Weekly paclitaxel and cisplatin with concurrent radiotherapy in locally advanced non-small-cell lung cancer: a phase I study

PURPOSE: Both cisplatin (CDDP) and paclitaxel have shown good antitumor activity in non-small-cell lung cancer (NSCLC) patients and are able to potentiate the antitumor effects of radiation therapy (RT). This study aimed to determine the maximum-tolerated doses (MTDs) of CDDP and paclitaxel (escalated alternately) when given concurrently with RT and to define the nature of the dose-limiting toxicity (DLT). PATIENTS AND METHODS: Chemotherapy-naive patients with locally advanced NSCLC received six weekly administrations of a CDDP-paclitaxel combination with concurrent local RT. The starting doses of CDDP and paclitaxel were 30 mg/m2/wk and 35 mg/m2/wk, respectively. RT was initially given at the dose of 1.2 Gy twice daily for 5 days per week for 5 weeks (total dose, 60 Gy) and at a single daily dose of 2 Gy for 5 days per week for 6 weeks in the last two cohorts of patients. The drug doses were escalated alternately until DLT occurred in more than one third of the patients in a given cohort. RESULTS: Overall, 25 patients were recruited through five different cohorts. All were assessable for toxicity. Esophagitis was the main toxicity and occurred in 16 of 25 patients (64%) and was grade 3 or 4 in five of them. At step 3 (CDDP 35 mg/m2/wk and paclitaxel 45 mg/m2/wk), two of five patients had to discontinue treatment because of severe esophagitis and one of these died of complications related to grade 4 esophagitis. However, keeping the same doses of chemotherapy and replacing hyperfractionation with a standard single-day fraction, weekly doses of CDDP and paclitaxel of 35 mg/m2 and 45 mg/m2 could be safely administered. Neutropenia was by far the most relevant hematologic toxicity and occurred in 33 of 141 weekly delivered courses, but it was of grade 4 in only four courses. Substantial pulmonary or neurologic toxicity was not observed in this study. Two complete responses (CRs) and 13 partial responses (PRs) were observed, for a 60% overall response rate (95% confidence interval [CI], 39% to 79%). The median survival time was 16 months, with a 66% 1-year survival probability. CONCLUSION: CDDP 35 mg/m2/wk and paclitaxel 45 mg/m2/wk can be safely administered with concurrent standard RT. The use of hyperfractionation is associated with a more frequent occurrence of severe esophagitis and requires a reduction of the CDDP dose to 30 mg/m2/ wk. Only future randomized trials will elucidate which of these two approaches (standard or hyperfractionated RT) is the better option to improve the outcome of patients with locally advanced NSCLC.     

p53 autoantibodies in the sera, cyst and ascitic fluids of patients with ovarian cancer

LY231514 is a novel antifolate that principally inhibits thymidylate synthase, but with additional folate-dependent enzyme targets. A Phase I study of single-agent LY231514 administered as a daily i.v. infusion over 10 minutes for 5 days, repeated every 3 weeks, was conducted to evaluate the maximum tolerated dose, pharmacokinetic profile, and antitumor activity of the drug using this schedule. Thirty-eight patients with advanced malignancies that were refractory or not amenable to standard therapy were treated with a total of 116 courses of LY231514, escalating treatment doses through 10 dose levels, from 0.2-5.2 mg/m2/day. No objective clinical responses were observed, although minor antitumor activity not fulfilling the response criteria was seen in three patients. A maximum tolerated dose of 4.0 mg/m2/day was determined, with neutropenia as the predominant dose-limiting toxicity. Reversible disturbances of liver biochemistry, fulfilling the protocol definitions of dose-limiting toxicity, were also observed. Other toxicities included diarrhea, mucositis, skin rash, and fatigue. Pharmacokinetic studies were performed at all treatment levels. Analysis showed a linear relation between administered dose and both maximum plasma concentration (Cmax) and area under the plasma concentration/time curve. The drug was cleared with a day 1 total body clearance of 108.9 +/- 38.8 ml/min/m2, with plasma concentrations declining with a mean harmonic terminal half-life of 1.4 +/- 0.98 h. When given by this schedule, LY231514 is tolerable, and Phase II studies are in progress.     

