Randomized, clinical trial of RT001: Early signals of efficacy in Friedreich's ataxia.

BACKGROUND: RT001 is a deuterated ethyl linoleate that inhibits lipid peroxidation and is hypothesized to reduce cellular damage and recover mitochondrial function in degenerative diseases such as Friedreich's ataxia. OBJECTIVE: To evaluate the safety, pharmacokinetics, and preliminary efficacy of RT001 in Friedreich's ataxia patients. DESIGN/METHODS: We conducted a phase I/II double-blind, comparator-controlled trial with 2 doses of RT001 in Friedreich's ataxia patients (9 subjects each cohort). Subjects were randomized 2:1 to receive either RT001 (1.8 or 9.0 g/day), or a matching dose of nondeuterated ethyl linoleate as comparator for 28 days. The primary endpoints were safety, tolerability, and pharmacokinetic analysis. Secondary endpoints included cardiopulmonary exercise testing and timed 25-foot walk. RESULTS: Nineteen patients enrolled in the trial, and 18 completed all safety and efficacy measurements. RT001 was found to be safe and tolerable, with plasma levels approaching saturation by 28 days. One subject with a low body mass index experienced steatorrhea taking a high dose and discontinued the study. Deuterated arachidonic acid (a brain-penetrant metabolite of RT001) was found to be present in plasma on day 28. There was an improvement in peak workload in the drug group compared to placebo (0.16 watts/kg; P = 0.008), as well as an improvement trend in peak oxygen consumption (change of 0.16 L/min; P = 0.116), and in stride speed (P = 0.15). CONCLUSIONS: RT001 was found to be safe and tolerable over 28 days, and improved peak workload. Further research into the effect of RT001 in Friedreich's ataxia is warranted. © 2018 International Parkinson and Movement Disorder Society.

Cholangiocarcinoma, sequential chemotherapy, and prognostic tests.

Introduction: Routine blood tests are prognostic tests for patients with cholangiocarcinoma. New drug regimens may produce a median overall survival of 2 years or more. Methods: This single practice, IRB-approved, phase II trial examines prognostic tests, Kaplan-Meier survival, and univariate Cox regression analyses. Eligibility requires: intent-to-treat; signed consent; advanced measurable intrahepatic cholangiocarcinoma, with or without resistance to the test drugs; any adult age; performance status 0-2; and expected survival of ≥ 6 weeks. Biweekly treatment, with 1/3 of standard dosages in mg/M2, includes: Gemcitabine 500; 5-Fluorouracil 1200 over 24 hours; Leucovorin 180; Irinotecan 80; and on day 2, Oxaliplatin 40. On progression, drugs are added on day 2: first, Docetaxel 25 precedes Oxaliplatin, with or without Mitomycin C 6 after Oxaliplatin. The next sequential additions are day 1, Cetuximab 400 total mg, then 200 mg weekly, and then Bevacizumab 10 mg/kg is substituted for Cetuximab (FDA IND# 119005). Results: For 35 patients, 19 with 1-2 lines of prior therapy, resistant tumors, and 16 no prior therapy, survival at 24-months is ≥ 72 and ≥ 58%, respectively. For 14 patients aged ≥ 70 years, ≥ 63% survive 24 months, P = 0.28. Validated tests that predict ≤ 6-month survivals find median survival times of 17-months through > 2-years when compared to patients with favorable tests: Neutrophils lymphocyte ratio > 3.0, HR = 6.54, P < 6.4x10-3; absolute neutrophil count > 8000/µl, HR = 4.95, P < 6.5x10-3; serum albumin < 3.5 g/dl, HR = 4.10, P < 0.03; and lymphocyte monocyte ratio< 2.1, HR = 1.6, P = 0.50. Overall, the 76 (60-90)% of patients with 0-2 out of 4 high risk tests survive ≥ 24 months, (P = 7.1x10-3). Treatments produce neither hospitalization, neutropenic fever, severe enteritis, nor severe neuropathies. Conclusion: Two-year survival is replicable and predictable. Findings warrant phase III validation tests of sequential regimens, re-challenge with recombination, low dosages, and blood tests that are associated with lethal mechanisms that impair response and survival.

