Phase-I dose finding and pharmacokinetic study of the novel hydrophilic camptothecin ST-1968 (namitecan) in patients with solid tumors.

PURPOSE: This is a first-in-human, phase I, dose-escalation study to determine the maximum tolerated dose (MTD) of intravenous, flat-dosed ST-1968 (namitecan), a new hydrophilic camptothecan derivative. METHODS: Namitecan was administered intravenously over 2 h on day 1 and day 8 every 21 days (D1-D8-Q21D), starting at a flat dose of 2.5 mg, and increased according to a 3 + 3 cohort design. Due to frequent skipping of day 8 dosing for cytopenias, the study was expanded to test namitecan dosing on day 1 every 21 days (D1-Q21) at a starting dose of 17.5 mg. Major dose-limiting toxicity (DLT) was defined as grade (G) 4 neutropenia persisting >5 days, febrile neutropenia, G3 thrombocytopenia or G2 non-hematological toxicity. RESULTS: Thirty-four patients were included into the D1-D8-Q21D group (2.5, 5, 10, 15, 17.5, 20 mg dosing cohorts), 29 patients into the D1-21D group (17.5, 20, 23, 27, 30 mg dosing cohorts). Neutropenia was the DLT in both groups, with 15 mg being defined as the recommended dose (RD) for the D1-D8-Q21D group, and 23 mg for the D1-Q21D group. Non-hematological toxicity was negligible. One patient with endometrial cancer in the D1-D8-Q21D group and one patient with cholangiocellular carcinoma in the D1-Q21D group experienced a partial remission. Namitecan exhibited fully dose-proportional pharmacokinetics. CONCLUSIONS: This study demonstrates clinical safety, favourable pharmacokinetics and preliminary antitumor activity of the novel hydrophilic camptothecin analogue namitecan in patients with heavily pretreated solid malignancies, when given either on a 2 out of 3 weeks or 3-weekly regimen.

Integrative population pharmacokinetic and pharmacodynamic dose finding approach of the new camptothecin compound namitecan (ST1968).

AIMS: Namitecan is a new camptothecan compound undergoing early clinical development. This study was initiated to build an integrated pharmacokinetic (PK) and pharmacodynamic (PD) population model of namitecan to guide future clinical development. METHODS: Plasma concentration-time data, neutrophils and thrombocytes were pooled from two phase 1 studies in 90 patients with advanced solid tumours, receiving namitecan as a 2 h infusion on days 1 and 8 every 3 weeks (D1,8) (n = 34), once every 3 weeks (D1) (n = 29) and on 3 consecutive days (D1-3) (n = 27). A linear three compartment PK model was coupled to a semiphysiological PD-model for neutrophils and thrombocytes. Data simulations were used to interrogate various dosing regimens and give dosing recommendations. RESULTS: Clearance was estimated to be 0.15 l h(-1), with a long terminal half-life of 48 h. Body surface area was not associated with clearance, supporting flat-dosing of namitecan. A significant and clinically relevant association was found between namitecan area under the concentration-time curve (AUC) and the percentage drop of neutrophils (r(2) = 0.51, P < 10(-4)) or thrombocytes (r(2) = 0.49, P < 10(-4)). With a target for haematological dose-limiting toxicity of <20%, the recommended dose was defined as 12.5 mg for the D1,8 regimen, 23 mg for the once every 3 week regimen and 7 mg for the D1-3 regimen. CONCLUSION: This is the first integrated population PK-PD analysis of the new hydrophilic topoisomerase I inhibitor namitecan, that is currently undergoing early clinical development. A distinct relationship was found between drug exposure and haematological toxicity, supporting flat-dosing once every 3 weeks as the most adequate dosing regimen.

Phase I study of olaparib in combination with liposomal doxorubicin in patients with advanced solid tumours.

