Search

Aim Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is an experimental drug delivery method that applies chemotherapy into the abdominal cavity as an aerosol under pressure. We present the first results obtained with PIPAC in colorectal peritoneal metastasis (CPM). Method This is a retrospective analysis. PIPAC was applied in 17 consecutive patients with pretreated CPM. All patients had previously undergone surgery, and 16 had undergone previous lines of systemic chemotherapy (median, two lines). The mean peritoneal metastasis index (peritoneal cancer index) was 16 ± 10. Forty-eight applications of PIPAC with oxaliplatin (92 mg/m2) were given every 6 weeks at 37°C and 12 mmHg for 30 min. The outcome criteria were microscopic pathological response, survival and adverse events according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Results Forty-eight PIPAC administrations were performed with no intra-operative complications. The mean number of PIPAC administrations per patient was 2.8 (minimum one, maximum six). Postoperative adverse events (CTCAE level 3) were observed in four patients (23%), no CTCAE level-4 adverse events were reported. The hospital mortality was zero. Objective tumour responses were observed in 12/17 patients (71%), and the overall responses were as follows: complete pathological response (seven patients), major response (four patients), partial response (one patient), no response (two patients) and not eligible (three patients). The mean survival after first PIPAC was 15.7 months. Conclusion Repeated PIPAC with oxaliplatin can induce the regression of pretreated CPM. The toxicity appears to be low. These preliminary results are encouraging and justify prospective clinical studies.

Background This multicenter, double-blind phase II study assessed the antitumor activity and toxicity profile of docetaxel with the antiangiogenic multikinase inhibitor sorafenib or matching placebo as a first-line treatment in patients with metastatic or locally advanced HER2-negative breast cancer. Patients and methods Patients were randomized 1:1 to receive docetaxel 100 mg/m2 on day 1 every 3 weeks in combination with sorafenib 400 mg bid or placebo on days 2–18 of each cycle until tumor progression, or unacceptable toxicity. Sorafenib/placebo could be continued at the investigator's discretion if docetaxel was stopped due to toxicity. Primary endpoint was progression free survival (PFS). Results From October 2008 to December 2013, 102 patients were randomized; 98 patients were evaluable. The trial was prematurely terminated due to slow accrual. Due to increased toxicity the dose of docetaxel was reduced to 75 mg/m2 and an increasing sorafenib dosing schedule was implemented as part of a protocol amendment. The addition of sorafenib to docetaxel did not improve PFS (8.2 vs. 7.3 months for docetaxel/placebo; HR 0.84, log rank p = 0.43), but led to higher rates of early treatment discontinuation. There were no statistically significant differences between sorafenib dosing schedules. Conclusions Addition of sorafenib to taxane-based first-line chemotherapy in patients with metastatic breast cancer failed to improve PFS and resulted in increased toxicity.

Until recently, acquired resistance to cytostatics had mostly been attributed to biochemical mechanisms such as decreased intake and/or increased efflux of therapeutics, enhanced DNA repair, and altered activity or deregulation of target proteins. Although these mechanisms have been widely investigated, little is known about membrane barriers responsible for the chemical imperviousness of cell compartments and cellular segregation in cytostatic-treated tumors. In highly heterogeneous cross-resistant and radiorefractory cell populations selected by exposure to anticancer agents, we found a number of atypical recurrent cell types in (1) tumor cell cultures of different embryonic origins, (2) mouse xenografts, and (3) paraffin sections from patient tumors. Alongside morphologic peculiarities, these populations presented cancer stem cell markers, aberrant signaling pathways, and a set of deregulated miRNAs known to confer both stem-cell phenotypes and highly aggressive tumor behavior. The first type, named spiral cells, is marked by a spiral arrangement of nuclei. The second type, monastery cells, is characterized by prominent walls inside which daughter cells can be seen maturing amid a rich mitochondrial environment. The third type, called pregnant cells, is a giant cell with a syncytium-like morphology, a main nucleus, and many endoreplicative functional progeny cells. A rare fourth cell type identified in leukemia was christened shepherd cells, as it was always associated with clusters of smaller cells. Furthermore, a portion of resistant tumor cells displayed nuclear encapsulation via mitochondrial aggregation in the nuclear perimeter in response to cytostatic insults, probably conferring imperviousness to drugs and long periods of dormancy until nuclear eclosion takes place. This phenomenon was correlated with an increase in both intracellular and intercellular mitochondrial traffic as well as with the uptake of free extracellular mitochondria. All these cellular disorders could, in fact, be found in untreated tumor cells but were more pronounced in resistant entities, suggesting a natural mechanism of cell survival triggered by chemical injury, or a primitive strategy to ensure stemming, self-renewal, and differentiation under adverse conditions, a fact that may play a significant role in chemotherapy outcomes.

Background The aim of this study was the evaluation of pharmacokinetic parameters, biomarkers, clinical outcome, and imaging parameters in metastatic colorectal cancer (mCRC) patients treated with FOLFIRI plus sunitinib. Methods mCRC patients with liver metastases were treated with FOLFIRI and sunitinib as 1st line therapy. At protocol-defined time points, multicontrast magnetic resonance imaging (MRI)measurements, computed tomography (CT) scans, pharmacokinetics (PK), and biomarker analyses were performed during the first and second treatment cycle. Thereafter, patients were treated until tumor progression, investigator’s decision due to toxicity, or patient withdrawal. Results 28 patients were screened, 26 were included, and 23 received at least one study medication. Full safety analysis was performed in 23 patients. Full PK and biomarker analyses were performed in 21 patients. Strong responses in tumor size reduction forced a change from the original imaging timing scheme. This unforeseen change in the timing scheme resulted in subgroups too small for meaningful statistical analysis of most imaging parameters. Thus, only a descriptive analysis of the MRI data was possible. In 21/22 patients, MRI showeda decrease of the liver metastases. Best response was partial remission (PR) in 8/17 patients. Plasma concentrations of sVEGFR-2 and sVEGFR-3 decreased in all patients. The majority of the patients developed some kind of toxicity not always deducible to FOLFIRI or sunitinib. Conclusions Due to the observed side effect profile, FOLFIRI plus sunitinib 37.5 mg per day cannot be recommended for previously untreated mCRC.

Background Peritoneal carcinomatosis (PC) is an unmet medical need. Despite recent improvements, systemic chemotherapy has limited efficacy. We report the first application of intraperitoneal chemotherapy as a pressurized aerosol in human patients. Methods Three end-stage patients with advanced PC from gastric, appendiceal, and ovarian origin were treated as a compassionate therapy. All patients had received previous systemic chemotherapy. A pressurized aerosol of CO2 loaded with doxorubicin 1.5 mg/m2 and cisplatin 7.5 mg/m2 (pressurized intraperitoneal aerosol chemotherapy, PIPAC) was applied into the abdomen for 30 min at a pressure of 12 mmHg and a temperature of 37 °C. Results No side-effects >2 CTCAE were observed, and the procedures were well tolerated. Early hospital discharge was possible (days 2–5). Nuclear presence of doxorubicin was documented throughout the peritoneum, reaching high local concentration (≤4.1 μmol/g) and plasma concentration was low (4.0–6.2 ng/ml). PIPAC created no significant adhesions, could be repeated, and was applied 6×, 4×, and 2×. Two patients showed a complete and one a partial histological remission. Mean survival after the first PIPAC was 288 days. One patient is alive after 567 days. Conclusions PIPAC shows superior pharmacological properties with high local concentration and low systemic exposure. PIPAC can induce regression of PC in chemoresistant tumors, using 10 % of a usual systemic dose. Electronic supplementary material The online version of this article (doi:10.1245/s10434-013-3213-1) contains supplementary material, which is available to authorized users.