Chemoradiotherapy Combined with Brachytherapy for the Definitive Treatment of Esophageal Carcinoma.

This study aims to investigate the effect of dose escalation with brachytherapy (BT) as an addition to definitive chemoradiotherapy (CRT) on local control and survival in esophageal cancer. From 2001 to 2020, 183 patients with locally limited or locally advanced esophageal cancer received definitive CRT with or without brachytherapy in a two-center study. External-beam radiotherapy was delivered at 50.4 Gy in 1.8 Gy daily fractions, followed by a sequential boost to the primary tumor of 9 Gy in 1.8 Gy daily fractions if indicated. Intraluminal high dose rate (HDR) Ir-192 brachytherapy was performed on 71 patients at 10 Gy in two fractions, with one fraction per week. The combined systemic therapy schedules used included 5-fluorouracil/cisplatin or 5-fluorouracil alone. Cisplatin was not administered in patients receiving brachytherapy. The median local progression-free survival was significantly extended in the BT group (18.7 vs. 6.0 months; p < 0.0001), and the median local control was also significantly prolonged (30.5 vs. 11.3 months, p = 0.008). Overall survival (OS) significantly increased in the BT group (median OS 22.7 vs. 9.1 months, p < 0.0001). No significant difference in the overall rate of acute toxicities was observed; however, the rate of acute esophagitis was significantly higher in the BT group (94.4% vs. 81.2%). Likewise, the overall rate of late toxicities (43.7% vs. 18.8%) was significantly higher in the BT group, including the rate of esophageal stenosis (22.5% vs. 9.8%). There was no difference in the occurrence of life-threatening or lethal late toxicities (grades 4 and 5). Brachytherapy, after chemoradiation with single-agent 5-FU, represents a safe and effective alternative for dose escalation in the definitive treatment of esophageal cancer.

Actionable tests and treatments for patients with gastrointestinal cancers and historically short median survival times.

BACKGROUND: Patients have difficult unmet needs when standard chemotherapy produces a median survival of less than 1 year or many patients will experience severe toxicities. Blood tests can predict their survival. METHODS: Analyses evaluate predictive blood tests to identify patients who often survive 1 and 2 years. A four-test model includes: albumin, absolute neutrophil count, neutrophil-lymphocyte ratio, and lymphocyte-monocyte ratio. Individual tests include: alkaline phosphatase, lymphocytes, white blood count, platelet count, and hemoglobin. Eligible patients have advanced: resistant 3rd line colorectal, and both resistant and new pancreatic and intrahepatic bile duct cancers. Eligibility characteristics include: biopsy-proven, measurable metastatic disease, NCI grade 0-2 blood tests, Karnofsky Score 100-50, and any adult age. Drugs are given at 1/4-1/3 of their standard dosages biweekly: gemcitabine, irinotecan, fluorouracil, leucovorin, and day 2 oxaliplatin every 2 weeks. In case of progression, Docetaxel is added (except colon cancer), with or without Mitomycin C, and next cetuximab (except pancreatic and KRAS BRAF mutation cancers). Bevacizumab is substituted for cetuximab in case of another progression or ineligibility. Consent was written and conforms with Helsinki, IRB, and FDA criteria (FDA #119005). RESULTS: Median survival is 14.5 months. Of 205 patients, 60% survive 12, and 37% survive 24 months (95% CI ± 8%). Survival is > 24, 13, and 3.8 months for patients with 0, 1-2, and 3-4 unfavorable tests, respectively. Individual "favorable and unfavorable" tests predict long and short survival. Neither age nor prior therapy discernibly affects survival. Net rates of clinically significant toxicities are less than 5%. CONCLUSION: Treatments reproduce predictable, greater than 12 and 24-month chances of survival for the aged and for patients with drug-resistant tumors. Evaluation of blood tests may change practice, expand eligibility, and personalize treatments. Findings support investigation of drug combinations and novel dosages to reverse resistance and improve safety.