Pharmacokinetic re-evaluation and phase I study of high dose epirubicin in advanced non-small cell lung cancer

We performed a phase I trial to evaluate the toxicity and the maximum tolerated dose of high dose epirubicin on a three-consecutive-day schedule on Japanese patients with advanced non-small cell lung cancer. Fourteen patients were entered in the study. At least three patients were assigned to each different dose level. Epirubicin was given intravenously daily for three day by bolus injection. The dose was started at 60 mg/m2/course and escalated by 30 mg/m2/course. Granulocytopenia was found to be the dose limiting toxicity with a maximum tolerated dose of 150 mg/m2/course. Thrombocytopenia and non-hematological toxicities were mild and well tolerated. The maximum tolerated dose was lower than that in Europe and Canada. Partial responses were observed in two out of five patients on 150 mg/m2/course. The recommended phase II dose for high dose epirubicin was demonstrated to be 120 mg/m2/course. A further dose-escalating study of epirubicin in conjunction with the administration of granulocyte colony stimulating factor is scheduled for the determination of its antitumor activity in non-small cell lung cancer.     

Clinical pharmacology of bruceantin by radioimmunoassay

During the phase I clinical trial of a new antitumor agent, bruceantin, the pharmacology was studied in 18 cancer patients. The drug was infused intravenously (IV) for 3 h at doses ranging from 1 to 3.6 mg/m2 per day for 5 days. The plasma drug disappearance curves were biphasic, with a fast initial half-life of less than 15 min. The second half-life (t1/2 beta) varied from 0.7 to 38 h among different patients and was not dose-related. The difference between the t1/2 beta on day 1 and that on day 5 was not significant. In patients with normal liver function, the mean plasma concentration at the end of infusion was 22 ng/ml, and the value of the area under the concentration X time curve (AUC) was 111 (ng/ml)h. In contrast, in patients with abnormal liver function the corresponding values were 115 ng/ml and 830 (ng/ml)h, respectively. In addition, these patients had a slower elimination half-life of 10.9 h and a decreased total clearance of 157 ml/min/m2, as compared with 2.6 h and 671 ml/min/m2, respectively, for the normal group. All these differences were statistically significant. Patients with abnormal liver function developed more severe toxicity, including fever, severe nausea, vomiting, and hypotension. Two patients with severe hepatic dysfunction received a reduced dose and developed no toxicity. These results demonstrated the importance of the effects of liver dysfunction on drug disposition and showed that the dosage should be reduced in patients with hepatic dysfunction.     

Insulin-induced lipohypertrophy treated by liposuction

BACKGROUND: The new intercalative agent Mitonafide was shown in early clinical trials to be toxic to the central nervous system when administered as a short intravenous infusion, but not when given as a 120-hour continuous infusion. Thus, clinical development in different tumor types was pursued using only this administration schedule. PATIENTS AND METHODS: Forty-nine patients with previously untreated non-small cell lung cancer (NSCLC) and at least one measurable site received Mitonafide as a 120-hour continuous (5 days) infusion every 3 weeks. The starting dose was 170 mg/m2/day x 5 in the first 26 patients and 200 mg/m2/day x 5 in the remainder. Patients were evaluated for toxicity after each course and for response every two courses and remained on treatment until excessive toxicity or disease progression were observed. A special test, the "Mini-mental state", was used to assess patients' cognitive functions. RESULTS: Of the 49 patients entered, 42 were evaluable for response and toxicity. Toxicity consisted mainly of myelosuppression and no neurologic side effects were observed. Only one patient presented a partial response. CONCLUSIONS: Although definitively safe with this schedule of administration, Mitonafide is not active in NSCLC.     

Long-term follow-up of a randomized post-induction therapy trial in acute myelogenous leukemia (a Southeastern Cancer Study Group trial)