WOS: 000411827200016, PubMed ID: 28961832, Background: This randomized study was designed to investigate the superiority of gemcitabine (gem) plus nimotuzumab (nimo), an anti-epidermal growth factor receptor monoclonal antibody, compared with gem plus placebo as first-line therapy in patients with advanced pancreatic cancer. Patients and methods: Patients with previously untreated, unresectable, locally advanced or metastatic pancreatic cancer were randomly assigned to receive gem: 1000 mg/m(2), 30-min i.v. once weekly (d1, 8, 15; q29) and nimo: fixed dose of 400 mg once weekly as a 30-min infusion, or gem plus placebo, until progression or unacceptable toxicity. The primary end point was overall survival (OS), secondary end points included time to progression, overall response rate, safety and quality of life. Results: A total of 192 patients were randomized, with 186 of them being assessable for efficacy and safety (average age 63.6 years). One-year OS/progression-free survival (PFS) was 34%/22% for gem plus nimo compared with 19%/10% for gem plus placebo (HR = 0.69; P = 0.03/HR = 0.68; P = 0.02). Median OS/PFS was 8.6/5.1 months for gem plus nimo versus 6.0/3.4 mo in the gem plus placebo group (HR = 0.69; P = 0.0341/HR = 0.68; P = 0.0163), with very few grade 3/4 toxicities. KRAS wildtype patients experienced a significantly better OS than those with KRAS mutations (11.6 versus 5.6 months, P = 0.03). Conclusion: This randomized study showed that nimo in combination with gem is safe and well tolerated. The 1-year OS and PFS rates for the entire population were significantly improved. Especially, those patients with KRAS wildtype seem to benefit. The study was registered as protocol ID OSAG101-PCS07, NCT00561990 and EudraCT 2007-000338-38., Oncoscience AG, Schenefeld, Germany, This multi-institutional, randomized phase IIb trial was sponsored by Oncoscience AG, Wedel (recently Schenefeld), Germany. There is no grant number applicable.

Radioimmunotherapy is considered as treatment option in recurrent and/or refractory B-cell non-Hodgkin lymphoma (B-NHL). To overcome the dose limiting bone marrow toxicity of IgG-based radioimmunoconjugates (RICs), we modified a humanized diabody with 5-, 10-, or 20-kDa polyethylene glycol (PEG) for CD22-targeted radioimmunotherapy using the low-energy β-emitter lutetium-177 ((177)Lu). A favorable pharmacokinetic profile was observed for the 10-kDa-PEG-diabody in nude mice being xenografted with subcutaneous human Burkitt lymphoma. Even at high doses of 16 MBq this diabody RIC was well tolerated by NOD Rag1(null) IL2rγ(null) (NRG) mice and did not reveal signs of organ long-term toxicity 80 days post injection. Combination therapy of the diabody RIC with unconjugated anti-CD20 Rituximab demonstrated therapeutic efficacy in established disseminated mantle cell lymphoma xenograft models. When compared with the combination of the IgG formatted (177)Lu anti-CD22 antibody and Rituximab, dual targeted therapy with the diabody RIC achieved an improved reduction of disease burden in the first nine days following treatment. The data indicate that the PEGylated anti-CD22 diabody may have potential for extending the repertoire of radiopharmaceuticals for the treatment of patients with B-NHL.

The aim of this work was to characterize the antitumoral activity of the plant compound 7-epi-nemorosone in prostate carcinoma cell lines. Prostate cancer is the most frequently diagnosed malignancy and the second-leading cause of cancer death in men. In spite of the current therapeutic options for this cancer entity, many patients die due to metastases in distant organs and acquired chemotherapy resistance. Thus, approaches to provide improvements in outcome and quality of life for such patients are urgently needed. Recently, the polyisoprenylated benzophenone 7-epi-nemorosone, originally collected by honeybees from Clusia rosea and Clusia grandiflora ( Clusiaceae ), has been described to be a potent antitumoral agent. Here, its activity in prostate carcinoma is reported. 7-epi-nemorosone was isolated from Caribbean propolis employing RP-HPLC techniques. Its cytotoxicity was assessed using the MTT proliferation assay in human androgen-dependent prostate carcinoma LNCaP cells including an MDR1 + sub-line. No cross-resistance was detected. FACS-based cell cycle analysis revealed a significant increase in the sub-G0/G1, G1, and depletion in the S phase populations. A concomitant down-regulation of cyclins D1/D3 and CDK 4/6 in LNCaP cells was detected by Western blot. Annexin-V-FITC labeling and caspase-3 cleavage assays showed that 7-epi-nemorosone induced apoptotic events. Major signal transduction elements such as p38 MAPK and Akt/PKB as well as androgen receptor AR and PSA production were found to be down-regulated after exposure to the drug. ERK1/2 protein levels and phosphorylation status were down-regulated accompanied by up-regulation but inhibition of the activity of their immediate upstream kinases MEK1/2. Additionally, Akt/PKB enzymatic activity was effectively inhibited at a similar concentration as for MEK1/2. Here, we demonstrate for the first time that 7-epi-nemorosone exerts cytotoxicity in an androgen-dependent prostate carcinoma entity by targeting the MEK1/2 signal transducer.

Background: BI 2536, a novel Polo-like kinase 1 inhibitor, was assessed in patients with unresectable advanced exocrine adenocarcinoma of the pancreas. Methods: The study employed a two-stage design. Randomised first-line patients received BI 2536 200 mg on day 1 (n=43) or 60 mg on days 1-3 (n=43) every 21 days. Recruitment of second-line patients was planned for a second stage dependent on an interim analysis demonstrating ≥2 responses in the first 18 evaluable patients following 12 weeks of treatment and/or tumour control ≥12 weeks in 5 patients per schedule. Primary end point was objective response rate (ORR). Results: By independent review, ORR was 2.3% (all partial) and 24.4% had stable disease as confirmed best response. The second stage was not initiated. Median overall and progression-free survivals were 149 (95% confidence interval (CI), 91-307) and 46 days (95% CI, 44-56). Most common drug-related adverse events were neutropenia (37.2%), leukopenia (29.1%), fatigue (29.1%) and nausea (22.1%); most common grade 3/4-related events were neutropenia (36.0%), leukopenia (27.9%) and thrombocytopenia (8.1%). Conclusion: Given the low ORR and poor survival, further development of BI 2536 monotherapy is not warranted in this population. © 2012 Cancer Research UK All rights reserved.

Sorafenib was the first oral antiangiogenic multikinase inhibitor (Raf kinases, VEGF receptors 1 - 3, PDGF-beta, Flt-3, c-kit) for advanced renal cell carcinoma (RCC) to be approved. Since 2005, a total of six drugs have been approved for the treatment of RCC.The preclinical and clinical development of sorafenib that led to its approval for advanced RCC is reviewed in this paper. Its safety, tolerability and efficacy are summarized and compared with other approved treatment options for RCC. Preliminary data on sequential treatment strategies and combination trials with other targeted drugs are also discussed.The efficacy and good tolerability of sorafenib in patients with RCC has already been confirmed by numerous studies. The drug proved to be suitable for patients of any age, with respect to efficacy and safety. Sequential use of sorafenib and other targeted drugs is characterized by only limited cross-resistance and many studies seem to indicate more clinical benefits and longer overall progression-free survival when sorafenib is administered as a first-line therapy. However, the optimal sequential therapy remains to be determined within prospective trials, such as the SWITCH study. In addition, we need predictive biomarkers to preselect the patients with the best chances of benefiting from sorafenib, in the context of personalized medicine.

Purpose S-1, an oral fluoropyrimidine derivative, has previously demonstrated anticancer efficacy in pancreatic cancer (PC), predominantly in Asian populations. This study evaluated the antitumor effect and safety of S-1 in Caucasian patients with metastatic PC. Methods Chemotherapy-naive patients received S-1 orally at 30 mg/m2 twice daily (BID) for 2 weeks, repeated every 3 weeks. Primary endpoint was ORR. Secondary endpoints included PFS, OS and safety assessment. The trial had a Simon’s two-stage design with 22 patients evaluable for efficacy in stage 1 and an additional 18 patients in stage 2, if ≥3/22 patients had a confirmed response at the first stage. Results Three out of 27 patients showed PR, however, detection of asymptomatic brain metastases in one of them prevented this study from proceeding to stage 2. The median PFS and OS for all patients was 3.5 and 9.1 months, respectively. The median duration of disease control for patients with SD or PR (n = 17) was 4.3 months. S-1 was well tolerated; fatigue was the most frequent grade 3/4 adverse event. Conclusions Efficacy data of PFS and OS are at least comparable to gemcitabine, the current standard of care. S-1 is active in Caucasian patients with metastatic PC.