BACKGROUND: Olaparib, an oral PARP inhibitor, has shown antitumour activity as monotherapy in patients with germline BRCA1/2 (gBRCA)-mutated breast and ovarian cancer. This study evaluated olaparib capsules in combination with liposomal doxorubicin (PLD) in patients with advanced solid tumours (NCT00819221). METHODS: Patients received 28-day cycles of olaparib, continuously (days 1-28) or intermittently (days 1-7), plus PLD (40 mg m(-2), day 1); seven olaparib dose cohorts (50-400 mg bid) were explored to determine the recommended dose. Assessments included safety, pharmacokinetics, pharmacodynamics and preliminary efficacy (objective response rate (ORR)). RESULTS: Of 44 patients treated (ovarian, n=28; breast, n=13; other/unknown, n=3), two experienced dose-limiting toxicities (grade 3 stomatitis and fatal pneumonia/pneumonitis (200 mg per 28-day cycle); grade 4 thrombocytopenia (400 mg per 7-day cycle)). The maximum tolerated dose was not reached using continuous olaparib 400 mg bid plus PLD. Grade ≥3 and serious AEs were reported for 27 (61%) and 12 (27%) patients, respectively. No major pharmacokinetic interference was observed between olaparib and PLD. The ORR was 33% (n=14 out of 42; complete response, n=3). A total of 13 responders had ovarian cancer: 10 were platinum-sensitive, 11 had a gBRCA mutation. CONCLUSIONS: Continuous/intermittent olaparib (up to 400 mg bid) combined with PLD (40 mg m(-2)) was generally tolerated and showed evidence of antitumour activity in ovarian cancer.

Outcome of patients with sarcoma and other mesenchymal tumours participating in phase I trials: a subset analysis of a European Phase I database.

BACKGROUND: Although sarcomas account for only 1% of all solid tumours, patients with sarcomas comprise a larger proportion of patients entering phase I trials, due to the limited number of registered or active drugs for these diseases. To help in patient selection, we evaluated the utility of the predictive Royal Marsden Score which had been derived in carcinoma patients. In addition, we analysed efficacy and toxicity regarding the sarcoma population enrolled in phase I trials. PATIENTS AND METHODS: We used data from a European Database comprising 2182 patients treated in phase I trials in 14 European institutions between 2005 and 2007. RESULTS: One hundred and seventy-eight patients diagnosed with advanced sarcoma or other mesenchymal tumours were identified and accounted for 217 phase I trial participations during the study period. Histological type, class of drug, number of metastatic sites, high serum lactate dehydrogenase activity (LDH), low albumin and high white blood cell count were independent prognostic factors. Poor performance status (PS), liver metastases and high leucocyte count were associated with increased risk of early death. The class of drug used was the strongest predictor of progression-free survival (PFS) duration, inhibitors of angiogenesis and histone deacetylase giving the best results. Poor PS, high serum LDH and low lymphocyte count correlated with shorter PFS. In this heterogeneous population, PFS with investigational agents appeared comparable with that previously published for patients receiving standard treatments beyond first line. CONCLUSION: Prognostic factors in sarcoma patients do not differ from a broader phase I population. Efficacy measures suggest that some patients with sarcoma derive benefit from therapy in this setting which could therefore be considered for patients with no remaining standard therapeutic option.

Working tables on Hormone Receptor positive (HR+), Human Epidermal growth factor Receptor 2 negative (HER2-) early stage breast cancer: Defining high risk of recurrence.

Hormone-receptor positive (HR+), Human-Epidermal-growth Factor negative (HER2-) breast cancer, including the Luminal A and the Luminal B subtypes, is the most common in women diagnosed with early-stage BC. Despite the advances in screening, surgery and therapies, recurrence still occurs. Therefore, it is important to identify early those factors that significantly impact the recurrence risk. Based on current evidence and their professional expertise, a Panel of oncologists discussed the definition of high risk of recurrence in early breast cancer. Histological grade, nodal involvement, genomic score, histological grade, tumor size, and Ki-67 proliferation index were rated as the most important factors to define the high risk in patients with early breast cancer. All these factors should be considered comprehensively to tailor the choice of treatment to the peculiar characteristics of each patient.

Fertility concerns, preservation strategies and quality of life in young women with breast cancer: Baseline results from an ongoing prospective cohort study in selected European Centers.

