Phase I safety, pharmacokinetic and pharmacodynamic trial of BMS-599626 (AC480), an oral pan-HER receptor tyrosine kinase inhibitor, in patients with advanced solid tumors.

PURPOSE: We studied the safety, tolerability, and recommended dose of BMS-599626, an orally bioavailable inhibitor of the human epidermal growth factor receptor (HER) family of receptor tyrosine kinases. PATIENTS AND METHODS: Patients with advanced solid tumors that expressed epidermal growth factor receptor (EGFR) and/or HER-2 were recruited and enrolled in a phase I, open-label, dose escalation trial of oral BMS-599626 starting at 100 mg/day given once daily for at least 28 days. RESULTS: Forty-five patients received BMS-599626 (100-660 mg/day). Dose-limiting toxic effects were reported at 660 mg/day (grade 3 elevation of hepatic transaminases [two patients] and QTc interval prolongation [one patient]), therefore the recommended maximum tolerated dose was 600 mg/day. The most frequent drug-related toxic effects were diarrhea (30% of patients), anorexia (13%), asthenia (30%), and cutaneous toxic effects, including skin rash (30%). Pharmacokinetic analysis demonstrated C(max) and exposure to BMS-599626 in patients increased with dose. Eleven patients had stable disease and received BMS-599626 for ≥ 4 months. Serial skin and tumor biopsies taken before and after treatment revealed expected changes in pharmacodynamic biomarkers, indicating that the EGFR and HER-2 pathways were affected. Positron emission tomography imaging showed a metabolic response in 2 of 10 patients evaluated. CONCLUSION: BMS-599626 was generally well tolerated, with disease stabilization across a range of tumor types and doses.

Sequential research-related biopsies in phase I trials: acceptance, feasibility and safety.

BACKGROUND: Sequential tumour biopsies are of potential interest for the rational development of molecular targeted therapies. PATIENTS AND METHODS: From June 2004 to July 2009, 186 patients participated in 14 phase I clinical trials in which sequential tumour biopsies (13 trials) and/or sequential normal skin biopsies (6 trials) were optional. All patients had to sign an independent informed consent for the biopsies. RESULTS: Tumour biopsies were proposed to 155 patients and 130 (84%) signed the consent while normal skin biopsies were proposed to 70 patients and 57 (81%) signed the consent. Tumour biopsies could not be carried out in 41 (31%) of the 130 consenting patients. Tumour biopsies were collected at baseline in 33 patients, at baseline and under treatment in 56 patients. Tumour biopsies were obtained using an 18-gauge needle, under ultrasound or computed tomography guidance. Only nine minor complications were recorded. Most tumour biopsy samples collected were intended for ancillary molecular studies including protein or gene expression analysis, comparative genomic hybridization array or DNA sequencing. According to the results available, 70% of the biopsy samples met the quality criteria of each study and were suitable for ancillary studies. CONCLUSIONS: In our experience, the majority of the patients accepted skin biopsies as well as tumour biopsies. Sequential tumour and skin biopsies are feasible and safe during early-phase clinical trials, even when patients are exposed to anti-angiogenic agents. The real scientific value of such biopsies for dose selection in phase I trials has yet to be established.

Phase I dose-escalating study of ES-285 given as a three-hour intravenous infusion every three weeks in patients with advanced malignant solid tumors.

BACKGROUND: ES-285 (spisulosine) is a novel compound derived from the marine mollusk Spisula polynoma with evidence of preclinical antitumor activity. This phase I clinical trial was designed to identify the maximum tolerated dose (MTD) and the recommended dose for phase II trials (RD), as well as to evaluate the safety profile, pharmacokinetics and preliminary efficacy data of ES-285 in patients with advanced solid tumors. PATIENTS AND METHODS: Sixty-one patients at two medical institutions were treated with a 3-h ES-285 intravenous infusion every 3 weeks. Nine dose levels were evaluated. RESULTS: No dose-limiting toxicities (DLTs) were observed during dose escalation from 4 to 128 mg/m(2). Six patients had seven DLTs at the three highest dose levels tested: 256 mg/m(2) (n = 2), 200 mg/m(2) (n = 3) and 160 mg/m(2) (n = 1). Grade 3/4 transaminase increases (n = 3), grade 3/4 central nervous system disorders [confusion (n = 2) and ataxia (n = 1)], and grade 3 pyrexia (n = 1) were the dose-limiting toxicities found with this ES-285 administration schedule. Pharmacokinetic analysis showed ES-285 dose linearity, wide distribution and a long half-life. One non-confirmed partial response was observed in a patient with metastatic melanoma treated with ES-285 128 mg/m(2), and 18 patients showed stable disease at different dose levels, lasting longer than 3 months in six patients. CONCLUSION: Dose level VIII (200 mg/m(2)) was considered the MTD, and dose level IX (160 mg/m(2)) was defined as the RD. Limited antitumor activity was observed.