There were only a few options 3 years ago to treat metastatic renal cell carcinoma (mRCC), a disease with a very poor prognosis. With the approval of targeted therapies for mRCC since December 2005, this situation has changed dramatically. Currently, oncologists can choose between several promising options to improve the longevity and quality of their patients' lives. A widely accepted treatment scheme for targeted therapies in mRCC does not yet exist. Based on a selective literature search, drawing on studies with six targeted therapies for mRCC, and including data from the latest American Society of Clinical Oncology (ASCO) and European Society for Medical Oncology (ESMO) Annual Meetings, this review introduces the available therapies, evaluates patient-specific criteria for their application and suggests an algorithm for a patient-based treatment scheme. Clinical experiences with sequential therapies are summarized and potential combination therapies discussed. In conclusion, the crucial criteria of the treatment scheme we propose are the tumor burden and the disease pace, as well as the quality of life of a patient. These define whether tumor control or tumor remission should be the primary therapeutic goal. This scheme suggests which kind of therapeutic sequence to pursue to optimize patient care in mRCC.

Her2/neu protein overexpression and gene amplification is found in 20–30% of breast cancer patients and correlates with poor clinical outcome. Patients who profit from anti-Her2/neu- therapy are routinely selected by examination of tumour specimens using immunohistochemistry (IHC) and fluorescence in situ hybridisation (FISH) separately. Many studies found a good correlation between both methods for score 1+ samples and for score 3+ samples, but not for score 2+ samples. In this study, we examined pleural and ascitic effusions with a combined approach using IHC and FISH on the same cells, under the following aspects: (1) frequency of Her2/neu protein expression and gene amplification in effusions; (2) correlation between score of protein expression and gene amplification; (3) impact of chromosome 17 polyploidy on Her2/neu protein expression. We examined 31 effusions from patients with breast cancer and 4 effusions from patients with ovarian cancer. Cytospins were analysed by IHC using two anti-Her2/neu antibodies and subsequently analysed by FISH with Her2/neu/CEP17 probes. Amplification was defined as: (1) Her2/neu gene copy number of more than 4 and (2) Her2/neu/CEP17 ratio of 2.0 or greater. A system combining IHC and FISH was developed and 35 effusion specimens were examined. As much as 25 of them were scored as positive. All of them contained cells with heterogeneous scores. A total of 18 of the samples contained cells with scores that ranged from 0 to 3+. In the other samples scores ranged from 0 to 1+ or 0 to 2+. Cells were analysed for Her2/neu gene amplification and chromosome 17 ploidy with regard to their scores. As much as 15 of all samples had mean Her2/neu copy numbers of >4, but only 12% (n = 3) of the positive samples were amplified according to Her2/neu/CEP17 ratio. Only 22, 9% (n = 8) were polyploid (mean CEP17 > 4); but 65, 7% (n = 23) of all specimens contained single polyploid cells. In some cases up to 100% of the score 3+ cells showed chromosome 17 polyploidy. Here protein overexpression might be caused by polyploidy rather than by gene amplification. In some samples, we found single cells with gene amplification but without protein expression and cells without amplification but with protein overexpression. The combination of IHC and FISH allows a differentiated analysis of single cells, which is especially important for effusions that are composed of heterogeneous cells. Therefore, cells with high gene amplification and/or protein overexpression can be detected and analysed even if their amount in the sample is small. Chromosome 17 polyploidy is important in some cases but this should be further examined on a larger series.

Telatinib (BAY 57-9352) is an orally available, small-molecule inhibitor of vascular endothelial growth factor receptors 2 and 3 (VEGFR-2/-3) and platelet-derived growth factor receptor beta tyrosine kinases. In this multicentre phase I dose escalation study, 71 patients with refractory solid tumours were enroled into 14 days on/7 days off (noncontinuous dosing) or continuous dosing groups to receive telatinib two times daily (BID). Hypertension (23%) and diarrhoea (7%) were the most frequent study drug-related adverse events of CTC grade 3. The maximum-tolerated dose was not reached up to a dose of 1500 mg BID continuous dosing. Telatinib was rapidly absorbed with median t(max) of 3 hours or less. Geometric mean C(max) and AUC(0-12) increased in a less than dose-proportional manner and plateaued in the 900-1500 mg BID dose range. Two renal cell carcinoma patients reached a partial response. Tumour blood flow measured by contrast-enhanced magnetic resonance imaging and sVEGFR-2 plasma levels decreased with increasing AUC(0-12) of telatinib. Telatinib is safe and well tolerated up to a dose of 1500 mg BID continuous dosing. Based on pharmacokinetic and pharmacodynamic criteria, 900 mg telatinib BID continuously administered was selected as the recommended phase II dose.

In this study, we investigated the kinetics of oxaliplatin-DNA adduct formation in white blood cells of cancer patients in relation to efficacy as well as oxaliplatin-associated neurotoxicity. Thirty-seven patients with various solid tumours received 130 mg m(-2) oxaliplatin as a 2-h infusion. Oxaliplatin-DNA adduct levels were measured in the first cycle using adsorptive stripping voltammetry. Platinum concentrations were measured in ultrafiltrate and plasma using a validated flameless atomic absorption spectrometry method. DNA adduct levels showed a characteristic time course, but were not correlated to platinum pharmacokinetics and varied considerably among individuals. In patients showing tumour response, adduct levels after 24 and 48 h were significantly higher than in nonresponders. Oxaliplatin-induced neurotoxicity was more pronounced but was not significantly different in patients with high adduct levels. The potential of oxaliplatin-DNA adduct measurements as pharmacodynamic end point should be further investigated in future trials.

Sorafenib is a multi-kinase inhibitor with antiangiogenic and antiproliferative activity. The activity of sorafenib in progressive hormone-refractory prostate cancer (HRPC) patients was investigated in a phase II clinical study. Progressive HRPC patients received sorafenib 400 mg bid p.o. continuously. Only patients with no prior chemotherapy, and either one-unidimensional measurable lesion according to RECIST-criteria or increasing prostate-specific antigen (PSA) values reflecting a hormone-refractory situation, were eligible for study entry. The primary study objective was the rate of progression-free survival of ⩾12 weeks (PFS12). Secondary end points were overall response, overall survival, and toxicity. Fifty-seven patients with PC were enrolled. Two patients had to be withdrawn from the set of eligible patients. According to RECIST criteria, 4 patients out of 55 evaluable patients showed stable disease (SD). According to PSA–response, we saw 11 patients with SD PSA and 2 patients were responders at 12 weeks (PFS12=17/55=31%). Among the 257 adverse events, 15 were considered drug related of maximum CTC-grade 3. Twenty-four serious adverse events occurred in 14 patients (14/55=26%). Seven of them were determined to be drug related. No treatment-related death was observed. Sorafenib has antitumour activity in HRPCP when evaluated for RECIST- and PSA-based response. Further investigation as a component of combination regimens is necessary to evaluate its definite or overall clinical benefit for HRPCP.

