinical activity against solid tumors at doses substantially below the MTD. We performed a phase I trial to determine a suitable phase II dose of SR233377 when administered as a 2-h intravenous infusion for five consecutive days. METHODS: A group of 25 patients with a range of solid tumor diagnoses and good performance status received SR233377 at eight dose levels ranging from 4.8 mg/m2 per day to 74.7 mg/m2 per day. Cycles were repeated every 35 days and patients were evaluated for response following two cycles of treatment. Doses were escalated in cohorts of three using a modified Fibonacci scheme. Pharmacokinetic sampling was performed during the first cycle in all patients. RESULTS: Toxicities of SR233377 on this schedule included neutropenia, fever, nausea, and dyspnea but all were mild and not dose-limiting. Asymptomatic prolongation of the corrected QT (QTc) interval during infusion in all patients monitored at the 74.7 mg/m2 dose level prompted closure of the study. QT lengthening correlated with increasing plasma concentrations of SR233377. SR233377 Cmax values increased linearly with dose, but substantial interpatient variability in SR233377 AUC, clearance, and half-life was noted. There was no evidence of drug accumulation when day 1 and day 5 AUC and Cmax values were compared. Seven patients displayed tumor growth inhibition lasting for 4 months or more. CONCLUSIONS: We conclude that SR233377 administered on a 5-day schedule is associated with tolerable clinical symptoms and some activity against a range of solid tumors but dosing is limited by QTc prolongation, a condition that predisposes to ventricular arrhythmias. Phase II development on this schedule is not recommended based on the occurrence of this concentration-dependent effect. Further investigation of alternative schedules of administration and of SR233377 analogues is warranted.

Phase I/pharmacokinetic study of the topoisomerase I inhibitor GG211 administered as a 21-day continuous infusion.

BACKGROUND: Preclinical results support a prolonged schedule of administration for topoisomerase I inhibitors, and we have previously demonstrated the safety and activity of the novel water-soluble topoisomerase I inhibitor GG211 when given as a 72-hour continuous infusion to cancer patients. PATIENTS AND METHODS: In a three-center international phase I trial, 38 patients received GG211 doses from 0.3 to 0.5 mg/m2/day by continuous intravenous infusions for seven, 14, and 21 days. Patients' median performance status was 1; nearly half had colorectal cancer, and 35 patients had prior chemotherapy. RESULTS: The first patient cohort received 0.3 mg/m2/day for seven days with no significant toxicities. Subsequent cohorts received continuous infusions for 14 and 21 days at this dose level with only mild myelosuppression noted. Dose-escalation on the 21-day schedule was then performed. No dose-limiting toxicity occurred at the 0.4 mg/m2/day dose level. Thrombocytopenia was dose-limiting with 0.5 mg/m2/day dosing but was not cumulative. Other grade 3 4 toxicities included neutropenia, nausea, vomiting, diarrhea, and fatigue. Partial responses occurred with 21-day infusion in two patients with breast and ovarian cancer at the 0.3 and 0.4 mg/m2/day dose levels, respectively. Mean GG211 lactone Css ranged from 0.17 to 0.64 ng/ml. CONCLUSION: The maximum tolerated dose of GG211 administered as a 21-day continuous infusion is 0.4 mg/m2/day with antitumor activity noted at tolerable doses.

A phase I clinical and pharmacokinetic study of the new topoisomerase inhibitor GI147211 given as a 72-h continuous infusion.