Hypogonadism in men with multiple sclerosis: Prevalence and clinical associations.

It has been hypothesized that multiple sclerosis (MS) has hormonal influences, and testosterone may have anti-inflammatory functions in this context. Given prior reports of lower testosterone levels in men with MS in archival serum samples, we evaluated the prevalence of hypogonadism in the clinical setting and its association with disability in men with MS. Subjects were screened for symptoms of hypogonadism using a clinical instrument, and those with positive screens had total and free morning testosterone levels checked. Of the 64 subjects who were screened, 50 (78%) had positive results, and 46 (92%) had morning testosterone levels checked. Among the latter, 5 were found to have testosterone levels below lower limit of normal. Other than the expected inverse relation with BMI, testosterone did not correlate with demographic or disease related factors. Baseline testosterone did not predict risk of EDSS or T25-FW progression or future MRI activity.

Preoperative oxaliplatin, capecitabine, and external beam radiotherapy in patients with newly diagnosed, primary operable, cT3NxM0, low rectal cancer: a phase II study.

PURPOSE: In patients with locally advanced rectal cancer (LARC), preoperative chemoradiation is known to improve local control, and down-staging of the tumor serves as a surrogate for survival. Intensification of the systemic therapy may lead to higher downstaging rates and, thus, enhance survival. This phase II study investigated the efficacy and safety of preoperative capecitabine and oxaliplatin in combination with radiotherapy. PATIENTS AND METHODS: Patients with LARC of the mid and lower rectum, T3NxM0 staged by MRI received radiotherapy (total dose 45 Gy) in combination with oral capecitabine (825 mg/m² twice a day on radiotherapy days; weeks 1-4) and oxaliplatin 50 mg/m² intravenously (days 1, 8, 15, and 22). Efficacy was evaluated as rate of tumor down-categorization at the T level. RESULTS: A total of 59 patients were enrolled (19 women, 40 men; median age of 61 years) and all were evaluable for efficacy and toxicity. Down-categorization at the T level was observed in 53% with pathological complete response in 6 patients (10%). Actual total radiotherapy, oxaliplatin and capecitabine doses received were 97%, 90%, and 93% of the protocol-specified preplanned doses, respectively. Grade 3/4 toxicity was observed in 15 patients (25%). The most frequent was diarrhea (12%). CONCLUSIONS: Preoperative chemoradiation with capecitabine and oxaliplatin is feasible in patients with MRI-proven cT3 LARC. The only clinically relevant toxicity was diarrhea. Overall, efficacy of the multimodality treatment was good, but not markedly exceeding that of 5-FU- or capecitabine-based chemoradiation approaches.

Improving Efficacy of Inhaled Technosphere Insulin (Afrezza) by Postmeal Dosing: In-silico Clinical Trial with the University of Virginia/Padova Type 1 Diabetes Simulator.

BACKGROUND: Technosphere(®) insulin (TI), an inhaled human insulin with a fast onset of action, provides a novel option for the control of prandial glucose. We used the University of Virginia (UVA)/Padova simulator to explore in-silico the potential benefit of different dosing regimens on postprandial glucose (PPG) control to support the design of further clinical trials. Tested dosing regimens included at-meal or postmeal dosing, or dosing before and after a meal (split dosing). METHODS: Various dosing regimens of TI were compared among one another and to insulin lispro in 100 virtual type-1 patients. Individual doses were identified for each regimen following different titration rules. The resulting postprandial glucose profiles were analyzed to quantify efficacy and the risk for hypoglycemic events. RESULTS: This approach allowed us to assess the benefit/risk for each TI dosing regimen and to compare results with simulations of insulin lispro. We identified a new titration rule for TI that could significantly improve the efficacy of treatment with TI. CONCLUSION: In-silico clinical trials comparing the treatment effect of different dosing regimens with TI and of insulin lispro suggest that postmeal dosing or split dosing of TI, in combination with an appropriate titration rule, can achieve a superior postprandial glucose control while providing a lower risk for hypoglycemic events than conventional treatment with subcutaneously administered rapid-acting insulin products.