BACKGROUND. S-1 is a promising oral fluoropyrimidine. The authors obtained extended Phase II safety and efficacy data in a multicenter setting for the S-1 plus cisplatin combination: The experimental arm of the global Phase III First-Line Advanced Gastric Cancer Study (FLAGS) is being compared with 5-fluorouracil/cisplatin. METHODS. Eligible patients had untreated, histologically confirmed advanced gastric cancer (AGC), a Karnofsky performance status (KPS) ≥70%, adequate organ function, and provided written consent. Patients received S-1 (25 mg/m2 twice daily on Days 1 through 21) plus cisplatin (75 mg/m2 on Day 1) every 28 days. The confirmed overall response rate (CORR) also was designated by an external review. The time to progression (TTP), median survival (MS), and safety were assessed. RESULTS. All 72 patients were assessed for safety and survival, and 64 patients were assessed for CORR. The median KPS was 90%. The median number of treatment cycles was 4. The CORR was 55% (95% confidence interval [95% CI], 42–67%). The median duration of response was >5 months. At 6 months, only an estimated 38% of patients had cancer progression. The estimated MS was 10.4 months (95% CI, 8.6–12.9 months). At least 1 serious adverse event occurred in 44% of patients. The frequent grade 3 or 4 toxicities (using the National Cancer Institute Common Toxicity Criteria), which occurred in >10% of patients, included fatigue/asthenia (24%), emesis (17%), nausea (15%), diarrhea (13%), and neutropenia (19%). Complicated neutropenia (1.4%) and grade 4 diarrhea (1.4%) were rare. CONCLUSIONS. The current extended data confirmed that S-1 combined with cisplatin had a highly desirable safety profile. The efficacy against AGC, according to an external review, was encouraging. FLAGS is expected to complete its accrual of 1050 patients by December 2007. Cancer 2007. © 2006 American Cancer Society.

Sorafenib (BAY 43-9006), a novel, oral multi-kinase inhibitor, blocks serine/threonine and receptor tyrosine kinases in the tumor and vasculature. Sorafenib demonstrated single-agent activity in Phase I studies, and was tolerated and inhibited tumor growth in combination with doxorubicin in preclinical studies. This Phase I dose-escalation study determined the safety, pharmacokinetics and efficacy of sorafenib plus doxorubicin.Thirty-four patients with refractory, solid tumors received doxorubicin 60 mg/m(2) on Day 1 of 3-week cycles, and oral sorafenib from Day 4 of Cycle 1 at 100, 200 or 400 mg bid.Common drug-related adverse events were neutropenia (56%), hand-foot skin reaction (44%), stomatitis (32%), and diarrhea (32%). The maximum tolerated dose was not reached. One patient with pleural mesothelioma achieved a partial response (modified WHO criteria) and remained on therapy for 39.7 weeks. Fifteen patients (48%) achieved stable disease for/=12 weeks. Doxorubicin exposure increased moderately with sorafenib 400 mg bid. The pharmacokinetics of sorafenib and doxorubicinol were not affected.Sorafenib 400 mg bid plus doxorubicin 60 mg/m(2) was well tolerated. The increased doxorubicin exposure with sorafenib 400 mg bid did not result in significantly increased toxicity; low patient numbers make the clinical significance of this unclear. These promising efficacy results justify further clinical investigation.

In this analysis of the safety and efficacy of BAY 43-9006 (sorafenib) -- a novel, oral multi-kinase inhibitor with effects on tumour and its vasculature -- pooled data were obtained from four phase I dose-escalation trials. Time to progression (TTP) was compared in patients with/without grade 2 skin toxicity/diarrhoea. Grade 3 hand-foot skin reactions (HFS; 8%) and diarrhoea (6%) were common. At the recommended 400mg bid dose for phase II/III trials (RDP), 15% of patients experienced grade 2/3 HFS, and 24% experienced grade 2/3 diarrhoea. Sorafenib induced stable disease for 6 months in 12% of patients (6% stabilized for 1 year). Patients receiving sorafenib doses at or close to the RDP, who experienced skin toxicity/diarrhoea, had a significantly increased TTP compared with patients without such toxicity (P < 0.05). Sorafenib was well tolerated at the RDP, and induced sustained disease stabilization, particularly in patients with skin toxicity/diarrhoea.

Sorafenib (BAY 43-9006), a multiple kinase inhibitor, has been shown to inhibit tumor growth and tumor angiogenesis by targeting Raf kinase, vascular endothelial growth factor receptor, and platelet-derived growth factor receptor. In phase I studies, sorafenib demonstrated single-agent activity in patients with advanced solid tumors and was successfully combined with oxaliplatin in preclinical studies. This phase I study investigated the safety, pharmacokinetics, and efficacy of sorafenib in combination with oxaliplatin.Twenty-seven patients with refractory solid tumors were enrolled in the initial dose-escalation part (cohorts 1, 2A, and 2B) and 10 additional patients with oxaliplatin-refractory colorectal cancer were subsequently enrolled in an extension part (cohort 3). Oxaliplatin 130 mg/m2 was given on day 1 of a 3-week cycle and oral sorafenib was administered continuously from day 4 of cycle 1 at 200 mg twice daily (cohort 1) or 400 mg twice daily (cohorts 2A, 2B, and 3).Adverse events were generally mild to moderate and the maximum tolerated dose was not reached. Common adverse events were diarrhea (52% of patients in the dose-escalation part and 20% in the extension part), sensory neuropathy (44% and 20%), and dermatologic toxicities (41% and 80%). No pharmacokinetic interaction between sorafenib and oxaliplatin was detectable. Two patients with gastric cancer had a partial response. Forty-three percent of patients in cohorts 1 and 2A/B and 78% of patients in cohort 3 exhibited stable disease foror=10 weeks.Continuous oral sorafenib 400 mg twice daily was safely combined with oxaliplatin without detectable drug interactions and showed preliminary antitumor activity in this phase I study. This dose is recommended for phase II studies.

BAY 43-9006 is a novel dual-action Raf kinase and vascular endothelial growth factor receptor (VEGFR) inhibitor that targets tumour cell proliferation and tumour angiogenesis. This Phase I study was undertaken to determine the safety profile, maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetics, and tumour response profile of oral BAY 43-9006 in patients with advanced, refractory solid tumours. BAY 43-9006 was administered daily for repeated cycles of 21 days on/7 days off. A total of 44 patients were enrolled at doses from 50 to 800 mg b.i.d. Pharmacokinetic profiles of BAY 43-9006 in plasma were determined during the first treatment cycle. The most frequently reported adverse events over multiple cycles were gastrointestinal (75%), dermatologic (71%), constitutional (68%), pain (64%), or hepatic (61%) related. A MTD of 400 mg b.i.d. BAY 43-9006 was defined. BAY 43-9006 was absorbed rapidly; steady-state conditions were reached within 7 days. BAY 43-9006 exposure increased nonproportionally with increasing dose. In all, 32 patients were evaluated for tumour response: 15 patients showed tumour progression, 16 patients experienced stable disease (>6 months in eight patients), and one patient with renal cell carcinoma achieved a partial response. BAY 43-9006 given for 21 days with 7 days off treatment was safe, well tolerated, and showed antitumour activity., Clinical Trial, Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't, info:eu-repo/semantics/published

Purpose BAY 43-9006 is a novel dual-action Raf kinase and vascular endothelial growth factor receptor inhibitor that inhibits tumor cell proliferation and angiogenesis. This study established the safety and pharmacokinetics of BAY 43-9006 in 69 patients with advanced refractory solid tumors. Patients and Methods BAY 43-9006 (50 to 800 mg) was administered once or twice daily on a varying weekly schedule. Pharmacokinetic sampling was performed in all patients; preliminary tumor response was also assessed. The effect of BAY 43-9006 on phorbol myristate acetate–stimulated ERK phosphorylation in peripheral blood lymphocytes was studied using flow cytometry. Results Mild to moderate diarrhea was the most common (55%) treatment-related adverse event. The maximum-tolerated dose was 400 mg bid continuous. Dose-limiting toxicities were grade 3 diarrhea and fatigue at 800 mg bid, and grade 3 skin toxicity at 600 mg bid. BAY 43-9006 pharmacokinetics were highly variable for single and multiple dosing, and toxicity did not appear to be dose dependent. Significant decreases of phorbol myristate acetate–stimulated ERK phosphorylation (P < .01) were identified at doses ≥ 200 mg bid continuous. Forty-five patients were assessable for efficacy; one patient had a partial response (hepatocellular carcinoma at 400 mg bid continuous), 25 patients had stable disease, with eight lasting > 6 months and five for >12 months. Eighteen patients had progressive disease, and tumor response could not be evaluated in one patient. Conclusion Oral BAY 43-9006 was well tolerated and appeared to provide some clinical benefits. Based on the results of this study, BAY 43-9006 at 400 mg bid continuous is recommended for ongoing and future studies.