A phase I, dose-finding study of sunitinib in combination with irinotecan in patients with advanced solid tumours.

BACKGROUND: Sunitinib is a multitargeted, oral tyrosine kinase inhibitor with antitumour and antiangiogenic activity. We investigated the safety and pharmacokinetics of sunitinib in combination with irinotecan in patients with advanced, refractory solid tumours. METHODS: Sunitinib was initially administered once daily at 37.5 mg per day on days 1-14 of a 21-day cycle, in which irinotecan 250 mg m(-2) was given on day 1. In a second cohort, the sunitinib dose was reduced to 25 mg per day. Blood samples were collected for pharmacokinetic studies. RESULTS: In the sunitinib 37.5 mg per day cohort, 3 out of 10 evaluable patients had objective responses, but dose-limiting toxicities (DLTs) of neutropenia, pneumococcal sepsis, and fatigue were observed. There were no DLTs in the sunitinib 25 mg per day cohort. Paired observations of pharmacokinetic parameter values of sunitinib and irinotecan alone vs the combination did not reveal significant drug-drug interactions. The maximum tolerated dose was defined as sunitinib 25 mg per day (days 1-14) with irinotecan 250 mg m(-2) (day 1), but no activity was observed at this dose. CONCLUSION: Although a higher sunitinib dose of 37.5 mg per day (days 1-14) with irinotecan showed preliminary evidence of antitumour activity, this dose was poorly tolerated. Therefore, this particular combination will not be pursued for further studies.

Inhibition of cellular mediated immunity in marihuana smokers.

The cellular mediated immunity of 51 young chronic marihuana smokers. as evaluated by the lyomphocyte response in vitro to allogeneic cells and to phytohemagglutinin, was significantly decreased and similar to that of patients in whom impairment of T (thymus derived) cell immunity is known to occur. This inhibition of blastogenesis might be related to an impairment of DNA synthesis.

Treatment outcome and survival in participants of phase I oncology trials carried out from 2003 to 2006 at Institut Gustave Roussy.

BACKGROUND: The oncology community usually perceives phase I oncology trials as associated with poor or limited benefits and substantial risks. There is scarce data concerning outcome and survival of patients enrolled in current phase I oncology trials. PATIENTS AND METHODS: We reviewed all phase I oncology trials conducted by investigators from the Adult Phase I Unit at Institut Gustave Roussy from 2003 to 2006. We report data concerning patient demographics, treatment outcome, toxicity, survival and type of care after trial exit. RESULTS: We analyzed 10 trials involving 180 participants. The overall response rate was 7.2%. Disease control (objective response plus stable disease) was achieved in 48.2% of patients. The rate of toxic death was 0.5%. In all, 38% of patients had at least one episode of grade 3 or 4 toxic events. The median progression-free survival and the median overall survival (OS) were 2.3 and 8.7 months, respectively. On multivariate analysis, a time between diagnosis of disease and inclusion in the phase I trial > or =24 months and evidence of disease control were statistically significant predictors of improved OS. CONCLUSION: Current phase I oncology trials are safe and are associated with clinical benefit in a substantial proportion of patients.

Irinotecan (CPT-11) high-dose escalation using intensive high-dose loperamide to control diarrhea.