GI147211 is a novel, totally synthetic camptothecin with promising preclinical and early clinical activity. This study was designed to determine the maximum tolerated dose of Gl147211 as a 72-h infusion and to describe its pharmacokinetics and pharmacodynamics on this schedule. In a single-arm, rising-dose study in patients with advanced cancer, eight cohorts of three or more patients received 72-h infusions of Gl147211 at doses ranging from 0.25 to 2.5 mg m(-2) day(-1). Forty-four patients received a total of 124 cycles. All patients had refractory tumours and 40 had received prior chemotherapy and/or radiotherapy. Whole-blood Gl147211 lactone, total blood and total concentrations were measured during and over the 12 h following the infusion. Myelosuppression was observed at all dose levels. Neutropenia was dose limiting at 2.0 mg m(-2) day(-1) in minimally pretreated patients, while both neutropenia and thrombocytopenia were limiting at 1.5 mg m(-2) day(-1) in those more heavily pretreated. Phlebitis occurred with infusions through peripheral veins early in this study, necessitating the use of central venous access. Other toxicities included mild nausea and vomiting, fatigue, headache, central venous catheter infections and alopecia. Three partial and two minor responses lasting 8-34+ weeks were noted in patients with ovarian, colon and breast carcinomas and hepatoma. Mean steady-state concentrations of Gl147211 increased with dose over a range of 0.25-1.24 ng ml(-1). The mean terminal elimination half-life was 7.5 h, and the clearance averaged 1074 ml min(-1) m(-2) over the doses studied. The mean fractional excretion of unchanged drug in urine was 0.114. Gl147211 lactone exposure correlated with haematological toxicity. The recommended phase II doses for this regimen are 1.75 mg m(-2) day(-1) and 1.2 mg m(-2) day(-1) for minimally pretreated and heavily pretreated patients respectively. At these doses, steady-state Gl147211 concentrations within the range of those effective in vitro were achieved. Extensive phase II evaluation of this compound and further phase I trials evaluating more prolonged infusions are ongoing.

Phase II study of N-phosphonacetyl-L-aspartate, recombinant interferon-alpha, and fluorouracil infusion in advanced squamous cell carcinoma of the head and neck.

BACKGROUND: 5-Fluorouracil (5-FU), as a single agent, produces a 15% response rate in advanced squamous cell carcinoma of the head and neck (SCCHN). N-phosphonacetyl-L-aspartate (PALA) inhibits pyrimidine biosynthesis and increases incorporation of 5-FU metabolites into ribonucleic acid (RNA). Recombinant alpha interferon-2b (rIFN-alpha-2b) may inhibit 5-FU clearance and blunt reflex rise in thymidylate synthetase, therefore enhancing inhibition of the target enzyme of 5-FU. METHODS: In an attempt to exploit their potential therapeutic synergy, we initiated a phase II trial combining PALA 250 mg/m2 by intravenous (IV) bolus day 1 with 5-FU 2600 mg/m2 24-hour IV infusion initiated 24 hours after PALA, followed by rIFNalpha-2b 10 million units (MU) by subcutaneous injection days 2, 3, and 4 in patients with advanced, measurable SCCHN incurable with surgery or radiotherapy. Treatment was repeated weekly; patients were assessed every 4-6 weeks. Pretreatment tumor specimens were analyzed for p53 mutations in exons 5-8 and for protein expression using the p53 polyclonal antibody CM-1. RESULTS: Nineteen patients were enrolled from November 1991 through February 1994. Median age was 59 years (range, 31-72 years). All had previously received definitive radiotherapy, and all but two had undergone surgical resection. Seven patients (37%) had received prior adjuvant chemotherapy. Median time from initial diagnosis to protocol enrollment was 17 months (range, 5 months to 10 years). Median performance status (PS) was 1. Primary tumor sites included oral cavity (8 patients), larynx (7 patients), oropharynx (3 patients), and hypopharynx (1 patient). The median serum transferrin was 241 (range, 141-333). Sixteen patients (84%) had sufficient pretreatment biopsy material for p53 analysis. Patients received a median of 6 weeks of treatment (range, 2-30 weeks). Six patients (32%) in the absence of disease progression failed to finish the first 6 weeks of treatment: 3 died of pulmonary insufficiency or pneumonia and 3 were removed from study during the first 6 weeks due to toxicity. Grade 2-3 flulike symptoms occurred in 17 patients (89%); grade > or = 3 fatigue occurred in 12 patients (63%), and grade > or = 2 stomatitis occurred in 5 (26%). Gastrointestional toxicity was minimal and myelosuppression mild. Of 13 evaluable patients, there were 2 partial responses (15%) lasting 3 months and 20 months; 5 patients with stable disease lasting 2, 2, 2.5, 3, and 4.5 months; and 6 with disease progression. For all 19 patients, the overall response rate was 11%, the median survival was 6 months and 1-year survival rate 26%. Lower transferrin values (< or =241) were associated with shortened median survival 2.5 vs 11 months). Increased p53 protein expression but not p53 mutations in pretreatment specimens also predicted inferior survival (median, 6 vs 11 months) after enrollment in study (p = .0124). CONCLUSIONS: Biochemical modulation of 5-FU by rIFNalpha-2b and PALA does not enhance its efficacy in patients with advanced SCCHN whose disease has progressed after prior radiotherapy. Serum transferrin and p53 protein expression segregate outcome in this group of uniformly treated patients.