Phase I and pharmacokinetic study of DX-8951f (exatecan mesylate), a hexacyclic camptothecin, on a daily-times-five schedule in patients with advanced leukemia.

PURPOSE: DX-8951f is a novel hexacyclic camptothecin-analogue topoisomerase I inhibitor with both in vitro antileukemic activity and myelosuppression as a dose-limiting toxicity in solid tumor Phase I studies. DX-8951f is active in a human acute myeloid leukemia (AML) severe combined immunodeficient mouse model. In a leukemia Phase I study, we investigated the toxicity profile and pharmacokinetics of DX-8951f in patients with primary refractory or relapsed AML or acute lymphocytic leukemia, myelodysplastic syndromes, or chronic myelogenous leukemia in blastic phase (CML-BP). EXPERIMENTAL DESIGN: DX-8951f was given as an i.v. infusion over 30 min daily for 5 or 7 days. The starting dose was 0.6 mg/m(2)/day for 5 days (3.0 mg/m(2)/course). Courses were given every 3-4 weeks according to toxicity and antileukemic efficacy. RESULTS: Twenty-five patients (AML, 21 patients; myelodysplastic syndrome, 1 patient; acute lymphocytic leukemia, 2 patients; CML-BP, 1 patient) were treated. Stomatitis was the dose-limiting toxicity, occurring in two of two patients treated at 1.35 mg/m(2)/day for 5 days, two of three treated at 1.2 mg/m(2)/day for 5 days, and one of six treated at 0.9 mg/m(2)/day for 7 days. The recommended Phase II dose was 0.9 mg/m(2)/day for 5 days. The pharmacokinetics of DX-8951 was linear and well fit by a two-compartment model. CONCLUSIONS: Phase II studies are warranted to further define the activity of DX-8951f in patients with hematological malignancies.

A Phase I and pharmocokinetic study of exatecan mesylate administered as a protracted 21-day infusion in patients with advanced solid malignancies.

PURPOSE: The purpose of this study was to assess the feasibility of administering exatecan, a water-soluble, potent camptothecin analogue, as a protracted 21-day continuous i.v. infusion (CIVI). The study also sought to determine the maximum tolerated dose (MTD) of exatecan on a 21-day CIVI schedule, characterize its pharmacokinetic behavior, and seek preliminary evidence of anticancer activity. EXPERIMENTAL DESIGN: Exatecan dose-schedule development was performed in two stages using the modified Continual Reassessment Method and single patient cohorts. First, patients with advanced solid malignancies were treated with exatecan (0.15 mg/m(2)/day) as a CIVI for 5 days, and the duration of the CIVI was incrementally increased from 5 to 21 days. In the second stage of the study, the dose was incrementally increased to derive a tolerable dose of exatecan administered as 21-day CIVI. The MTD was defined for both minimally pretreated (MP) and heavily pretreated (HP) patients as the highest dose level at which the incidence of dose-limiting toxicity does not exceed 20%. RESULTS: Thirty-one patients were treated with 100 courses of exatecan at 6 dose-schedule levels. The incidence of the principal dose-limiting toxicities, neutropenia and thrombocytopenia, was unacceptably high at exatecan doses exceeding 0.15 mg/m(2)/day as a 21-day CIVI, which was determined to be the MTD for both MP and HP patients. The pharmacokinetics of exatecan were dose-proportional, and mean [coefficient of variation (percentage) steady-state concentration (plasma concentration at steady-state)] values ranged from 6.88 (80.6) to 19.41 (74.2) ng/ml at exatecan dose levels ranging from 0.15 to 0.30 mg/m(2)/day, which are similar to IC(50) values against human tumor cell lines treated for shorter periods. Mean pharamacokinetic parameters for total exatecan derived from a compartmental model included clearance and volume of distribution values of 1.39 (86.9) liters/h/m(2) and 39.66 (197.4) liters, respectively. Two HP patients with non-small cell lung and unknown primary carcinomas had partial responses, and objective evidence of anticancer activity and clinical benefit were noted in several other individuals. CONCLUSIONS: The administration of exatecan as a 21-day CIVI at doses as high as 0.15 mg/m(2)/day is safe and feasible for both MP and HP patients. The characteristics of the myelosuppressive effects of exatecan on this schedule, the paucity of severe nonhematological toxicities, and documented anticancer activity in several drug-refractory malignancies warrant further evaluation of the merits of administering exatecan by either a CIVI or alternate drug delivery systems to achieve protracted systemic exposure.