Raf kinase plays a central role in oncogenic signaling and acts as a downstream effector of Ras in the extracellular signal-regulated (ERK) kinase pathway. BAY 43-9006 (BAY) is a novel signal transduction inhibitor that prevents tumor cell proliferation and angiogenesis through blockade of the Raf/MEK/ERK pathway at the level of Raf kinase and the receptor tyrosine kinases vascular endothelial growth factor receptor-2 and platelet-derived growth factor receptor-beta. The present study evaluates the effects of combining BAY and platinum derivatives on human colorectal cancer cells using different incubation protocols. Our data show that the combination of oxaliplatin or cisplatin with BAY results in marked antagonism irrespective of the used application schedule. Furthermore, BAY abrogates the cisplatin-induced G2 arrest as well as the G1 arrest induced by oxaliplatin. BAY alone arrests cancer cells in their current cell cycle phase and affects cell cycle regulative genes. Specifically, BAY reduced the protein expression of p21Cip1 as well as cyclin D1, and inhibits the expression of cdc2 (cdk1). Utilizing atom absorption spectrometry, BAY significantly reduced cellular uptake of platinum compounds and thereby the generation of DNA adducts. Taken together, co-incubation with BAY results in reduced cellular uptake of platinum compounds and consecutively reduced generation of DNA adducts, and eventually decreased cellular cytotoxicity in human colorectal cancer cells. Our results indicate that the Raf kinase inhibitor BAY 43-9006 might also directly or indirectly interact with platinum transporter proteins in vitro.

The importance of the MAP kinase pathway, which includes the kinases Raf, MEK1/2, and ERK1/2, for the proliferation and survival of tumor cells recently increased with the discovery of activating BRAF mutations in human tumors. Therefore, in addition to a role in controlling tumors with Ras mutations and activated growth factor receptors, inhibitors of Raf kinase may harbor therapeutic potential in tumors carrying a BRAF oncogene. A variety of agents have been discovered to interfere with Raf kinase, including antisense oligonucleotides and small molecules. These inhibitors prevent the expression of Raf protein, block Ras/Raf interaction, or obstruct its kinase activity. Raf inhibitors that are currently undergoing clinical evaluation show promising signs of anti-cancer efficacy with a very tolerable safety profile. Clinically most advanced is the Raf inhibitor BAY 43-9006, which recently entered phase III clinical testing. This review addresses the rationale for targeting Raf kinase and the current status of various pharmacological approaches.

Background: The aim of this study was to define the maximum tolerated dose (MTD), dose-limiting toxicity (DLT) and pharmacokinetics of the camptothecin glycoconjugate BAY 38-3441, administered as an infusion for 30 min on two separate schedules every 3 weeks. Patients and methods: A total of 81 patients with advanced solid tumors were treated with BAY 38-3441 either at doses of 20, 40, 67, 100, 140, 210, 315, 470 and 600 mg/m2/day for 1 day every 3 weeks (single-dose schedule), or at doses of 126, 189, 246, 320 and 416 mg/m2/day once daily for three consecutive days every 3 weeks (3-day schedule). Plasma sampling was performed to characterize the pharmacokinetics of BAY 38-3441 and camptothecin with these schedules. Results: DLTs included renal toxicity, granulocytopenia and thrombocytopenia on the single-day schedule at doses ≥470 mg/m2/day, and diarrhea and thrombocytopenia on the 3-day schedule at doses ≥320 mg/m2/day. Other non-DLTs were gastrointestinal, dermatological and hematological. Pharmacokinetics of BAY 38-3441 and camptothecin appear to be dose-dependent, but not linear. Conclusions: Renal toxicity was dose-limiting for BAY 38-3441 using 30-min infusions on the single-dose schedule. Dose escalation to 470 mg/m2/day is feasible using a 2-h infusion. However, because of the superior safety profile, we recommend the 3-day schedule for BAY 38-3441 at a dose of 320 mg/m2/day as 30-min infusions for further phase II studies.

Chemically synthesized, small interfering RNAs (siRNA) are currently used as a new class of therapeutic molecules, allowing the controlled down-regulation of pathologically relevant gene expression e.g., oncogenes and other similar targets in cancer [1, 2, 3].However, the overall negative charge of siRNA molecules (up to 40 negative charg-es) and the relatively high molecular weight (12,000 – 14,000 Da) prevent the functional uptake of these novel therapeutic molecules in vivo. Besides the inefficient uptake and the degradation in endosomal compartments at the cellular level, non-formulated siRNAs are rapidly cleared by renal excretion from the blood stream when administered i.v. [4].To overcome these limitations, a variety of non-viral nanoparticles (50 – 200 nm) have been recently developed enabling chemically synthesized siRNA to be used therapeuti-cally for inhibition of RNAi-mediated tumor growth. Atu027 is a novel RNAi therapeutic agent based on cationic lipoplexes containing chemically stabilized siRNAs, which target Protein Kinase N3 (PKN3) gene expression in the vascular endothelium (Figure 1) [5]. PKN3, a member of the AGC kinase fam-ily, has been identified as a promising, novel therapeutic target in cancer cells for inhibiting tumor progression and lymph node metasta-sis formation [6]. These studies have revealed that PKN3 mediates malignant cell growth downstream of the chronically activated phosphoinositide 3-kinase (PI3K) pathway [6]. Recently, PKN3 has also been considered as a suitable therapeutic target for modulating tumor-associated angiogenesis. Preclinical data, obtained in various cancer mouse mod-els, revealed target-specific, RNAi-mediated silencing of PKN3 expression and significant inhibition of tumor progression and metasta-sis formation [

Background The oral multikinase inhibitor regorafenib improves overall survival (OS) in patients with metastatic colorectal cancer (CRC) for which all standard treatments have failed. This study investigated regorafenib plus modified FOLFOX (mFOLFOX6) as first-line treatment of metastatic CRC. Methods In this single-arm, open-label, multicentre, phase II study, patients received mFOLFOX6 on days 1 and 15, and regorafenib 160 mg orally once daily on days 4-10 and 18-24 of each 28-day cycle. The primary end-point was centrally assessed objective response rate (ORR). Secondary end-points included disease control rate (DCR), OS, progression-free survival (PFS) and safety. Results Median overall treatment duration with any study drug was 9.9 months (range 0.6-19.6); median treatment duration with regorafenib was 7.7 months (range 0.1-19.5); six patients remained on regorafenib for more than 1 year. Fifty-three patients received at least one dose of regorafenib. ORR was 43.9% (all partial responses); DCR was 85.4%; median OS was not reached; median PFS was 8.5 months. Treatment-emergent adverse events were experienced by all patients but were manageable with dose modifications. Conclusion Regorafenib + mFOLFOX6 as first-line treatment in patients with metastatic CRC did not improve ORR over historical controls. Regorafenib plus mFOLFOX6 did not appear to be associated with a markedly worse tolerability profile versus mFOLFOX6 alone. ClinicalTrials.gov identifier: NCT01289821.

The mitogen activated protein kinases (MAPKs) are conserved proteins that regulate cell growth, division and death. Although activated in the cytosol, the MAPKs translocate to the nucleus upon activation and phosphorylate a large number of nuclear proteins. Investigating how Ras transmits extracellular growth signals, the MAPK pathway has emerged as the crucial route between membrane-bound Ras and the nucleus. The MAPK pathway represents a cascade of phosphorylation events including three pivotal kinases, namely Raf, MEK (MAP kinase kinase), and ERK (MAP kinase). These kinases present new opportunities for the development of novel anti-cancer drugs designed to be target-specific and probably less toxic than conventional chemotherapeutic agents. A number of drugs inhibiting Ras, Raf or MEK are currently under clinical investigation. This review addresses the rationale for targeting the MAP kinase pathway and the current status of various pharmacological approaches.