A phase III clinical trial was designed to determine if more intensive induction and consolidation therapy for acute myeloblastic leukemia increases the remission rate and prolongs survival. A minor objective was to determine if the use of non-cross resistant drugs was more effective than the same drugs used for induction. Patients with untreated leukemia between the ages of 15 and 50 were given daunorubicin 45 mg/m2 for the first 3 days of a 10-day continuous infusion of cytosine arabinoside, initially at a dose of 2000 mg/m2 but reduced to 100 mg/m2 because of toxicity. Those under 36 achieving a complete remission and with an histocompatible donor were assigned to a transplant arm. The rest were randomized to receive one of three consolidation arms: A, cytosine arabinoside, 200 mg/m2 daily for 7 days and daunorubicin 45 mg/m2 daily for 3 days for three courses; B, one course as in Arm A followed by amsacrine, 120 mg/m2 daily for 5 days followed by a 5-day continuous infusion of azacytidine, 150 mg/m2/day; C, thioguanine and cytosine arabinoside, 100 mg/m2 every 12 h and daunorubicin 10 mg/m2 daily for 5 days for three courses followed by four maintenance courses of cytosine arabinoside, 100 mg/m2 daily for 5 days and daunorubicin, 45 mg/m2 for 2 days every 13 weeks. From 1981 to 1986, 398 eligible patients were enrolled and 219 achieved a complete remission. The initial induction dose of cytosine arabinoside was reduced after five of 29 patients exhibited fatal gastrointestinal toxicity. Only 11 patients were assigned to the transplant arm. There were no significant differences in the consolidation arms. The 5 year disease-free survivals were 38, 31 and 27% in arms A, B, and C respectively. Intensive consolidation therapy with the same or different drugs used in induction was as effective as lower dose consolidation followed by maintenance therapy.     

Genetic diversity of nifH gene sequences in paenibacillus azotofixans strains and soil samples analyzed by denaturing gradient gel electrophoresis of PCR-amplified gene fragments

PURPOSE: To determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetic profile of the dolastatin 15 analog LU103793 when administered daily for 5 days every 3 weeks. PATIENTS AND METHODS: Fifty-six courses of LU103793 at doses of 0.5 to 3.0 mg/m2 were administered to 26 patients with advanced solid malignancies. Pharmacokinetic studies were performed on days 1 and 5 of course one. Pharmacokinetic variables were related to the principal toxicities. RESULTS: Neutropenia, peripheral edema, and liver function test abnormalities were dose-limiting at doses greater than 2.5 mg/m2 per day. Four of six patients developed DLT at 3.0 mg/m2 per day, whereas two of 12 patients treated at 2.5 mg/m2 per day developed DLT. Pharmacokinetic parameters were independent of dose and similar on days 1 and 5. Volume of distribution at steady-state (Vss) was 7.6 +/- 2.0 L/m2, clearance 0.49 +/- 0.18 L/h/m2, and elimination half-life (t1/2) 12.3 +/- 3.8 hours. Peak concentrations (Cmax) on day 1 related to mean percentage decrement in neutrophils (sigmoid maximum effect (Emax) model). Patients who experienced dose-limiting neutropenia had significantly higher Cmax values than patients who did not, whereas nonhematologic DLTs were more related to dose. CONCLUSION: The recommended dose for phase II evaluations of LU103793 daily for 5 days every 3 weeks is 2.5 mg/m2 per day. The lack of prohibitive cardiovascular effects and the generally acceptable toxicity profile support the rationale for performing disease-directed evaluations of LU103793 on the schedule evaluated in this study.     

CNS glia are targets for GDNF and neurturin

Carboplatin is one of the most common drugs used for radiochemotherapy of cancer. However, the best way to combine the drug with fractionated radiotherapy has not been established. In the present study the authors investigated which maximum tolerated daily bolus dose of carboplatin would allow safe radiopotentiation for 10 consecutive radiotherapy days, the scheme being repeated twice during the 6 weeks that a conventional radiotherapy scheme lasts. Seventy-two patients with lung or pelvis malignancies were included in a dose escalation study. Twenty-four patients comprised the first baseline cohort and were treated with radiotherapy alone. The daily dose of carboplatin was escalated starting from 38 mg/m2 daily (for 10 days) and increasing by 7 mg/m2 per day. Six patients were to be included in each cohort. All 12 patients treated at the 38 mg/m2 and 45 mg/m2 dose level completed two cycles of 10-day carboplatin treatment with no grade III-IV toxicity. Granulocyte colony-stimulating factor effectively averted the incidence of neutropenia and allowed the administration of the second carboplatin 10-day cycle in five of six patients at the 52 mg/m2 daily dose level. Platelet grade III-IV toxicity was observed in all 12 patients (six supported with granulocyte colony-stimulating factor and six with granulocyte colony-stimulating factor and recombinant human erythropoietin) treated at the 59 mg/m2 daily dose level and none of them received the second cycle of chemotherapy. Twelve patients were treated at the same dose level using amifostine 500 mg before carboplatin infusion. Two patients interrupted chemotherapy because of severe nausea and vomiting. Nine of 10 who accomplished the 10-day treatment had platelet levels more than 90,000/microl on day 28 and completed the second 10-day cycle without severe toxicity. Acute radiation toxicity did not increase in the carboplatin cohorts. In this study the authors established a high-dose fractionated carboplatin schedule that can be safely administered during radical radiotherapy.     