Oesophageal cancer: exploring controversies overview of experts' opinions of Austria, Germany, France, Netherlands and Switzerland.

BACKGROUND: Oesophageal carcinoma is a rare disease with often dismal prognosis. Despite multiple trials addressing specific issues, currently, many questions in management remain unanswered. This work aimed to specifically address areas in the management of oesophageal cancer where high level evidence is not available, performing trials is very demanding and for many questions high-level evidence will not be available in the forseeable future. METHODS: Two experts of each national, oesophageal cancer research group from Austria, France, Germany, the Netherlands and Switzerland were asked to provide statements to controversial issues. After an initial survey, further questions were formulated and answered by all experts. The answers were then discussed and qualitatively analysed for consensus and controversy. RESULTS: Topics such as indications for PET-CT, reasons for induction chemotherapy, radiotherapy dose, the choice of definitive chemo-radiotherapy versus surgery in squamous cell cancer, the role of radiotherapy in adenocarcinoma and selected surgical issues were identified as topics of interest and discussed. CONCLUSION: Areas of significant controversy exist in the management of oesophageal cancer, mostly due to high-level evidence. This is not expected to change in the upcoming years.

Strategies for designing GPCR-focused libraries and screening sets.

In recent years drug discovery has progressively moved away from a traditional single-target focus toward a family-based approach. The development of knowledge relating to targets and ligands of the same protein family has been actively pursued to support more predictive and efficient pharmaceutical research. The design of focused libraries and screening sets for the G protein-coupled receptor (GPCR) family has been undertaken along several different routes. A first approach has been ligand-based, relying either on physicochemical properties or on privileged substructures of GPCR ligands, but despite some success this approach has suffered from the near absence of knowledge coming from the receptor. To strengthen the weak link between the chemical and biological aspects, new databases have been developed and have steadily moved toward integrated information systems. Several research groups have reported novel approaches to library design and compound selection based on two- or three-dimensional mapping of the ligand-receptor interaction sites. The development of homology models derived from the rhodopsin crystal structure, the use of site-directed mutagenesis in relation to ligand structure-activity relationships (SARs), and the integration of informatics analyses have been critical elements for driving new designs in a modern chemogenomics environment.

Epidemiological aspects of hadron therapy: a prospective nationwide study of the Austrian project MedAustron and the Austrian Society of Radiooncology (OEGRO).