Purpose Atu027 is a novel liposomal RNA interference therapeutic that includes a short-interfering RNA (siRNA), which silences expression of protein kinase N3 in the vascular endothelium. Atu027 has previously been shown to inhibit local tumor invasion as well as lymph node and pulmonary metastasis in mouse cancer models. This first-in-human study aimed to assess the safety, tolerability, and pharmacokinetics of Atu027 while evaluating therapeutic effects on both primary tumors and metastatic lesions. Patients and Methods Thirty-four patients with advanced solid tumors received 10 escalating doses of Atu027 without premedication, as one single followed by eight intravenous infusions twice per week during a 28-day cycle. Response was monitored by computed tomography/magnetic resonance imaging at baseline, at the end of treatment (EoT), and at final follow-up (EoS), and was assessed according to RECIST. Results Atu027 was well tolerated up to dose levels of 0.336 mg/kg; most adverse events (AEs) were low-grade toxicities (grade 1 or 2). No maximum tolerated dose was reached. Plasma levels of siRNA strands and lipids were dose proportional, peaking during 4-hour infusion. Disease stabilization was achieved in 41% of patients at EoT (n = 14 of 34 treated patients); eight patients had stable disease at EoS, and some experienced complete or partial regression of metastases. sFLT1 (soluble variant of vascular endothelial growth factor receptor-1) decreased from pretreatment levels in most patients after dose levels 04 to 10. Conclusion Atu027 was safe in patients with advanced solid tumors, with 41% of patients having stable disease for at least 8 weeks. In view of these results, further clinical trials have been initiated, and sFLT1 will be investigated as a potential biomarker.

Relapse of cancer months or years after an apparently successful therapy is probably caused by cancer stem cells (CSCs) due to their intrinsic features like dormant periods, radiorefraction, and acquired multidrug resistance (MDR) phenotypes, among other mechanisms of cellular drug evasiveness. Thus, the lack of currently efficacious interventions remains a major problem in the treatment of malignancies, together with the inability of existing drugs to destroy specifically CSCs. Neuroblastomas per se are highly chemotherapy-refractory extracranial tumors in infants with very low survival rates. So far, no effective cytostatics against this kind of tumors are clinically available. Therefore, we have put much effort into the development of agents to efficiently combat this malignancy. For this purpose, we tested several compounds isolated from Cuban propolis on induced CSCs (iCSC) derived from LAN-1 neuroblastoma cells which expressed several characteristics of tumor-initiating cells both in in-vitro and in-vivo models. Some small molecules such as flavonoids and polycyclic polyprenylated acylphloroglucinols (PPAP) were isolated using successive RT-HPLC cycles and identified employing mass spectrometry and NMR spectroscopic techniques. Their cytotoxicity was first screened in sensitive cell systems by MTT proliferation assays and afterwards studied in less sensitive neuroblastoma iCSC models. We found several compounds with considerable anti-iCSC activity, most of them belonging to the PPAP class. The majority of the compounds act in a pleiotropic manner on the molecular biology of tumors although their specific targets remain unclear. Nevertheless, two substances, one of them a flavonoid, induced a strong disruption of tubulin polymerization. In addition, an unknown compound strongly inhibited replicative enzymes like toposimerases I/II and DNA polymerase. Here, we report for the first time cytotoxic activities of small molecules isolated from Caribbean propolis which could be promising therapeutics or lead structures against therapy-refractory neuroblastoma entities. *Contributed equally.

Chromosomal breakage resulting from stabilization of DNA topoisomerase II covalent complexes by epipodophyllotoxins may play a role in the genesis of leukemia-associated MLL gene translocations. We investigated whether etoposide catechol and quinone metabolites can damage the MLL breakpoint cluster region in a DNA topoisomerase II-dependent manner like the parent drug and the nature of the damage. Cleavage of two DNA substrates containing the normal homologues of five MLL intron 6 translocation breakpoints was examined in vitro upon incubation with human DNA topoisomerase IIalpha, ATP, and either etoposide, etoposide catechol, or etoposide quinone. Many of the same cleavage sites were induced by etoposide and by its metabolites, but several unique sites were induced by the metabolites. There was a preference for G(-1) among the unique sites, which differs from the parent drug. Cleavage at most sites was greater and more heat-stable in the presence of the metabolites compared to etoposide. The MLL translocation breakpoints contained within the substrates were near strong and/or stable cleavage sites. The metabolites induced more cleavage than etoposide at the same sites within a 40 bp double-stranded oligonucleotide containing two of the translocation breakpoints, confirming the results at a subset of the sites. Cleavage assays using the same oligonucleotide substrate in which guanines at several positions were replaced with N7-deaza guanines indicated that the N7 position of guanine is important in metabolite-induced cleavage, possibly suggesting N7-guanine alkylation by etoposide quinone. Not only etoposide, but also its metabolites, enhance DNA topoisomerase II cleavage near MLL translocation breakpoints in in vitro assays. It is possible that etoposide metabolites may be relevant to translocations.

A number of indenoisoquinolines were prepared and evaluated for cytotoxicity in human cancer cell cultures and for activity vs topoisomerase 1 (top1). The two most cytotoxic indenoisoquinolines proved to be cis-6-ethyl-5,6,12,13-tetrahydro-2,3-dimethoxy-8, 9-(methylenedioxy)-5,11-dioxo-11H-indeno[1,2-c]isoquinoline (21) and cis-6-allyl-5,6,12,13-tetrahydro-2,3-dimethoxy-8, 9-(methylenedioxy)-5,11-dioxo-11H-indeno[1,2-c]isoquinoline (22), both of which displayed submicromolar mean graph midpoints when tested in 55 human cancer cell cultures. Two of the most potent top1 inhibitors were 6-(3-carboxy-1-propyl)-5,6-dihydro-5, 11-dioxo-11H-indeno[1,2-c]isoquinoline (26) and 6-ethyl-2, 3-dimethoxy-8,9-(methylenedioxy)-11H-indeno[1,2-c]isoquinolinium chloride (27), both of which also inhibited top2, unwound DNA, and are assumed to be DNA intercalators. However, two additional potent top1 inhibitors, 6-allyl-5,6-dihydro-2,3-dimethoxy-8, 9-(methylenedioxy)-5,11-dioxo-11H-indeno[1,2-c]isoquinoline (13c) and 5,6-dihydro-6-(4-hydroxybut-1-yl)-2,3-dimethoxy-8, 9-methylenedioxy-5,11-dioxo-11H-indeno[1,2-c]isoquinoline (19a), did not unwind DNA and did not affect top2. Some of the DNA cleavage sites detected in the presence of the indenoisoquinolines were different from those seen with the camptothecins. The cleavage sites induced by the indenoisoquinolines were reversed by salt treatment, which is consistent with the reversible trapping of top1 cleavable complexes by the indenoisoquinolines. In general, the potencies of the indenoisoquinolines as top1 inhibitors did not correlate with their potencies as cytotoxic agents, as some of the most cytotoxic agents had little if any effect on top1. On the other hand, the most potent of the indenoisoquinolines vs top1 were not the most cytotoxic. In several cases, moderate activity was observed for both cytotoxicity and activity vs top1.

Camptothecin (CPT) is a specific topoisomerase I (top1) poison which traps top1 cleavable complexes; e.g. top1-linked DNA single-strand breaks with 5'-hydroxyl and 3'-top1 linked termini. CPT is also a potent anticancer agent and several of its derivatives have recently shown activity in the chemotherapy of solid tumors. Our aim was to apply the ligation-mediated polymerase chain reaction (LM-PCR) method to DNA extracted from CPT-treated cells in order to: (i) evaluate LM-PCR as a sensitive technique to detect in vivo CPT-induced cleavable complexes; (ii) investigate the frequency and distribution of CPT-induced DNA damage in vivo ; and (iii) compare the distribution and intensity of cleavage sites in vivo and in vitro. This report describes a protocol allowing the sequencing of top1-mediated DNA strand breaks induced by CPT in the coding strand of the 18S rRNA gene of human colon carcinoma cells. CPT or its clinical derivatives, topotecan, CPT-11, SN-38, and 9-aminocamptothecin differed in their potency and exhibited differences in their DNA cleavage pattern, which is consistent with our previous in vitro studies [Tanizawa et al . (1995) Biochemistry , 43, 7200-7206]. CPT-induced DNA cleavages induced in the presence of purified top1 were induced at the same sites in the human 18S rDNA. However, the relative intensity of the cleavages were different in vivo and in vitro. Because mammalian cells contain approximately 300 copies of the rDNA gene per genome, rDNA could be used to monitor CPT-induced DNA cleavage in different cell lines and possibly in tumor samples.