BACKGROUND: Diarrhea is a serious side effect that may prevent the administration of high doses of the antitumor drug Irinotecan (CPT-11). PURPOSE: Intensive, high-dose loperamide was used in an attempt to control or downstage CPT-11-induced diarrhea and thus permit the use of higher dose intensities of CPT-11. METHODS: Twenty-three patients with various cancers were treated with doses of CPT-11 ranging from 400 to 600 mg/m2, administered as a 30-minute intravenous infusion every 3 weeks. Starting 8 hours or more after the administration of CPT-11, any episode of diarrhea was treated with 2 mg of loperamide taken every 2 hours. Patients stopped taking loperamide only after a 12-hour diarrhea-free period. If diarrhea was not controlled after 3 consecutive days of nonstop loperamide intake, or if the patient was dehydrated, loperamide was stopped and the patient was hospitalized for intravenous fluids. If blood or mucus were found in the stools at any time during diarrhea, loperamide was stopped and the patient was hospitalized. RESULTS: Seventeen of 23 patients had diarrhea while on CPT-11 treatment. Eighty-two CPT-11 cycles were administered to these 17 patients, and diarrhea occurred in 49 of these cycles, at a median time-to-onset of 6 days after CPT-11 administration. The loperamide protocol was followed in 46 of the 49 episodes of diarrhea, with 21 capsules of loperamide the median number being taken (range, 5-72). Only one patient was hospitalized for failure to respond to loperamide, and no major toxicity was associated with loperamide use. Fourteen of the 17 patients who experienced diarrhea were rechallenged with CPT-11 three or more times, and seven patients six or more times. CONCLUSIONS: High-dose loperamide controlled diarrhea in patients receiving CPT-11 and allowed administration of higher doses of CPT-11. IMPLICATIONS: The effectiveness of CPT-11 might be increased by higher dose intensities, which can be made tolerable by control of diarrhea with loperamide.

Pharmacological and preclinical toxicological studies of 1,2-diaminocyclohexane(isocitrato)platinum(II).

The antitumor activity of a new highly water-soluble platinum derivative, (1,2-diaminocyclohexane)(isocitrato)platinum(II) (NSC 350602; PHIC), was studied in L1210 leukemia cells inoculated into mice. PHIC was found to be active for i.p. graft-i.p. treatment, i.p. graft-i.v. treatment, and i.v. graft-p.o. treatment. A significant activity was observed on early and advanced L1210 leukemia even when the treatment was delayed 6 days after the graft. A comparison between the activities of PHIC, cisplatin (NSC 119875), and (4-carboxyphthalato)(1,2-diaminocyclohexane)-platinum(II) (NSC 271674; DACCP) for i.p. graft-i.p. treatment indicated that the highest activity was observed for divided doses rather than single dose in the case of PHIC and DACCP and not for cisplatin. Under these conditions, PHIC gave larger treated versus control survival time values or a greater number of surviving animals than did cisplatin and DACCP. No cross-resistance between PHIC and cisplatin could be detected in L1210 leukemia cells resistant to cisplatin. Mutagenicity studies on Salmonella typhimurium revealed that PHIC is far less mutagenic than cisplatin on TA100 and TA98 strains. Other pharmacological parameters, such as growth inhibition rate of cultured L1210 cells, penetration, and DNA binding in L1210 cells inoculated in mice, were compared for PHIC and cisplatin together with their in vitro rates of hydrolysis and platinum:DNA adducts. No nephrotoxicity was detected with PHIC at the maximum nonlethal dose level in mice in contrast to results with cisplatin. A preclinical study was conducted in baboons at 100, 150, and 200 mg/kg. No nephrotoxicity could be detected at a dose of 100 mg/kg without prehydration for six courses at 3-week intervals. At 200 mg/kg, an increase of blood creatinine was controlled by prehydration. Gastrointestinal toxicity was mild during the three regimens. Phase I clinical trials are under way.

Quantitative mapping of 4'-iododeoxyrubicin in metastatic squamous cellcarcinoma by secondary ion mass spectrometry (SIMS) microscopy.