Suppression of renin secretion in the isolated rat kidney by cycloheximide

Because 1,2:5,6-dianhydrogalactitol (NSC-132313 (DAG; the main conversion reaction product of the treatment of dibromodulcitol by mild akali or human serum) showed considerable antitumor activity in various mouse and rat tumor systems, a phase I study in 50 patients was conducted with five daily iv treatments repeated every 6 weeks. Thrombocytopenia was the dose-limiting toxicity. At a dose of 40 mg/m2/day for 5 days, the median platelet nadir was 31,000/mm3 and occurred on day 20; the plate count returned to normal within 8 days. At the same dose, the median white blood cell (WBC) nadir was 2,300/mm3 also on day 20-, the WBC count returned to normal within 7 days. Anemia, nausea, and vomiting were usually mild to moderate. No renal, hepatic, central nervous system, cardiac, or pulmonary toxicity was identified. Antitumor effects of DAG were observed in patients with renal, bladder, and small-cell lung cancers. An iv dose of 20-30 mg/m2/day for 5 consecutive days, repeated every 5-6 weeks, was recommended for phase II studies.     

Loss of biological activity due to Glu-->Arg mutation at residue 11 of the B subunit of cholera toxin

PURPOSE: To determine the maximum tolerated dose, toxicities, and potential antitumor activity of edatrexate (E), an antifolate agent with enhanced in vitro antitumor activity as compared with methotrexate (M), when given in combination with vinblastine, doxorubicin, cisplatin, and filgrastim (G-CSF) to patients with advanced malignancies. PATIENTS AND METHODS: Thirty-seven patients with advanced malignancies were treated with escalating doses of edatrexate in combination with vinblastine (V), doxorubicin (A), cisplatin (C), and filgrastim (EVAC/G-CSF) following three different subsequently developed schedules. Schedule 1 was patterned after the MVAC regimen, a combination chemotherapy program with activity against different epithelial malignancies, and consisted of E, 40 mg/m2/day, days 1/15/22; V, 3 mg/m2/day, days 2/15/22; A, 30 mg/m2/ day, day 2; C, 70 mg/m2/day, day 2; repeated every 28 days. Schedules 2 and 3 were designed to avoid observed dose-limiting toxicity on schedule 1 consisting of transient elevation of serum creatinine levels and delayed myelosuppression. Schedule 2 consisted of E, 40 or 60 mg/ m2/day, days 1 and 15; V, 3 mg/m2/day, days 2 and 15; A, 30 mg/m2/day, day 2; C, 30 mg/m2/day, days 1 and 2; cycled every 28 days. Schedule 3 consisted of E, 60 to 120 mg/m2/day, day 1; V, 3 mg/m2/day, day 2; A, 30 mg/m2/day, day 2; C, 30 mg/m2/day, days 1 and 2; cycled every 21 days. Filgrastim 5 micrograms/kg/day was given to all patients subcutaneously until the absolute neutrophil count was greater than 10,000/microL postnadir. Three patients were treated on schedule 1, 10 on schedule 2 (four at an E dose of 40 mg/m2/day and six at an E dose of 60 mg/m2/day), and 24 on schedule 3 (six at each of the following E dosages: 60, 80, 100, and 120 mg/m2/day). RESULTS: Dose-limiting toxicities of grade 3 to 4 leukopenia and transient elevation of serum creatinine values were observed in two of three patients treated on schedule 1. A dose-limiting toxicity of grade 3 to 4 leukopenia was noted in two of six patients treated on schedule 2 at an edatrexate dose of 60 mg/m2/day. Two of six patients treated on schedule 3 at an edatrexate dose of 120 mg/m2/day had a dose-limiting toxicity of grade 3 stomatitis (one patient) and grade 3 cytopenia (one patient). Nineteen of 37 patients with evaluable or measurable disease had a response to treatment (response rate 51%, 95% confidence intervals = 35%-67%). Nine of 15 patients with metastatic non-small cell lung cancer responded, including one complete remission (response rate 60%, confidence intervals = 35%-85%). A median survival of 517 days (confidence interval = 163-808 days) and a 1-year survival rate of 60% (confidence interval = 35%-85%) was seen in patients with advanced non-small cell lung cancer. CONCLUSIONS: The maximum tolerated dose and the recommended phase II dose of edatrexate is 100 mg/m2/day when administered as part of the EVAC/G-CSF program following schedule 3. Promising antineoplastic activity against non-small cell lung carcinomas was observed, and a phase II study is planned.     