Gemcitabine plus treosulfan (GeT) is under investigation in metastatic uveal melanoma. In this phase II trial, cisplatin was added to a GeT regimen to investigate the efficacy and toxicity of two alkylating agents in combination with gemcitabine. Patients received 30 or 40 mg/m2 of cisplatin, 1000 mg/m2 of gemcitabine and 3000 mg/m2 of treosulfan on days 1 and 8. Therapy was repeated on day 29. A maximum of six cycles was administered. Nineteen patients were included in the trial, of whom 17 were evaluable for response. No objective response was observed; seven patients (41%) had stable disease and 10 (59%) progressed. The median progression-free survival of all 19 patients was 3.0 months [95% confidence interval (CI), 1.8–3.1]; the median overall survival was 7.7 months (95% CI, 1.9–13.8). Grade 3 and 4 thrombopenia and leucopenia occurred in eight and nine of the 19 patients, respectively. The addition of cisplatin to the GeT regimen results in excessive haematological toxicity without improvement in efficacy.

Objective To assess the activity of laparoscopic Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) in women with recurrent, platinum-resistant ovarian cancer. Methods Prospective case series using repeated courses q 28–42days of PIPAC containing cisplatin 7.5mg/m 2 and doxorubicin 1.5mg/m 2 at 12mmHg and 37°C for 30min. Objective tumor response was defined as tumor regression on histology and peritoneal carcinomatosis index (PCI) improvement on repeated video-laparoscopy. Results 34 PIPAC procedures were performed in 18 women, in 8 instances combined with cytoreductive surgery (CRS). Eight women had repeated PIPAC and objective tumor response was observed in 6 (complete remission: 1; partial remission: 2; stable disease: 3). Five adverse events WHO grade≥2 were noted, 3 of them after combined CRS. No perioperative mortality occurred. Median follow-up was 192days (min. 13–max. 639). Cumulative survival after 400days was 62% and mean actuarial survival time was 442days. In a multivariable regression analysis with objective tumor response (yes vs. no) as the dependent variable and PIPAC (1 vs.>1), patient age ( 1000U/mL), and the presence of ascites (yes vs. no) as independent variables, PIPAC independently predicted objective tumor response. Conclusion PIPAC has activity in women with recurrent, platinum-resistant ovarian cancer and should be investigated in prospective clinical trials.

Background Metastatic colorectal cancer (mCRC) is commonly treated with 5-fluorouracil, folinic acid, and oxaliplatin or irinotecan. The multitargeted kinase inhibitor, regorafenib, was combined with chemotherapy as first- or second-line treatment of mCRC to assess safety and pharmacokinetics (primary objectives) and tumor response (secondary objective). Patients and methods Forty-five patients were treated every 2 weeks with 5-fluorouracil 400 mg/m2 bolus then 2400 mg/m2 over 46 h, folinic acid 400 mg/m2, and either oxaliplatin 85 mg/m2 or irinotecan 180 mg/m2. On days 4–10, patients received regorafenib 160 mg orally once daily. Results The median duration of treatment was 108 (range 2–345 days). Treatment was stopped for adverse events or death (17 patients), disease progression (11 patients), and consent withdrawal or investigator decision (11 patients). Six patients remained on regorafenib at data cutoff (two without chemotherapy). Drug-related adverse events occurred in 44 patients [grade ≥3 in 32 patients: mostly neutropenia (17 patients) and leukopenia, hand–foot skin reaction, and hypophosphatemia (four patients each)]. Thirty-three patients achieved disease control (partial response or stable disease) for a median of 126 (range 42–281 days). Conclusion Regorafenib had acceptable tolerability in combination with chemotherapy, with increased exposure of irinotecan and SN-38 but no significant effect on 5-fluorouracil or oxaliplatin pharmacokinetics.

Flavonoids are a heterogeneous group of polyphenolic compounds found ubiquitously in a wide variety of plants. Their chemical structure is based on 2-phenyl chromen, also known as flavan [1]. Flavonoids display a wide range of pharmacological properties, including antiinflammatory, antioxidative, antiviral, antibacterial and antiproliferative activities [1, 2]. Previous studies carried out by our group described the cytotoxic activity of mucronulatol, a flavonoid found originally in Indigofera sp. [3]. Here we describe for the first time diverse flavonoids, isolated from Caribbean propolis, which show high cytotoxic activitiy in various cancer cell lines.

Regorafenib (BAY 73-4506) is a novel, orally active, diphenylurea multikinase inhibitor of VEGFR1-3, c-KIT, TIE-2, PDGFR-β, FGFR-1, RET, RAF-1, BRAF and p38 MAP kinase.This review covers the preclinical development of regorafenib as well as the pivotal Phase I studies. The safety profile of regorafenib is discussed in context with other oral multikinase inhibitors bearing a similar target profile. Current clinical developments, especially in colorectal cancer (CRC) and gastrointestinal stromal tumor (GIST), are addressed. Open questions on clinically useful biomarkers predicting response with regard to a personalized therapy strategy are also being discussed.Regorafenib (BAY 73-4506) is a novel, orally active multikinase inhibitor that is well tolerated in preclinical mouse models as well as clinically according to Phase I - III trials performed. The toxicity profile is comparable with other oral multikinase inhibitors with similar molecular targets. Regorafenib has promising antineoplastic activity in various tumor types. Two large, randomized Phase III pivotal registration studies in patients with GIST and CRC, respectively, already completed enrolment, with final results being awaited. Further extensive clinical development as a single agent or in combination with standard chemotherapeutic agents in various malignant tumors is ongoing. Moreover, regorafenib has recently been granted Orphan Drug Status for GIST tumors and 'fast track' status for both GIST and CRC by the FDA.

Background: In a phase I dose-escalation study, regorafenib demonstrated tolerability and antitumour activity in solid tumour patients. The study was expanded to focus on patients with metastatic colorectal cancer (CRC). Methods: Patients received oral regorafenib 60–220 mg daily (160 mg daily in the extension cohort) in cycles of 21 days on, 7 days off treatment. Assessments included toxicity, response, pharmacokinetics and pharmacodynamics. Results: Thirty-eight patients with heavily pretreated CRC (median 4 prior lines of therapy, range 0–7) were enrolled in the dose-escalation and extension phases; 26 patients received regorafenib 160 mg daily. Median treatment duration was 53 days (range 7–280 days). The most common treatment-related toxicities included hand–foot skin reaction, fatigue, voice change and rash. Twenty-seven patients were evaluable for response: 1 achieved partial response and 19 had stable disease. Median progression-free survival was 107 days (95% CI, 66–161). At steady state, regorafenib and its active metabolites had similar systemic exposure. Pharmacodynamic assessment indicated decreased tumour perfusion in most patients. Conclusion: Regorafenib showed tolerability and antitumour activity in patients with metastatic CRC. This expanded-cohort phase I study provided the foundation for further clinical trials of regorafenib in this patient population.