Secondary ion mass spectrometry microscopy enables quantitative mapping of chemical elements in tissue sections. It was used for the detection of 127I contained in 4'-iododeoxyrubicin (IDX). Metastatic cutaneous squamous cell carcinoma from 7 patients participating in a phase I study (IDX dose, 80 mg/m2, 10-min i.v. infusion) were biopsied 10 min after drug administration and compared to 3 controls who did not receive any treatment (one squamous cell carcinoma and 2 gastric carcinomas). Biopsy specimens were fixed and embedded in methacrylate resin. Then, serial semithin sections (3 microns) were analyzed simultaneously with ionic and optimal microscopes in order to identify the histological structures given by the 31P distribution in which 127I in IDX was mapped. The iodine signal was undetected in controls and found mainly in the nuclei of tumor cells of the treated patients. Its concentration, measured in at least 30 nuclei of each specimen, was undetectable in 8% of the nuclei and 91% of them were within 1 and 16 ng/mg. The mean concentration of each specimen ranged from 5 to 23 ng/mg. This study demonstrates the capacity of ion microscopy to localize a cytotoxic drug (IDX) in a human biopsy specimen without the need for radioactive labeling and enables the evaluation of drug penetration in cancer cells which is critical for its activity.

Evidence for the importance of 5'-deoxy-5-fluorouridine catabolism in humans from 19F nuclear magnetic resonance spectrometry.

The use of a new methodology, 19F nuclear magnetic resonance, has allowed detection of all the fluorinated metabolites in the biofluids of patients treated with 5'-deoxy-5-fluorouridine (5'-dFUrd) injected i.v. at a dose of 10 g/m2 over 6 h. This technique, which requires no labeled drug, allows a direct study of the biological sample with no need for extraction or derivatization and a simultaneous identification and quantitation of all the different fluorinated metabolites. As well as the already known metabolites, unmetabolized 5'-dFUrd, 5-fluorouracil, and 5,6-dihydro-5-fluorouracil, the presence of alpha-fluoro-beta-ureidopropionic acid, alpha-fluoro-beta-alanine (FBAL), N-carboxy-alpha-fluoro-beta-alanine, and the fluoride anion F- is reported. The catabolic pathway proposed for 5'-dFUrd is analogous to that of 5-fluorouracil, completed with FBAL----F- step, and the plasmatic equilibrium of FBAL with N-carboxy-alpha-fluoro-beta-alanine, its N-carboxy derivative. The quantitative analysis of the different metabolites found in plasma and urine emphasizes the significance of the catabolic pathway. High concentrations of alpha-fluoro-beta ureidopropionic acid and FBAL are recovered in plasma from 3 h after the beginning of the perfusion to 1 h after its end. The global urinary excretion results show that there is a high excretion of 5'-dFUrd and metabolites. Unchanged 5'-dFUrd and FBAL are by far the major excretory products and are at nearly equal rates. The protocol followed in this study produces relatively low but persistent plasmatic concentrations of 5-fluorouracil throughout the perfusion.

Immune-related adverse events with immune checkpoint blockade: a comprehensive review.

Cancer immunotherapy is coming of age; it has prompted a paradigm shift in oncology, in which therapeutic agents are used to target immune cells rather than cancer cells. The first generation of new immunotherapies corresponds to antagonistic antibodies that block specific immune checkpoint molecules cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death protein (PD-1) and its ligand PD-L1. Targeting these checkpoints in patients living with cancer had led to long-lasting tumour responses. By unbalancing the immune system, these new immunotherapies also generate dysimmune toxicities, called immune-related adverse events (IRAEs) that mainly involve the gut, skin, endocrine glands, liver, and lung but can potentially affect any tissue. In view of their undisputed clinical efficacy, anti-CTLA-4 and anti-PD-1 antibodies are entering in the routine oncological practice, and the number of patients exposed to these drugs will increase dramatically in the near future. Although steroids can be used to treat these IRAEs, the associated immunosuppression may compromise the antitumour response. Oncologists must be ready to detect and manage these new types of adverse events. This review focuses on the mechanisms of IRAE generation, putative relationship between dysimmune toxicity and antitumour efficacy, as a basis for management guidelines.

High incidence of p53 alterations (mutation, deletion, overexpression) in head and neck primary tumors and metastases; absence of correlation with clinical outcome. Frequent protein overexpression in normal epithelium and in early non-invasive lesions.