A phase I and pharmacokinetic study of tallimustine [PNU 152241 (FCE 24517)] in patients with advanced cancer.

Tallimustine [PNU 152241 (FCE 24517)] is a synthetic derivative of the DNA minor groove binder distamycin A, in which the NH2-terminal formyl group is substituted by benzoyl mustard. In this Phase I clinical trial, patients with advanced solid tumors received i.v. bolus injections of tallimustine daily for 3 consecutive days. Patients were treated at six dosage levels of 33.3 micrograms/m2/day to 250 micrograms/m2/day for 3 consecutive days, with courses of therapy repeated every 28 days. Detailed pharmacokinetic blood sampling was performed during the first 3 days of the first course of tallimustine. The plasma samples were analyzed by high-performance liquid chromatography with UV detection. Forty-eight eligible patients were treated at all six dosage levels. The dominant dose-related toxicity of tallimustine was neutropenia, becoming dose limiting at 250 micrograms/m2/day. At this dosage level, one patient experienced febrile neutropenia, and a second patient died on study of indeterminate cause. Thrombocytopenia was not observed, and only 10 patients developed anemia < 8.0 gm/dl. Sporadic elevation of liver enzymes or bilirubin was observed but was not dose related. Pharmacokinetic analysis gave reliable results for 33 patients. For most patients, analysis of the data best fit a three-exponential model. Dose-related increases in areas under the concentration-time curve and end-of-infusion concentrations were observed. There was no significant plasma accumulation of tallimustine over the 3 days of administration. The terminal half-life of tallimustine in individual patients ranged from 6.83 to 39.02 h following the last dose. In summary, the recommended Phase II dosage for tallimustine is 200 micrograms/m2/day for 3 consecutive days every 28 days. Neutropenia is the principal toxicity of this agent at this dosage and schedule.

Phase I trial of the thymidylate synthase inhibitor AG331 as a 5-day continuous infusion.