OBJECTIVES: Most research addressing needs and concerns of young patients with breast cancer (≤40 years) is retrospective. The HOHO European protocol is a prospective multicenter cohort study of young women with newly diagnosed breast cancer, about fertility, psychosocial and quality of life concerns. Here we report the baseline data and focus on predictors of fertility concerns. MATERIALS AND METHODS: Patient surveys and medical record review were used. The baseline survey included sociodemographic, medical and treatment data as well as questions on fertility concerns and preservation strategies. Subscales from the CAncer Rehabilitation Evaluation System-Short Form (CARES-SF) were administered to measure specific quality of life aspects. Uni- and multivariable modeling were used to investigate predictors of greater fertility concern. RESULTS: Among 297 eligible respondents, 67% discussed fertility issues before starting therapy, 64% were concerned about becoming infertile after treatment, and 15% decided not to follow prescribed therapies. Fifty-four percent of women wished future children before diagnosis; of these, 71% still desired biologic children afterwards. In multivariable analysis, not having children was the only patient characteristic significantly associated with fertility concerns at diagnosis. Twenty-seven percent used fertility preservation strategies. Women who received chemotherapy reported greater physical (p = 0.021) and sexual difficulties (p = 0.039) than women who did not. Women who were married or had a partner reported less psychosocial problems than single women (p = 0.039). CONCLUSIONS: Young women with newly diagnosed breast cancer have several concerns, including, but not limited to, fertility. The HOHO European study provides valuable information to develop targeted interventions.

Partial characterization of SUVi, a new mammalian gene induced by UV-C and expressed during the S phase of the cell cycle.

By using a lacZ-based gene-trap approach, we identified a mammalian gene induced by UV-C in a Chinese hamster ovary cell clone (Menichini P et al. [1997]: Nucleic Acids Res 25:4803-4807). The activity of the encoded protein fused to a bacterial beta-galactosidase was followed through the hydrolysis of different beta-galactosidase substrates. In this study we describe how the expression of this gene is modulated during the cell cycle and in response to UV-irradiation. We show that the beta-galactosidase activity was virtually undetectable in quiescent cells (G[0]), started to increase when cells progressed in G(1), and reached a maximum in mid-S phase, indicating a possible role of the endogenous protein during DNA synthesis. Following UV-irradiation, besides a delay of the progression through the S phase, a twofold increase of the reporter protein activity in all phases of the cell cycle was observed. The partial sequence analysis showed that this gene, here named SUVi (for S phase UV-inducible), contains a domain that is highly conserved among different helicases. Together, these data suggest that the SUVi gene could be involved in DNA synthesis, a process that takes place both in the S phase and in the processing of UV-induced damage.

Treatment of liver metastases from colorectal cancer: what is the best approach today?

Liver is the common site for metastases from colorectal cancer. The 5-year overall survival rate of patients following radical operations is 25%. Surgery can be carried out in only 10-15% of the patients, yet it remains the potential curative treatment for resectable lesions. For the unresectable cancers, only chemotherapy is recommended. New drugs such as Irinotecan prolongs the overall survival of patients affected by advanced disease. In patients with unresectable metastases at diagnosis, pre-surgical treatment with Oxaliplatin leads to reduction of the lesions, allowing resection in 16% of cases. Chemotherapy may be delivered directly into the liver via the hepatic artery. No, clinical trials, to date, have shown convincing survival results in patients treated with this procedure. Combined hepatic artery and systemic treatment may provide a new strategy as adjuvant therapy for patients undergoing resections.

Sister chromatid exchange induction in peripheral blood lymphocytes of traffic police workers.

Traffic police workers, as a population exposed to urban atmosphere, were compared with a control population exposed to indoor air pollution levels. Sister chromatid exchanges (SCEs) as a biomarker of effect were measured in peripheral blood lymphocytes of 54 exposed subjects and 35 controls, and environmental concentration of polynuclear aromatic hydrocarbon (PAH) tracer compounds was detected by personal air samplers. The mean exposure level to benzo[a]pyrene in our group of traffic policemen (3.4 mg/m3) was in the range that has been estimated in urban areas in Europe during the last 10 years. No difference in SCE levels was found between exposed workers (7.36, SD 1.35) and controls (7.47, SD 1.28). No correlation was observed between SCE/cell and airborne PAH concentration in the traffic worker population. A positive regression of SCE on exposure estimate was found only in the non-smoking group of police workers. Our findings suggest that exposure to urban air pollution does not induce relevant cytogenetic effects.

Aflatoxin exposure and cytogenetic alterations in individuals from the Gambia, West Africa.