We have analysed 78 head and neck carcinomas (50 node metastases and 28 primary tumors including 13 matched specimens) in 65 patients for p53 alterations. Mutations were found in 54 (69%) tumors. Of the 53 mutations within exons, 40 (76%) were missense, five (9%) nonsense and eight (15%) microdeletions or microinsertions. Twenty-five (47%) mutations were transitions mostly G-->A (40%) and 20 (38%) were transversions, mostly G-->T (25%), thus confirming the role of tobacco carcinogens in the induction of these mutations. The incidence of mutations was not different in primary tumors (68%) and node metastases (70%) indicating that this gene alteration was not related to the metastatic dissemination. For eight patients, mutations were observed in matched primary tumors and metastases, indicating clonal dissemination of tumor cells in most of these carcinomas. There was a good correlation between mutations and protein overexpression (Fisher's exact test P < 10(-4). Immunostaining was also observed in basal cells from normal epithelium and in early lesions adjacent to the primary tumor in 11/15 (73%) specimens irrespective of the presence of mutation in the corresponding tumors. These data confirm that p53 overexpression is an early event in the multistep process of epithelial cell carcinogenesis. Loss of heterozygosity for the TP53 locus was detected in 54% of tumors but no association was found with mutation (Fisher's exact test P = 0.14). No mdm-2 amplification was detected in any tumors. No correlation was found between mutation and clinical parameters, the 5-year survival rates were not different (log rank test P = 0.39) in patients with and without mutation. In conclusion, we have shown that p53 gene mutations and deletions and protein overexpression are frequent in the most aggressive head and neck carcinomas but are not associated with disease progression. The presence of protein in normal mucosa and in non-invasive lesions may constitute a biomarker for early stages of carcinogenesis.

Pharmacokinetics and metabolism of 4'-iodo-4'-deoxy-doxorubicin in humans.

PURPOSE: 4'-iodo-4'-deoxydoxorubicin is a new anthracycline that currently is under clinical evaluation. To improve the management of future trials, we have determined its pharmacokinetics and metabolism during a phase I/II study and have tried to relate the parameters obtained to the hematologic toxicity of the drug in terms of the survival of blood cells. PATIENTS AND METHODS: The pharmacologic study included 19 patients who were entered at dose levels that ranged between 6 and 90 mg/m2; nine patients were treated at 80 mg/m2, which is close to the maximum recommended dose level. Blood sampling was performed from the end of the bolus infusion to 48 hours after treatment. Drug and metabolites were extracted and analyzed by high-performance liquid chromatography (HPLC), and the data were processed by nonlinear fitting to multicompartment models. RESULTS: Plasma concentrations were best fitted to a three-compartment model with half-lives of 5.2 minutes, 0.79 hours, and 10.3 hours. The total body clearance and volume of distribution at steady state were high (350 L/h/m2 and 2,065 L/m2). The drug was metabolized extensively to a 13-dihydroderivative, 4'-iodo-4'-deoxy-doxorubicinol; the mean area under the curve (AUC) ratio metabolite/parent drug was the highest observed ever for an anthracycline (12.1 +/- 7.4); the metabolite was cleared from the plasma with an elimination half-life of 15.3 hours. The AUCs of the parent compound and its metabolite were related linearly to the dose administered, and showed no saturation phenomenon. Urinary excretion was studied in nine patients and showed a cumulative elimination of less than 6% of the dose administered, two thirds of which were eliminated in the first 12 hours after injection. Ninety-three percent to 100% of the elimination of fluorescent compounds occurred in the form of the metabolite. Drug concentration in five tumor samples showed a rapid uptake of the drug from plasma and a preferential uptake of the parent drug compared with the metabolite. Blood cell counts after 4'-iodo-4'-deoxydoxorubicin treatment showed significant correlations among the surviving fractions of both granulocytes and platelets and the AUCs of the parent drug and its metabolite; the most significant correlations were obtained for the granulocytes and the metabolite. Significant correlations between AUCs and blood-cell survivals were maintained, even if only the nine patients treated at the dose of 80 mg/m2 were taken into account for the computation. CONCLUSIONS: Our results especially show that myelosuppression that is induced by 4'-iodo-4'-deoxydoxorubicin can be well predicted by the measure of the AUC of the drug and its metabolite. This could be used for the further development of the drug toward high-dosage schedules.

Phase I and pharmacologic studies of the camptothecin analog irinotecan administered every 3 weeks in cancer patients.