Phase I study of docetaxel dose escalation in combination with fixed weekly gemcitabine in patients with advanced malignancies

PURPOSE: To determine the maximum-tolerated dose of monthly docetaxel combined with fixed-dose weekly gemcitabine and describe the dose-limiting toxicities (DLTs) of the combination. PATIENTS AND METHODS: Patients with refractory solid tumors were treated with gemcitabine days 1, 8, and 15 every 4 weeks at a fixed dose of 800 mg/m2. Two docetaxel administration schedules were studied, with the drug administered either day 1 or day 15 at doses of 45, 60, 75, and 100 mg/m2 per cycle. RESULTS: Forty patients received 132 cycles of chemotherapy. On the day-1 schedule, the maximum-tolerated docetaxel dose was the highest planned dose of 100 mg/m2 with two DLT episodes among 12 patients treated with 34 cycles at this dose level. On the day-15 schedule, delivery of the planned docetaxel doses was not feasible because of thrombocytopenia and hepatic dysfunction. Hematologic toxicities included grade 4 neutropenia in 16 patients, with three episodes of febrile neutropenia; grades 3 to 4 thrombocytopenia in nine patients; and anemia that required RBC transfusions in 10 patients. For patients treated at the highest docetaxel dose level, myelosuppression was not dose limiting and only one of 34 cycles was complicated by febrile neutropenia. The most common nonhematologic toxicities were asthenia, flu-like symptoms, and fluid retention. Antineoplastic activity was noteworthy, with partial responses in nine of 21 patients with pretreated non-small-cell lung cancer (NSCLC; 43%; 95% confidence interval, 22 to 66), in four of seven patients with breast cancer, and in one patient with esophageal adenocarcinoma. CONCLUSION: Gemcitabine 800 mg/m2 days 1,8, and 15 can be safely combined with docetaxel 100 mg/m2 day 1 of a 28-day cycle. The observed antitumor activity warrants phase II evaluation.     

Mineral waters: instead of soap or better than soap?

Prolonged oral etoposide is an active regimen in small and nonsmall cell carcinoma of the lung, carcinomas of the breast and ovary, germ cell tumors, and in lymphoma. A Phase II trial was conducted by the Gynecologic Oncology Group to determine its activity in endometrial carcinoma. Twenty-six patients with advanced or recurrent endometrial carcinoma were entered into study; one patient was ineligible because of an incorrect cell type. The remaining eligible patients were treated with etoposide at a starting dose of 50 mg/m2/day (30 mg/m2/day with prior radiotherapy) for 21 days. Based on hematologic toxicity, a dose escalation to a maximum dose of 60 mg/m2/day was prescribed. Twenty-two patients were evaluable for response and 25 were evaluable for toxicity. Fourteen had received prior radiotherapy and 24 had received prior chemotherapy. A median of two courses were given (range, 1-10). Grade 3 or 4 leukopenia occurring in 52% was the most common complication (grade 3, 36%; grade 4, 16%). Grade 4 thrombocytopenia occurred in 16% of patients. There were no objective responses including four patients with serous papillary carcinoma. This regimen is not significantly active as second-line therapy in endometrial carcinoma.     

A phase I-II study of paclitaxel, ifosfamide, and vinorelbine with filgrastim (rhG-CSF) support in advanced non-small-cell lung cancer