BACKGROUND: The planned MedAustron hadron therapy facility is designed to compare proton and carbon ion beam therapy under the same technical conditions. For the calculation of the number of potential patients for hadron therapy so far, only epidemiological estimations on cancer incidence are available without inclusion of the percentage of patients routinely referred to conventional radiotherapy. MATERIALS AND METHODS: Nationwide prospective survey to collect disease and treatment related data on patients receiving conventional radiotherapy at all 12 treatment facilities. Epidemiological cancer incidence (Statistic Austria 1999) were correlated with the number of patients receiving conventional radiotherapy. Based on published clinical and experimental results on proton and carbon ion therapy, a calculation of patient's subgroups suitable for hadron therapy was performed at five European University hospitals involved in the HICAT, CNAO, ETOILE and MEDAustron project. Using the mean values of the University specific percentages per tumour site, the number of potential patients was estimated. RESULTS: In Austria, a total of 3783 patients started radiotherapy during the study period of 3 months resulting in an approximated number of 15132 patients per year. The number of potential patients was estimated to 2044 per year, representing 5.6% of all newly diagnosed cancer patients and 13.5% of all irradiated cancer patients. CONCLUSION: There is a clear place for a hadron therapy facility in Austria, based on pattern of care in radiotherapy, cancer incidence and indications.

The med AUSTRON/OGRO patterns of care study on radiotherapy indications in Austria.

PURPOSE: In Austria a national survey was conducted by Med AUSTRON/Osterreichische Gesellschaft for Radio--Onkologie, Radiobiologie und Medizinische Radiophysik (OGRO) in order to estimate the indications, patient numbers and radiotherapy treatment planning procedures and performances at all Austrian radiotherapy institutes. Results were correlated with incidence rates (Austrian cancer registry) to determine patterns of radiotherapy practice in Austria. MATERIAL AND METHODS: At 12 radiotherapy departments of Austria data of all patients receiving irradiation within a 3 months (2002/2003) period were assessed. On the basis of a questionnaire number of treated patients, indications, and parameters of disease (stage, histology) and treatment modalities were evaluated. Results were analysed with regard to different tumour groups, according to academic and non academic hospitals, and correlated with epidemiological data on cancer incidence. RESULTS: In total, 3783 patients were registered within this period. According to the different tumour entities percentages of patients receiving radiotherapy within initial treatment varied from 3% to 90 % (e.g. brain tumours: 77%, breast cancer: 90%, prostate cancer: 35%). The most frequent indications to radiotherapy per radiotherapy department were breast cancer (range 22%-35%; mean 26%), urological tumours (range 6%-27%; mean 12%) and bone metastases (mean 10%, range 3%-17%). CONCLUSION: In Austria breast cancer, urological tumours and bone metastases are representing the most common indications to radiotherapy. Among the different departments variations in indications to radiotherapy were observed. Our study is the first evaluation of radiotherapeutic management in Austria.

[Fatal bleeding complications caused by Evans syndrome (autoimmune thrombocytopenia and hemolytic anemia) and type II autoimmune hepatitis in a 56-year-old patient]. / Fatale Blutungskomplikationen durch Evans-Syndrom (autoimmune Thrombozytopenie und hämolytische Anämie) und Autoimmunhepatitis Typ II bei einer 56-jährigen Patientin.

BACKGROUND: Autoimmune hepatitis is a rare form of hepatitis of nonviral origin. Two main subentities have been described. The classical lupoid hepatitis (type I) is characterized by hypergammaglobulinemia and the presence of lupus erythematosus cells due to antinuclear antibodies. Autoimmune hepatitis type II, which is associated with antiliver/kidney microsomal antibodies type 1 (LKM 1) shows a more aggressive clinical course than autoimmune hepatitis type I and is frequently (41% of cases) associated with other immunologic diseases. CASE REPORT: In the present study we report a case of autoimmune hepatitis Type II, associated with autoimmune thrombocytopenia and hemolytic anemia, in a 56-year-old patient. The patient's death was caused by a fatal association of a failing coagulation system due to liver dysfunction and a severe autoimmune thrombocytopenia. The aggressive course of the thrombocytopenia even after splenectomy demonstrated that the splenic enlargement due to the portal hypertension was only a minor factor in the destruction of the thrombocytes. Interestingly, some findings of this case such as the advanced age, the presence of anti-smooth muscle antibodies and HLA-DR4 are usually associated with autoimmune hepatitis type I. CONCLUSION: The findings of this case indicate that concomitant autoimmune diseases can worsen the prognosis of autoimmune hepatitis. Prednisolone and azathioprine might not be sufficient to treat aggressive forms of autoimmune hepatitis. Immunosuppressive regimens administered to recipients after organ transplantation might be used as a therapy of autoimmune hepatitis in multicenter clinical trials.