Aflatoxin-albumin adducts in peripheral blood provide a measure of exposure to aflatoxin over the previous 2-3 months. In the present study, the levels of these adducts were determined in a group of individuals from The Gambia, West Africa and were compared in a cross-sectional study to the levels of various cytogenetic alterations (chromosomal aberrations, micronuclei, sister chromatid exchanges) in the same individuals to test whether an increase in genetic damage is associated with an increased exposure in this population. Of 35 subjects tested for aflatoxin-albumin adducts, all but 3 were positive. There were no correlations between the adduct level and the number of cytogenetic abnormalities at the individual level. A comparison of the cytogenetic alterations was made between Gambian individuals and a group of 22 healthy people from Italy where aflatoxin exposure is expected to be low. The levels of structural chromosomal aberrations, sister chromatid exchanges and micronuclei were all higher in the former group. Overall, these data are indicative of a higher exposure to genotoxins in Gambian subjects, one of which are aflatoxins, but suggest that more specific genetic markers of aflatoxin exposure are required to further examine the link between aflatoxin exposure and genetic alterations.

Phase I clinical and pharmacokinetic study of trabectedin and doxorubicin in advanced soft tissue sarcoma and breast cancer.

The combination of trabectedin (T) and doxorubicin (D) was brought into clinical development in soft tissue sarcoma (STS) and advanced breast cancer (ABC) because of its in vitro and in vivo additive anti-tumour effect, the fact that there are no overlapping toxicities and the anti-tumour activity of T in those tumours. Feasibility and anti-tumour activity of T+D administered every 3 weeks were evaluated in 38 patients (STS=29, ABC=9) untreated for advanced disease. D was given at 60 mg/m(2) and T at escalating doses from 600 to 800 microg/m(2), which was the maximum tolerated dose due to dose-limiting febrile neutropenia and asthenia. The recommended dose--given to 18 patients in total--was 700 microg/m(2) T with 60 mg/m(2) D. The pharmacokinetic profile of T and D at cycle 1 was analysed in 20 patients. The most common toxicities included a severe but reversible ASAT/ALAT increase (94%), nausea/vomiting, neutropenia, asthenia/fatigue, stomatitis. Partial response and stable disease were assessed in 18% and 56% of STS patients and in 55% and 33% of ABC patients. No pharmacokinetic interaction between T and D was observed. The lack of cumulative toxicity and related complications and the promising activity in STS support further development of T+D.

Phase I clinical and pharmacokinetic study of trabectedin and cisplatin in solid tumours.

AIM OF THE STUDY: To define the maximum tolerated dose (MTD) and toxicity of trabectedin (T) and cisplatin (C) given on days 1 and 8 every 3 weeks to adult patients with advanced solid tumours. Plasma pharmacokinetics at cycle 1 and a preliminary anti-tumour activity assessment in ovarian and non-small cell lung cancer (OC, NSCLC) were secondary objectives. METHODS: In the dose finding part (DFP) of the study the dose of T given at each administration was escalated by 100 microg/m(2) increments from 300 microg/m(2) up to the MTD, with a fixed dose of C of 40 mg/m(2). The recommended dose (RD) was assessed in the previously treated and untreated OC and NSCLC patients in the expansion of the RD (ERD) part of the study. T was administered with corticosteroids pre-medication as 3-h infusion and C as 30-min infusion. RESULTS: Thirty-nine patients were treated in the DFP and 10 in the ERD. The MTD of T was 700 microg/m(2) due to dose-limiting neutropaenia and the RDs in the previously treated/untreated patients were 500 and 600 microg/m(2), respectively. Most common toxicities were nausea/vomiting (67%), asthenia/fatigue (55%) and reversible ASAT/ALAT elevation (51%). Time to recovery from myelosuppression was dose-dependent and treatment could be repeated after > or = 4 weeks in the majority of patients at 600 microg/m(2). Confirmed partial responses were observed in 4 of 13 evaluable OC patients and in 1 with uterine leiomyosarcoma. No pharmacokinetic interaction was observed. CONCLUSION: The administration of T and C on days 1 and 8 resulted in prolonged neutropaenia requiring treatment delay. The evaluation of a single every 3 week schedule is worthwhile because of the hints of anti-tumour activity observed in OC.

Phase I study of bortezomib with weekly paclitaxel in patients with advanced solid tumours.