PURPOSE: We designed a phase I-II trial of three active agents, paclitaxel, ifosfamide, and vinorelbine, in advanced non-small-cell lung cancer (NSCLC) to: 1) define the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) of paclitaxel with filgrastim (G-CSF) support; and 2) determine the overall response rate and median survival of patients treated on this regimen. PATIENTS AND METHODS: We treated cohorts of patients with stage IIIB or IV NSCLC with ifosfamide 1.2-1.6 g/m2/day x 3 and vinorelbine 20-25 mg/m2/day x 3 and escalating doses of paclitaxel at 100-175 mg/m2 on day 2 with G-CSF support on a 21-day cycle. One prior experimental single-agent chemotherapy regimen was allowed. RESULTS: Fifty-six patients, were enrolled on this trial: 27 on the phase I portion of the study and an additional 29 at the recommended phase II dose (RPTD). Thirteen patients had received prior chemotherapy. Paclitaxel doses of 175 mg/m2 and 150 mg/m2 produced dose-limiting myelosuppression, and the RPTD was determined to be paclitaxel 135 mg/m2 with ifosfamide 1.2 g/m2/day on days 1-3 and vinorelbine 20 mg/m2/ day on days 1-3 with G-CSF support. The overall response rate was 18%, with a median survival of 6.1 months. Six of 35 patients (17%) treated at the RPTD achieved a partial response to therapy. Grade IV neutropenia was observed in 19 of 35 patients at this dose, with eight patients suffering febrile neutropenia. CONCLUSIONS: This non-cisplatin-containing three-drug regimen has substantial toxicity and low activity in advanced NSCLC, and does not seem to improve on prior regimens. It is unclear whether the lack of efficacy relates to an antagonistic reaction between the specific drugs, administration schedule, or to subtherapeutic doses of the individual agents.     

Southwest Oncology Group phase II trial of concurrent carboplatin, etoposide, and radiation for poor-risk stage III non-small-cell lung cancer

PURPOSE: A phase II study was conducted by the Southwest Oncology Group (SWOG) to assess the efficacy and toxicity of concurrent carboplatin, etoposide, and thoracic radiation (XRT) in a defined population of poor-risk patients with stage III non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with stage III NSCLC were eligible if they were excluded from cisplatin-based protocols because of poor pulmonary or renal function, history of congestive heart failure, hearing loss, peripheral neuropathy, or weight loss. Carboplatin 200 mg/m2 daily intravenously days 1, 3, 29, and 31 and etoposide 50 mg/m2 daily intravenously days 1 through 4 and 29 through 32 were administered. Beginning day 1, XRT was delivered at 1.8 to 2.0 Gy daily to a total dose of 61 Gy. RESULTS: Within a period of 1 year, 63 patients were registered and 60 were eligible. Patient characteristics were age 47 to 79 years, performance status 0 to 1 (82%) and 2 (18%), and stages IIIA (60%) and IIIB (40%) NSCLC. The most common grades 3 and 4 toxicities included leukopenia (50%), thrombocytopenia (23%), and esophagitis (15%). There were no treatment-related deaths. The overall confirmed response rate was 29%, and median overall survival was 13 months (95% confidence interval, 11 to 14 months). The 2-year survival rate was 21%. CONCLUSION: This chemoradiotherapy regimen is well tolerated in poor-risk patients and yields a median survival similar to that of good-risk patients who received cisplatin-based chemoradiotherapy. This chemoradiotherapy regimen will be compared with XRT alone in poor-risk patients with stage III NSCLC in a randomized phase III trial.     

Paclitaxel by 96-hour continuous infusion in combination with cisplatin: a phase I trial in patients with advanced lung cancer

PURPOSE: To determine the maximum-tolerated dose (MTD) of paclitaxel administered by 96-hour continuous infusion in combination with cisplatin, to determine if the addition of granulocyte colony-stimulating factor (G-CSF) permits significant paclitaxel dose escalation, and to assess the toxicity and preliminary activity of this combination in patients with advanced lung cancer. PATIENTS AND METHODS: Fifty patients with untreated lung cancer were enrolled: 42 had advanced non-small-cell lung cancer (NSCLC) and eight had extensive-stage small-cell lung cancer (SCLC). Patients received paclitaxel doses of 100 to 180 mg/m2/96 hours and cisplatin doses of 60 to 80 mg/m2 as a single 30-minute bolus injection at the end of the paclitaxel infusion. RESULTS: Two of six patients experienced dose-limiting neutropenia at a dose of paclitaxel 140 mg/m2/96 hours and cisplatin 80 mg/m2. With G-CSF support, one of three patients experienced both dose-limiting mucositis and fatal neutropenic sepsis at a dose of paclitaxel 180 mg/m2/96 hours and cisplatin 80 mg/m2. Significant peripheral neuropathy developed in five patients and occurred after six or more cycles of therapy. Thirty-three of 42 patients with NSCLC had measurable disease; the objective response rate was 55%, with two complete responses and 16 partial responses. For all 42 patients with NSCLC, the median time to progression and median survival duration were 5 months and 10 months, respectively. The actuarial 1-year survival rate was 41%. Of eight SCLC patients, four responded to therapy, and the median survival duration for all SCLC patients was 11 months. CONCLUSION: The MTD without G-CSF is paclitaxel 120 mg/m2/96 hours and cisplatin 80 mg/m2, and the MTD with G-CSF is paclitaxel 160 mg/m2/96 hours and cisplatin 80 mg/m2. Infusional paclitaxel with cisplatin is well tolerated and active in patients with advanced NSCLC.     