Combining different targeted anticancer agents may improve clinical outcomes. This Phase I study investigated cediranib, an oral inhibitor of vascular endothelial growth factor signalling in combination with saracatinib, an oral Src inhibitor. The primary endpoint was safety/tolerability. Secondary assessments included pharmacokinetics and preliminary efficacy. Patients and Methods Patients with advanced solid tumours received cediranib 20, 30 or 45 mg/day for 7 days followed by daily treatment with cediranib at the same dose plus saracatinib 175 mg/day. Results Thirty-nine patients received cediranib (20 mg, n = 6; 30 mg, n = 6; 45 mg, n = 27 [n = 20 in cohort expansion]) plus saracatinib. In the cediranib 45 mg cohort, 59% of patients required dose reduction/pause compared with 33% in each of the other two cohorts. There was one dose-limiting toxicity (hypertension; 45 mg cohort). The most common adverse events were hypertension (67%), diarrhoea (62%), dysphonia (46%) and fatigue (39%). There was no evidence of a clinically significant effect of saracatinib on cediranib pharmacokinetics and vice versa. 22/35 evaluable patients had a best response of stable disease. Conclusions All cediranib doses were tolerated; however, in patients with advanced solid tumours, for combination with saracatinib 175 mg/day, cediranib 20 or 30 mg/day was more sustainable than 45 mg/day.

Introduction Nimotuzumab is a humanized monoclonal antibody that binds to the EGFR. Based on phase I data, the recommended dose has been established at 200 mg weekly. This study was aimed at evaluating the safety and efficacy of nimotuzumab monotherapy in patients (pts) with locally advanced or metastatic pancreatic cancer. Methods Pts who failed first line standard chemotherapy for advanced disease and had at least one measurable lesion were eligible for the study. Nimotuzumab was given intravenously at 200 mg once weekly for 6 weeks (wks). Follow up by CT scan was performed after 8 weeks. Pts continued receiving treatment 3-weekly until disease progression or unacceptable toxicity occurred. Endpoints included tumor response (RECIST), progression-free survival (PFS), and safety. Results A total of 56 pts were enrolled for treatment (ECOG status of 1 [n = 41] or 0 [n = 15]), the majority (47 pts) had metastatic disease. Nearly half of the pts [n = 26] received ≥2 regimens. Pts evaluable for response: n = 36; CR: 0; PR: 0; SD: 6 pts. Median PFS for pts with SD was 19.2 weeks, for all pts 6.7 weeks (95% CI: 6.43–7.14 weeks). PFS after 1 year was 10.3% with a median overall survival of 18.1 weeks. Treatment-related adverse events were generally mild including rash grade 1 in 5 pts. After a single dose of 200 mg, the t1/2 was calculated to 45 h. Conclusion These data confirm that nimotuzumab is safe and very well tolerated. To improve efficacy, a randomized, placebo-controlled trial with Gem has been initiated.

S-1 is a novel oral fluoropyrimidine comprised of FT and two modulators, gimeracil (CDHP) and oteracil potassium (Oxo). This study investigated the food effects on the pharmacokinetics (PK) of Oxo, other components of S-1, and their metabolites at different gastric pH adjusted by proton pump inhibitor (PPI).Patients with and without PPI were treated with S-1 at 30 mg/m(2) twice daily orally on days 1-7 under either fed or fasting condition, and then were crossed over to fasting/fed conditions on days 15-21 with washout on days 8-14 and 22-28.The study enrolled 55 patients including 27 PK-evaluable patients. For the single-dose and multiple-dose pharmacokinetics, the administration of S-1 under fed conditions resulted in decreased exposure to Oxo relative to fasting administration. There was a marginal decrease in exposure to CDHP and 5-FU under fed versus fasting conditions, although FT exposure was not altered by food, which demonstrated lack of food effect. PPI administration together with S-1 did not significantly change its bioavailability.Oxo exposure was reduced under fed compared to fasting condition. To increase the bioavailability of S-1, the administration of S-1 under fasting condition was more effective in the western countries.

Sorafenib (BAY 43-9006), a multikinase inhibitor, has been shown to inhibit tumor growth and tumor angiogenesis by targeting Raf kinase, vascular endothelial growth factor receptor, and platelet-derived growth factor receptor. This study investigated the safety, pharmacokinetics, and preliminary efficacy of sorafenib in combination with gemcitabine and cisplatin.Patients with advanced solid tumors were treated with 75 mg/m(2) cisplatin on day 1 and 1,250 mg/m(2) gemcitabine on days 1 and 8 of each 21-day cycle. On day 5 of cycle 1, sorafenib 400 mg twice daily was started and continued throughout the complete treatment cycles without interruption.Nineteen patients were valid for safety analysis. The most frequent toxicities related to the cytotoxic agents were hematological disorders. Sorafenib-related toxicities were skin-related, gastrointestinal, and constitutional symptoms. No clinically relevant pharmacokinetic drug-drug interaction between sorafenib, cisplatin, and gemcitabine was detected. AUC(0-72) and C (max) of total and unbound platinum were only marginally changed by concomitant sorafenib. Concomitant sorafenib increased mean AUC and C (max) of gemcitabine by 12 and 21%.Sorafenib as continuous oral treatment in combination with gemcitabine and cisplatin demonstrated an acceptable safety profile. No clinically relevant pharmacokinetic interaction was detected. Preliminary antitumor activity, pharmacokinetic, and safety data support the recommendation of 400 mg sorafenib twice daily in combination with cisplatin and gemcitabine to be further evaluated in clinical studies.

Purpose: We diagnosed de novo bladder dysfunction in several breast cancer patients under cancer-specific therapy with trastuzumab. The goal of this retrospective analysis was to investigate whether bladder dysfunction is common in a larger population of breast cancer patients receiving trastuzumab therapy. Patients and Methods: We identified 93 patients who received at least two doses of trastuzumab at our institution in the years 2003–2006. 57 of those patients were still alive at the time of this analysis. We mailed a validated global questionnaire for the assessment of incontinence (King’s Health Questionnaire, KHQ) to them, additionally asking for bladder dysfunction observed under trastuzumab therapy. Results: 43 (75%) of the patients returned the questionnaire, 11 (25%) of them reporting severe de novo bladder dysfunction under therapy. Significant differences between symptomatic and asymptomatic patients were detected in all KHQ subscales. Previous conditions and surgeries as well as medications, especially hormonal therapy, were excluded as underlying causes. However, there were more patients under taxane-based chemotherapy in the symptomatic group. Conclusions: The epidermal growth factor receptor is involved in the cellular response to mechanical stretch in the urinary bladder. Based on our findings, we hypothesize that interfering with this pathway may well be the cause of symptomatic bladder dysfunction in patients under trastuzumab medication. A prospective study is required to further elucidate this hypothesis.

Objectives: Polyisoprenylated acylphloroglucinols have recently emerged as antitumoral agents. This study aims at elucidating the antiretroviral activity of two such compounds which were isolated from Caribbean propolis: 7-epi-nemorosone and plukenetione A, the structure of which is based on an adamantane moiety. Plukenetione A is for the first time shown to have antiretroviral activity. Material and methods: The isolation of both small molecules was carried out using RP-HPLC. Their antiretroviral activity was studied based on lentiviral particles produced in HEK293T cells from the SIV-based vector VLABH; their cytotoxicity was monitored by MTT proliferation assay. The antiviral activity of 7-epi-nemorosone was studied in CEMx174-SEAP infected with the HIV-1- strain pNL4.3wt. Reverse transcriptase inhibition was determined by a standard two-step RT-PCR using MMLV RT. Results: 7-epi-nemorosone and plukenetione A were found to be potent antilentiviral agents in the employed system, inhibiting viral infection at concentrations below 1 μM/2 μM, respectively. Whereas 7-epi-nemorosone was not able to inhibit the reverse transcriptase in vitro (IC 50 > 25 μM), plukenetione A effectively inhibited its enzymatic activity at an IC 50 of 1.75 μM. Conclusions: Despite 7-epi-nemorosone and plukenetione A sharing some structural core elements, the mechanism of action involved in their antiretroviral activity seems to be different. We propose that 7-epi-nemorosone inhibits the viral replication by interrupting the Akt/PKB signaling cascade, as was demonstrated previously in various cell lines. Since plukenetione A effectively inhibits the enzymatic activity of MMLV reverse transcriptase at concentrations that show antilentiviral activity, we suggest that this small molecule acts by interfering with the enzyme's catalytic site.