BACKGROUND: The combination of a proteasome inhibitor with a taxane has potential clinical synergism that prompted a clinical test. PATIENTS AND METHODS: The maximum tolerated dose (MTD) and recommended dose (RD) of intravenous (i.v.) Bortezomib (B) (days 1, 4, 8, 11) and i.v. Paclitaxel (PTX) (days 1, 8) every 3 weeks was evaluated in patients with advanced solid tumours. The RD was tested in patients with breast, ovarian and prostate cancer. At the RD, microarray analysis of transcriptional profiles was carried out before and after the first dosing in peripheral blood mononuclear cells (PBMC). RESULTS: Thirty-one patients were enrolled and 22 were treated at the RD that corresponded to B 1.3mg/m(2) and PTX 100mg/m(2). The main toxicity was cumulative peripheral neuropathy (76% of patients; grade 3-4 in 9%) that required treatment discontinuation in six patients, followed by diarrhoea (55%) and fatigue (41%). Nine partial responses (30%) were observed (three breast cancer, four ovary, two prostate patients). Significant (p<0.05) and consistent changes (>70% of patients) in transcriptome were observed. CONCLUSIONS: The incidence of peripheral neuropathy and the anti-tumour activity comparable to that of single-agent PTX do not support further development of this regimen.

Acute left ventricular dysfunction due to Tako-tsubo syndrome after induction of general anesthesia.

Tako-tsubo cardiomyopathy is a recently described form of transient ventricular dysfunction that is not associated with coronary vessels obstruction, although its clinical manifestations are often similar to those of myocardial ischemia. This syndrome is possibly due to an excess of catecholamines, and it is associated with emotional and physical stress and surgery. However, the pathophysiological relation to anaesthesia has not yet been clarified. We report a case of Tako-tsubo cardiomyopathy that ensued immediately after induction of general anaesthesia for elective surgery in a patient submitted to laparoscopic cholecystectomy. The patient was first treated as if affected by myocardial ischemia, but a rapidly performed emergency coronary angiography showed normal epicardial coronary vessels with a significant reduction of left ventricular function. The coronary angiography ruled out the diagnosis of typical myocardial ischemia and allowed for the arrival at the correct diagnosis. The transient ventricular ballooning was attributed to the recently described Tako-tsubo syndrome. Prompt treatment allowed control of symptoms, and the patient was safely treated and discharged on day 15. Although it is difficult to identify the cause of this syndrome, it may be argued that, during general anaesthesia and particularly at induction, the imperfect control of catecholamine excess may induce cardiac damage in predisposed subjects.

A-line autoregression index monitoring to titrate inhalational anaesthesia: effects on sevoflurane consumption, emergence time and memory.

BACKGROUND: A-line autoregression index (AAI) is a parameter derived from auditory evoked potentials proposed as depth of anaesthesia monitor. We evaluated the effects of AAI guidance on sevoflurane consumption, emergence time, explicit and implicit memory. METHODS: One hundred patients submitted to major abdominal surgery were randomized into two groups. In group A (n = 50), sevoflurane was titrated according to AAI (target = 20 +/- 5), in group B (n = 50) according to clinical signs. Anaesthesia was induced with fentanyl, propofol, atracurium and maintained with sevoflurane. The mean value of sevoflurane consumption (g/min) and emergence time has been assessed in both groups. After emergence, A test of explicit memory was administered. We assessed implicit memory using a category generation test. RESULTS: In group A, mean sevoflurane consumption was significantly (P = 0.0001) reduced by 20.4% and mean emergence time was significantly (P = 0.00012) shorter by 2 min with respect to group B. No patients experienced explicit memory while the difference between the two groups in implicit memory results was not significant (P = 0107). CONCLUSIONS: AAI titration of anaesthesia allows a significant reduction in sevoflurane consumption and emergence time without significant effects on the incidence of explicit and implicit memory. Nevertheless the relationship between AAI and memory requires studies in larger groups of patients.

A gene trap approach to isolate mammalian genes involved in the cellular response to genotoxic stress.

Treatment of cells with DNA damaging agents leads to induction of a variety of genes involved in different cellular processes. We have applied a lacZ-based gene trap strategy to search for new mammalian genes induced by genotoxic stress. A population of 32 x 10(3) neo r clones stably transfected with a gene trap vector was obtained, stained with fluorescein di-beta-d-galactopyranoside and analyzed by flow activated cell sorting and replica plating. This strategy allowed isolation of 30 neo r 'putative inducible' cell lines expressing lacZ only after a DNA damaging treatment. For three clones the site of integration and the degree of inducibility after UV treatment were determined by Southern blot and beta-galactosidase measurement respectively. One cell line (clone VI) showed a single integration site and a reproducible 3-fold induction of beta-galactosidase activity following UV irradiation. Fused transcripts were isolated from induced cells and a portion of the trapped gene was amplified by rapid amplification of cDNA ends. Sequence analysis and comparison with available gene and protein databanks revealed that the gene was novel.