Five days of oral topotecan (Hycamtin), a phase I and pharmacological study in adult patients with solid tumours

Topotecan is a specific inhibitor to topoisomerase I. An oral formulation of topotecan is available with a bioavailability of 32-44% in humans. A phase I and pharmacological study of the oral formulation of topotecan administered daily for 5 days every 21 days was performed in adult patients with solid tumours to determine the maximum tolerated dose (MTD). Adult patients with a WHO performance status < or = 2 adequate haematological, hepatic and renal functions, with malignant solid tumours refractory to standard forms were entered into the study. Pharmacokinetics were performed on days 1 and 4 of the first course using a validated high performance liquid chromatographic assay. 29 patients entered the study, all patients were evaluable for toxicity and response. The doses studied in the 29 patients were 1.2, 1.8, 2.3, 2.7 mg/m2/day and a fixed dose of 4 mg/day without surface area adjustment. A total of 109 courses were given. Dose limiting toxicity (DLT) was reached at a dose of 2.7 mg/m2/day and consisted of CTC (NCI-Common Toxicity Criteria) grade IV granulocytopenia. The regimen was well tolerated. Non-haematological toxicities were mild, including fatigue, anorexia, nausea, vomiting and diarrhoea. A significant correlation was observed between the percentage decrease in white blood cells versus the area under the curve (AUC(t)) of topotecan lactone (R = 0.76 P < 0.01) which was modelled by a sigmoidal Emax function. The correlation coefficient between the absolute topotecan dose administered and the AUC(t) was R = 0.52 (P = 0.04). Pharmacokinetics of the fixed dose of 4 mg/day were comparable to the 2.3 mg/m2/day dose. DLT in this phase I study of five daily doses of oral topotecan every 21 days was granulocytopenia. The recommended dose for phase II studies is 2.3 mg/m2/day or alternatively, a fixed dose of 4 mg/day.     

Phase I study of cyclophosphamide (NSC 26271) by 72-hour continuous intravenous infusion

A phase I clinical study of cyclophosphamide administered by 72-hour continuous intravenous infusion was conducted in 13 patients with various types of advanced solid tumors to evaluate the drug's toxicity and efficacy. The initial dosage of 300 mg/m2/day X 3 days repeated at 3-week intervals was progressively increased by 150 mg/m2/day-increments to a maximum dosage of 750 mg/m2/day. The dose-limiting toxicities were hematologic and gastrointestinal. Neutropenia was more severe than was thrombocytopenia. The lowest granulocyte count less than 500/mm3 occurred during more than half of the treatment courses at doses of 600 mg/m2 and higher. Severe nausea and vomiting were observed in patients during three of four treatment courses at the 750 mg/m2 dose level. None of the patients had microscopic hematuria or symptoms suggestive of cystitis. Partial response occurred in a patient with parotid cancer metastatic to the lung. Disease stabilization occurred in four patients, while six patients had progression of disease. The recommended starting dosage of cyclophosphamide by continuous intravenous infusion for phase II trials is 600 mg/m2/day X 3 every 3 weeks for patients with good bone marrow reserve.     

Phase I clinical and pharmacokinetic study of titanocene dichloride in adults with advanced solid tumors