Postoperative morbidity following chemoradiation for locally advanced low rectal cancer.

BACKGROUND: Postoperative morbidity remains a significant clinical problem and may alter long-term outcome particularly after neoadjuvant chemoradiation in patients with locally advanced low rectal cancer. The aim of the present study was to identify a potential long-term effect of postoperative morbidity. METHODS: Analysis of prospectively collected data of 90 consecutive patients who underwent neoadjuvant chemoradiation and curative mesorectal excision for locally advanced (cT3/4, Nx, M0/1) adenocarcinoma of the mid and lower third of the rectum during a 7-year period (1996-2002). RESULTS: Major postoperative complications occurred in 17.8% and minor complications in 26.6% of patients. Hospital mortality and 30-day mortality was 0%. Infectious complications were seen in 34.5%. The leading causes of infectious complications were anastomotic leakage and perineal wound infection. Postoperative morbidity was statistically significantly associated with gender (P < 0.05), pre-therapeutic haemoglobin level (P < 0.05), ASA score (P < 0.05), hospitalisation (P < 0.001) and clinical long-time course (P < 0.01). Moreover, early postoperative morbidity was proven as an independent prognostic factor concerning disease-free (P < 0.05) and overall survival (P < 0.05). CONCLUSION: Early postoperative morbidity in patients with preoperative chemoradiation due to locally advanced low rectal cancer is demonstrated as an independent prognosticator. Gender, pre-therapeutic haemoglobin level and ASA score indicate patients at risk for early postoperative complications and may therefore serve as predictive features.

Randomized phase III study of exatecan and gemcitabine compared with gemcitabine alone in untreated advanced pancreatic cancer.

PURPOSE: Exatecan mesylate is a hexacyclic, water-soluble, topoisomerase-1 inhibitor. Exatecan has single-agent and combination activity with gemcitabine in advanced pancreatic cancer. A multicenter, randomized, phase III trial comparing exatecan plus gemcitabine versus gemcitabine alone in advanced pancreatic cancer was conducted. PATIENTS AND METHODS: Eligibility criteria included Karnofsky performance status > or = 60%, locally advanced or metastatic pancreatic adenocarcinoma, and no prior chemotherapy. Radiation alone for locally advanced disease was permitted. Patients were randomly assigned on a 1:1 basis. For the exatecan plus gemcitabine arm, exatecan 2.0 mg/m2 and gemcitabine 1,000 mg/m2 were administered on days 1 and 8, every 3 weeks. Gemcitabine alone was dosed at 1,000 mg/m2 up to 7 weeks in the first cycle, then once a week for the first 3 weeks of a 4-week cycle. Tumor assessment was performed every 6 weeks. The primary end point was overall survival. An intent-to-treat analysis was used. RESULTS: From August 2001 to January 2003, 349 patients were randomly assigned, 175 to exatecan plus gemcitabine and 174 to gemcitabine alone. Twenty-four patients (6.9%) were not treated. The median survival time was 6.7 months for exatecan plus gemcitabine and 6.2 months for gemcitabine alone (P = .52). One complete response (CR; < 1%) and 11 partial responses (PRs; 6.3%) were observed in the exatecan plus gemcitabine treatment group, and one CR (< 1%) and eight PRs (4.6%) were observed in the gemcitabine-alone group. Grade 3 and 4 toxicities were higher for the exatecan plus gemcitabine arm versus the gemcitabine alone arm; neutropenia (30% v 15%) and thrombocytopenia (15% v 4%). CONCLUSION: Exatecan plus gemcitabine was not superior to gemcitabine alone with respect to overall survival in the first-line treatment of advanced pancreatic cancer.