PURPOSE: A phase I study was undertaken to determine the maximum-tolerated dose (MTD), principal toxicities, and pharmacokinetics of the novel topoisomerase I inhibitor irinotecan (CPT-11). PATIENTS AND METHODS: Sixty-four patients meeting standard phase I eligibility criteria were included (24 women, 40 men; median age, 51 years; primary sites: colon, head and neck, lung, pleura; 60 of 64 had been previously treated). Pharmacokinetics was determined by high-performance liquid chromatography (HPLC). RESULTS: One hundred ninety CPT-11 courses were administered as a 30-minute intravenous (IV) infusion every 3 weeks (100 to 750 mg/m2). Grade 3 to 4 nonhematologic toxicities included diarrhea (16%; three hospitalizations), nausea and vomiting (9%), asthenia (14%), alopecia (53%), elevation of hepatic transaminases (8%), and one case of skin toxicity. An acute cholinergic syndrome was observed during CPT-11 administration. Diarrhea appeared dose-limiting at 350 mg/m2, but this was circumvented by using a high-dose loperamide protocol that allowed dose escalation. Dose-dependent, reversible, noncumulative granulocytopenia was the dose-limiting toxicity (nadir, days 6 to 9; median recovery time, 5 days). Grade 3 to 4 anemia was observed in 9% of patients. One patient died during the study, 8 days after CPT-11 treatment. Two complete responses (cervix, 450 mg/m2; head and neck, 750 mg/m2) and six partial responses in fluorouracil (5-FU)-refractory colon cancer were observed (260 to 600 mg/m2). Pharmacokinetics of CPT-11 and active metabolite SN-38 were performed in 60 patients (94 courses). CPT-11 plasma disposition was bi- or triphasic, with a mean terminal half-life of 14.2 +/- 0.9 hours (mean +/- SEM). The mean volume of distribution (Vdss) was 157 +/- 8 L/m2, and total-body clearance was 15 +/- 1 L/m2/h. The CPT-11 area under the plasma concentration versus time curves (AUC) and SN-38 AUC increased linearly with dose. SN-38 plasma decay had an apparent half-life of 13.8 +/- 1.4 hours. Both CPT-11 and SN-38 AUCs correlated with nadir leukopenia and granulocytopenia, with grade 2 diarrhea, and with nausea and vomiting. CONCLUSION: The MTD of CPT-11 administered as a 30-minute IV infusion every 3 weeks is 600 mg/m2, with granulocytopenia being dose-limiting. At 350 mg/m2, diarrhea appeared dose-limiting, but high-dose loperamide reduced this toxicity and allowed dose escalation. For safety reasons, the recommended dose is presently 350 mg/m2 every 3 weeks; more experience must be gained to establish the feasibility of a higher dose in large multicentric phase II studies. However, when careful monitoring of gastrointestinal toxicities is possible, a higher dose of 500 mg/m2 could be recommended in good-risk patients. The activity of this agent in 5-FU-refractory colorectal carcinoma makes it unique and mandates expedited phase II testing.

Leukemoid reaction, bone marrow invasion, fever of unknown origin, and metastatic pattern in the natural history of advanced undifferentiated carcinoma of nasopharyngeal type: a review of 255 consecutive cases.

PURPOSE: This study is an analysis of frequency and relationship regarding two undifferentiated carcinoma of nasopharyngeal type (UCNT)-associated paraneoplastic syndromes (PNS): leukemoid reaction (LR) and fever of unknown origin (FUO) with bone marrow invasion (BMI) and metastatic pattern. PATIENTS AND METHODS: A consecutive UCNT patient cohort (N = 255) with locally advanced (n = 142) or metastatic (n = 113) disease receiving chemotherapy alone or in combination with radiotherapy was studied. All patients had a complete baseline work-up that included bone marrow biopsy. RESULTS: UCNT has distinctive features among head and neck squamous cell cancers (HNSCC). These include early subclinical dissemination, with 70% of metastases appearing within 18 months of first symptoms. Metastases are common in bone (65% v 25% in HNSCC), liver (29% v 23%), and lung (18% v 84%), and BMI is observed in 25% of UCNT patients with metastases. Metastases likelihood is related to lymph node involvement, with 64% of patients with metastases having N3 disease. Involved lymph nodes in contrasted CT scans revealed hypodensity in 26% of UCNT patients versus 79% in patients with other HNSCC. Hypercalcemia was observed in one case. LR was identified in 41 patients (16%); in 26 of the 41 patients (64%) it was observed concomitant with N3 and/or metastatic disease. FUO was found in 23 patients (9%) and was associated in four instances with BMI and in 17 with LR (in four instances with both). Brain metastases or meningeal carcinomatosis were not observed despite the high rate of skull base compromise. Paraneoplastic signs were observed in 47 of 255 cases (18.5%) and were more frequent in patients with metastases. However, PNS were observed in 15 patients with negative metastases work-up. CONCLUSION: The PNS described could help in the diagnosis and follow-up of UCNT patients because they may be the first manifestation of the disease or may reappear with relapse. BMI is a frequent finding in patients with metastases and is unrelated to PNS.