This Phase I dose-escalation clinical trial of a lyophilized formulation of titanocene dichloride (MKT4) was conducted to determine the maximum tolerated dose, the dose-limiting toxicity (DLT), and pharmacokinetics of titanium (Ti) after a single i.v. infusion of MKT4. Forty patients with refractory solid malignancies were treated with a total of 78 courses. Using a modified Fibonacci scheme, 15 mg/m2 initial doses of titanocene dichloride were increased in cohorts of three patients up to level 11 (560 mg/m2) if DLT was not observed. The maximum tolerated dose was 315 mg/m2, and nephrotoxicity was DLT. Two minor responses (bladder carcinoma and non-small cell lung cancer) were observed. The pharmacokinetics of plasma Ti were assessed in 14 treatment courses by atomic absorption spectroscopy. The ratio for the area under the curve(0-infinity) in plasma and whole blood was 1.2. The following pharmacokinetic parameters were determined for plasma, as calculated in a two-compartment model: biological half-life t1/2beta in plasma was 22.8+/-11.2 h (xh +/- pseudo-SD), peak plasma concentration cmax approximately 30 microg/ml at a dose of 420 mg/m2, distribution volume Vss= 5.34+/-2.1 L (xa +/- SD), and a total clearance CItotal = 2.58+/-1.23 ml/min (xa +/- SD). There was a linear correlation between the area under the curve(0-infinity) of Ti in plasma and the titanocene dichloride dose administered with a correlation coefficient r2 of 0.8856. Plasma protein binding of Ti was in the 70-80% range. Between 3% and 16% of the total amount of Ti administered were renally excreted during the first 36 h. The recommended dose for Phase II evaluation is 240 mg/m2 given every 3 weeks with i.v. hydration to reduce renal toxicity.     

VRCTC-310--a novel compound of purified animal toxins separates antitumor efficacy from neurotoxicity

Two purified animal venom toxins, crotoxin and cardiotoxin, have been combined to produce a unique natural product (VRCTC-310) currently under investigation as an antitumor agent by the National Cancer Institute. In vitro, it has demonstrated cytotoxic disease specificity and a unique mechanism of action when submitted to COMPARE analysis. In vivo, tolerance was developed to the neurotoxic properties of crotoxin which allowed comparison of several schedules of fixed and escalating daily i.m. doses to mice bearing s.c. Lewis Lung carcinoma. An 83% inhibition of tumor growth was achieved using an escalating dose schedule starting at 1.8 mg/kg and reaching 6.3 mg/kg/day on day 20. Although some irritation around the sites of i.m. injection was noted, animal weight loss was negligible and there were no other signs of adverse toxicity. This natural product represents a new, membrane interactive anticancer agent which produces a unique spectrum of cytotoxicity in vitro and which has demonstrated interesting in vivo antitumor efficacy.     

Phase I trial of temozolomide (NSC 362856) in patients with advanced cancer

Temozolomide (TMZ) is a new imidazotetrazine derivative with early clinical activity in glioma and melanoma. The purpose of this Phase I study is to characterize the toxicity, pharmacokinetics, and antitumor activity of TMZ administered on an oral 5-day schedule to patients with or without prior exposure to nitrosourea (NU). Thirty-six eligible patients received a total of 77 cycles of therapy with TMZ administered p.o. at doses ranging from 50 mg/m2/day to 250 mg/m2/day for 5 days, every 4 weeks. Separate dose escalations were carried out in patients, with or without prior exposure to NU. Pharmacokinetic studies were performed during the first cycle of treatment on days 1 and 5. Dose-limiting toxicity was thrombocytopenia, and the maximally tolerated doses for patients with and without prior exposure to NU were 150 mg/m2/day for 5 days (total dose, 750 mg/m2) and 250 mg/m2/day for 5 days (total dose, 1250 mg/m2), respectively. Significant (grade 3 or higher) thrombocytopenia was observed in six patients during cycle 1. The median times to nadir and recovery were 17 and 15 days, respectively. Nonhematological toxicity was generally manageable and consisted of fatigue, nausea, and vomiting. There were two complete responses (one glioma and one melanoma) in patients without prior NU. No objective responses were seen in patients with prior NU treatment. Pharmacokinetic studies showed rapid absorption with a mean time to peak concentration of 60 min and mean t1/2 of 109 min (range, 80-121 min). The area under the curve and the peak plasma concentrations were linear over the dose range of 50-250 mg/m2/day. The mean apparent oral clearances on day 1 for patients with and without prior NU exposure were 102+/- 27 and 115+/- 22 ml/min/m2, respectively. Apparent oral clearances on days 1 and 5 were found to differ with respect to NU exposure (P = 0.047). Renal clearance of the parent drug and its metabolism to 3-methyl-2, 3-dihydro-4-oxoimidazo[5,1-d]tetrazine-8-carboxylic acid were minor pathways of TMZ elimination. We conclude that TMZ is well tolerated in this oral 5-day schedule with dose-limiting thrombocytopenia and that it has promising activity in glioma and melanoma. The recommended doses for Phase II studies in patients with and without prior NU are 125 mg/m2/day for 5 days and 225 mg/m2/day for 5 days, respectively.