AG331 (N6-[4-(morpholinosulfonyl)benzyl]-N6-methyl-2, 6-diaminobenz-[c,d]-indole glucuronate) is a lipophilic thymidylate synthase inhibitor with activity in solid tumor models. On the basis of preclinical data supporting regimens of frequent drug administration, we performed a Phase I trial of AG331 as a 5-day continuous infusion repeated every 3 weeks. Twenty-nine patients were entered at doses ranging from 25 to 1000 mg/m2/day. The major side effects were mild to moderate fatigue, nausea, vomiting, diarrhea, and fever. At doses >/=400 mg/m2, acute reversible elevation of bilirubin, aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyltranspeptidase was observed. All patients who received >/=600 mg/m2/day experienced elevated alanine aminotransferase. Elevated liver function tests were evident by day 3 of the infusion and had resolved by day 8 in the majority. This toxicity was dose limiting at 1000 mg/m2/day, at which dose two of two patients developed grade 4 reversible hyperbilirubinemia in addition to the enzyme elevations. Serum and urine samples were analyzed by a novel high-pressure liquid chromatography method for the determination of the pharmacokinetics of AG331. Over the 50-1000 mg/m2/day dose range, mean total clearance ranged from 11.6 to 30.0 liters/h/m2, and volume of distribution at steady state ranged from 279.5 to 758.7 liters/m2. These parameters were dose independent over the dose range tested. The harmonic mean terminal half-life of AG331 was 20.2 h. Less than 5% of an AG331 dose is eliminated unchanged in the urine. Both the administered dose and exposure to the drug were related to the changes in bilirubin and aminotransferase blood levels. Evidence for inhibition of thymidylate synthase was obtained at doses ranging from 100 to 1000 mg/m2 in seven patients; plasma deoxyuridine concentrations at end-infusion were 1.8-3.8-fold higher than pretreatment values. Because of the nature of toxicity on this schedule, more extensive Phase II evaluation is not recommended, although an AG331 dose of 800 mg/m2/day for 5 days is tolerable. Exploration of less frequent dose administration is under way.

Phase I trial of etoposide, doxorubicin and cisplatin (EAP) in combination with GM-CSF.

The aim of this study was to ameliorate the toxicity of the etoposide, doxorubicin and cisplatin (EAP) regimen and to investigate the feasibility of dose escalation, using the molgramostim form of granulocyte macrophage-colony stimulating factor (GM-CSF) 10 micrograms/kg/day s.c. into the regimen. The design of the trial allowed for amended scheduling of the agents in the event of suboptimal results. Initially the regimen comprised etoposide 120 mg/m2, days 1-3, doxorubicin 40 mg/m2, day 1, and cisplatin 40 mg/m2, days 2 and 8. GM-CSF was begun on day 4 and continued until recovery of granulocyte counts. Courses were repeated every 21 days. 3 patients were treated at these doses. 5 patients received escalated doses (etoposide 180 mg/m2; doxorubicin 60 mg/m2; cisplatin 60 mg/m2) on this schedule; 4 out of 5 had intolerable myelosuppression (grade IV neutropenia or thrombocytopenia lasting > or = 7 days). These results prompted the administration of the day 8 cisplatin dose on day 3, with GM-CSF beginning on day 4. At the lowest doses of each agent (etoposide 120-doxorubicin 40-cisplatin 40), 3 of 6 patients had intolerable myelosuppression, and 3 patients had febrile neutropenia. Dose escalation of all of the drugs to etoposide 180 mg/m2, doxorubicin 60 mg/m2, cisplatin 60 mg/m2 resulted in documented infections in 4 out of 4 patients. GM-CSF toxicity included rash, dyspnoea, arrhythmias and pericardial effusions. The conclusion was that the use of GM-CSF does not permit escalation of drug doses on either schedule of EAP administration, and that these results do not support the combined use of GM-CSF and EAP.

Dynamics of sulfur dioxide absorption in excised porcine tracheae.

The absorption of sulfur dioxide (SO2) into excised porcine tracheae was characterized by a step-response experiment in which SO2 outlet concentration was monitored during the 30-min interval following introduction of inlet concentrations of 0.1-0.6 ppm at steady air flows of 2.7-11.0 liter/min. These data were analyzed with a diffusion-reaction theory incorporating three independent parameters--a gas phase mass transfer coefficient, kg, a tissue phase diffusivity x solubility product, D(alpha RT)2, and a tissue phase reaction constant, kr. While single values of 17 sec-1 for kr and 0.28 m2/sec for D(alpha RT)2 were sufficient to simulate all the data, it was necessary to vary kg from a 0.032 to 0.121 m/sec in direct proportion to the gas flow. Based on these parameter values, gas phase resistance accounts for about one-fourth of the total resistance to absorption in gas and tissue phases combined. All three parameters were independent of inlet concentration, implying that diffusion, solubility, and irreversible reaction of SO2 in tissue are all linear processes.