Etoposide bioavailability after oral administration of the prodrug etoposide phosphate in cancer patients during a phase I study.

PURPOSE: The purpose of this study was to determine the bioavailability (F) of etoposide (E;VP-16) after oral administration of the water-soluble prodrug etoposide phosphate (EP;BMY-40481) during a phase I trial in cancer patients. PATIENTS AND METHODS: Twenty-nine patients received oral EP (capsules, 50 to 150 mg/m2/d of E equivalent) for 5 days in week 1 (course 1), followed every 3 weeks thereafter by a daily intravenous (i.v.) infusion for 5 days of E (80 mg/m2, 1-hour i.v. infusion; course 2); in three patients, the i.v. E course was given before oral EP. Plasma and urine E pharmacokinetics (high-performance liquid chromatography [HPLC]) were performed on the first day of oral EP administration and on the first day of i.v. E. RESULTS: Twenty-six of 29 patients completed two courses or more, whereas three patients received only one course due to toxicity. Myelosuppression was dose-dependent and dose-limiting, with grade 4 leukoneutropenia in four of 15 patients at 125 mg/m2 and in five of seven patients at 150 mg/m2. One patient died of meningeal hemorrhage related to grade 4 thrombocytopenia. Other toxicities were infrequent and/or manageable. No objective response was observed. The maximum-tolerated dose (MTD) is therefore 150 mg/m2, and the recommended oral dose of EP for phase II trials in this poor-risk patient population is 125 mg/m2. Twenty-six patients had pharmacokinetic data for both oral EP and i.v. E, whereas three had pharmacokinetic data on the i.v. E course only. After oral administration of EP, the pharmacokinetics of E were as follows: mean absorption rate constant (Ka), 1.7 +/- 1.7 h-1 (mean +/- SD); lag time, 0.3 +/- 0.2 hours; time of maximum concentration (t(max)), 1.6 +/- 0.8 hours; and mean half-lives (t1/2), 1.6 +/- 0.2 (first) and 10.3 +/- 5.8 hours (terminal); the increase in the area under the plasma concentration-versus-time curve (AUC) of E was proportional to the EP dose. After the 1-hour i.v. infusion of E, maximum concentration (C(max)) was 15 +/- 3 micrograms/mL; mean AUC, 88.0 +/- 22.0 micrograms.h/mL; mean total-body clearance (CL), 0.97 +/- 0.24 L/h/m2 (16.2 mL/min/m2); and mean t1/2, 0.9 +/- 0.6 (first) and 8.1 +/- 4.1 hours (terminal). The 24-hour urinary excretion of E after i.v. E was significantly higher (33%) compared with that of oral EP (17%) (P < .001). Significant correlation was observed between the neutropenia at nadir and the AUC of E after oral EP administration (r = .58, P < .01, sigmoid maximum effect [E(max)] model). The mean F of E after oral administration of EP in 26 patients was 68.0 +/- 17.9% (coefficient of variation [CV], 26.3%; F range, 35.5% to 111.8%). In this study, tumor type, as well as EP dose, did not significantly influence the F in E. There was no difference in F of E, whether oral EP was administered before or after i.v. E. Compared with literature data on oral E, the percent F in E after oral prodrug EP administration was 19% higher at either low ( < or = 100 mg/m2) or high ( > 100 mg/m2) doses. CONCLUSION: Similarly to E, the main toxicity of the prodrug EP is dose-dependent leukoneutropenia, which is dose-limiting at the oral MTD of 150 mg/m2/d for 5 days. The recommended oral dose of EP is 125 mg/m2/d for 5 days every 3 weeks in poor-risk patients. Compared with literature data, oral EP has a 19% higher F value compared with oral E either at low or high doses. This higher F in E from oral prodrug EP appears to be a pharmacologic advantage that could be of potential pharmacodynamic importance for this drug.