A phase II clinical and pharmacokinetic study of intravenous exatecan mesylate (DX-8951f) in patients with untreated metastatic gastric cancer.

PURPOSE: To determine the anti-tumor activity DX-8951f when administered as a 30-minute infusion daily for 5 days every 3 weeks to patients with previously untreated metastatic gastric cancer, and to evaluate toxicities and pharmacokinetics (PK) of DX-8951f in this patient population. PATIENTS AND METHODS: Forty-one patients were enrolled. All had previously untreated metastatic gastric cancer. DX-8951f was administered until disease progression or unacceptable toxicity. Responses were assessed after every 2 courses using RECIST criteria. RESULTS: Thirty-nine patients were evaluable. Two patients achieved a partial response (PR) and 18 achieved stable disease (SD), including five patients with unconfirmed PR. A total of 141 courses of therapy were delivered (median 3, range 1-10). The most common drug-related toxicity was neutropenia. Non-hematologic toxicities were mostly mild to moderate; the most common were nausea, vomiting and anorexia. Plasma concentrations of DX-8951 (the anhydrous form of DX-8951f) were well described using a linear 2-compartment PK model. All concentrations and dose events were simultaneously modeled and explained by the population PK model. There was no evidence of non-linearity in the elimination PK, auto-inhibition or induction of DX-8951 clearance over the five days of administration. CONCLUSIONS: DX-8951f had modest activity against metastatic gastric cancer and its PK was dose-proportional. The toxicity profile was predictable and manageable. Further development of this agent is warranted.

A Phase II study of intravenous exatecan administered daily for 5 days, every 3 weeks to patients with biliary tract cancers.

PURPOSE: Exatecan is a hexacyclic topoisomerase-1 inhibitor that has broad in vitro and in vivo activity. A multicenter phase II study to determine the antitumor activity of exatecan was conducted in patients with advanced cholangiocarcinoma and gallbladder carcinoma. METHODS: Patients with 0 to 1 prior chemotherapy regimens, adequate major organ function, and metastatic disease were eligible. Exatecan was administered at a dose of 0.5 mg/m2 IV over 30 minutes daily on days 1 through 5 every 21 days. The primary end point was overall response rate: complete response and partial response (PR). A Simon optimal 2-stage design was employed. Response was assessed every 6 weeks. RESULTS: Forty-two patients were enrolled. Two of 41 evaluated patients (4.9%) had a PR, 4 patients (9.8%) had a minor response, and 12 had stable disease. Twenty patients (51.2%) had progressive disease. The major toxicity was grade 3/4 neutropenia. The median overall survival was 7 months. The 6-month survival rate was 56.1% and the 12-month survival rate was 31.7%. CONCLUSION: Exatecan has minimal activity in advanced biliary tree cancers. Toxicity was predictable and manageable.

Parametrization strategy for the MolFESD concept: quantitative surface representation of local hydrophobicity.

We derive a new model for the established concept of the molecular free energy surface density (MolFESD) yielding a more rigorous representation of local surface contributions to the overall hydrophobicity of a molecule. The model parametrization makes efficient use of both local and global information about solvation thermodynamics, as formulated earlier for the problem of predicting free energies of hydration. The free energy of transfer is separated into an interaction contribution and a term related to the cavity formation. Interaction and cavity components are obtained from the statistical three-dimensional (3D) free energy density and a linear combination of surface and volume terms, respectively. An appropriate molecular interaction field generated by the program Grid is used as an approximate representation of the interaction part of the 3D free energy density. We further compress the 3D density by means of a linear combination of localized surface functions allowing for the derivation of local hydrophobic contributions in the form of a free energy surface density. For a set of 400 compounds our model yields significant correlation (R(2) = 0.95, sigma = 0.57) between experimental and calculated log P values. The final model is applied to establish a correlation between partial free energies of transfer for a series of sucrose derivatives and their relative sweetness, as studied earlier in the group of the authors. We find considerable improvement regarding the rms error of the regression thus validating the presented approach.