Combined systemic chemoimmunotherapy in advanced diffuse malignant mesothelioma. Report of a phase I-II study of weekly cisplatin/interferon alfa-2a.

PURPOSE: To assess the tolerance, toxicity, and antitumoral activity of the weekly combination of cisplatin (CDDP) and interferon alfa-2a (IFNalpha2a) in advanced diffuse malignant mesothelioma (DMM). PATIENTS AND METHODS: Twenty-six patients with DMM (23 pleural and three peritoneal), previously untreated, were enrolled onto this study between August 1991 and December 1992. All patients had measurable disease defined by computed tomographic (CT) scan and diagnostic confirmation by histopathology review panel. IFNalpha2a (3 x 10(6) IU subcutaneously on days 1 to 4) and CDDP (60 mg/m2/wk on day 2) were given weekly. Initially planned as a 5-weeks-on/3-weeks-off treatment cycle, poor patient tolerance observed in the first 12 patients treated (group A) led to schedule adaptation with a shorter treatment sequence and prolongation of the rest period (4 weeks on/4 weeks off) in the following 14 patients (group B). At least two cycles were administered to each patient in the absence of tumor progression. RESULTS: Twenty-six patients were assessable for toxicity and 25 for efficacy (World Health Organization [WHO] criteria). Sixty-eight cycles of IFN/CDDP were given, with a median of three cycles per patient (range, one to five). Toxicity was mainly clinical, with progressive anorexia, asthenia, and prolonged nausea/emesis; these side effects have limited treatment acceptance in many patients. Thrombocytopenia and leukopenia were rarely noted as treatment-limiting toxicities. Objective responses (all partial) were obtained in 10 patients (95% confidence interval [CI], 20% to 60%). The median response duration was 11 months (range, 6 to 18). The median time to progression (TTP) for the whole cohort was 6 months and the median survival time was 12 months (range, 5 to 32). Objective responders had a significantly longer median TTP (21 months) and survival time (25 months) than nonresponders (3 and 8 months, respectively). CONCLUSION: The results of this pilot phase I-II study show encouraging antitumor activity in this traditionally resistant tumor, even if the specific contribution of IFN remains speculative and needs further clinical research. Our ongoing program is exploring the dose-intensity impact of IFN dose within the same combination.

High dose-intensity of irinotecan administered every 3 weeks in advanced cancer patients: a feasibility study.

PURPOSE: To assess, on a multicenter basis, the feasibility of treating advanced cancer patients with high-dose irinotecan. PATIENTS AND METHODS: Thirty-five patients who met the usual phase I criteria (26 men and nine women) were included. Primary tumor sites were colon, head and neck, unknown primary, kidney, liver, and others. All had been previously treated. Irinotecan was given at the maximum-tolerated dose (MTD) (600 mg/m2) or the level below (500 mg/m2) as a 30-minute infusion once every 3 weeks. RESULTS: Eighteen patients were entered in the four participating centers at the MTD of 600 mg/m2. This dose level was clearly shown not to be feasible: 14 patients (78%) had grade 3 to 4 neutropenia, with febrile episodes in 11 patients; grade 3 to 4 diarrhea was observed in nine patients; and one toxic death occurred. Subsequently, 17 not heavily pretreated patients were included at 500 mg/m2 and carefully monitored. The safety of this dose level was considered acceptable: 41% of patients had grade 3 to 4 neutropenia, 24% experienced grade 3 to 4 diarrhea, and no febrile granulocytopenia or toxic death occurred. Six partial responses were documented in metastatic colorectal cancer, all in patients who had previously received conventional chemotherapy, four in patients who had exhibited progressive disease under fluorouracil (5FU)-based chemotherapy. CONCLUSION: We plan to study the higher dose-intensity 500-mg/m2 level on good-risk and carefully monitored patients. This could enlarge the spectrum of tumors sensitive to irinotecan and improve the already good results observed in colorectal cancers.