Streamlining clinical research: an ESMO awareness call to improve sponsoring and monitoring of clinical trials.

BACKGROUND: During recent years, the burden of bureaucracy in clinical research has increased dramatically, adversely impacting the activity of investigators and clinical research teams. Although compliance with the Declaration of Helsinki, the guidelines for Good Clinical Practice (GCP), and other applicable regulations remains unquestionable, their overinterpretation and substitution by the internal operating procedures of sponsors and Contract Research Organizations (CROs) have increased the administrative burden. A survey conducted by the European Society for Medical Oncology (ESMO) Clinical Research Observatory (ECRO) among 940 investigators confirmed that they considered that the administrative burden in clinical research is excessive; that administrative procedures could be reduced without affecting the safety and the rights of the patients and the quality of the data; and that bureaucracy represents an obstacle for clinical research. METHODS: A panel of physicians with extensive experience in clinical research, composed by members of the ECRO and the ESMO Scientific Medical and Public Policy divisions, analyzed clinical trial procedures related to administrative workflow, pharmacovigilance, and medical care. RESULTS: The panel identified situations that generate debate between investigators and sponsors/CROs and selected real clinical scenarios that exemplify such situations. The panel discussed and proposed specific recommendations for those situations, based on GCP. CONCLUSIONS: This initiative aspires to streamline clinical research procedures and to become a platform for discussion among all clinical trial stakeholders, with the aim of promoting the sustainability of clinical research and the care of cancer patients.

Acarbose protects from central and peripheral metabolic imbalance induced by benzene exposure.

Benzene is a well-known human carcinogen that is one of the major components of air pollution. Sources of benzene in ambient air include cigarette smoke, e-cigarettes vaping, and evaporation of benzene containing petrol processes. While the carcinogenic effects of benzene exposure have been well studied, less is known about the metabolic effects of benzene exposure. We show that chronic exposure to benzene at low levels induces a severe metabolic imbalance in a sex-specific manner, and is associated with hypothalamic inflammation and endoplasmic reticulum (ER) stress. Benzene exposure rapidly activates hypothalamic ER stress and neuroinflammatory responses in male mice, while pharmacological inhibition of ER stress response by inhibiting IRE1α-XBP1 pathway significantly alleviates benzene-induced glial inflammatory responses. Additionally, feeding mice with Acarbose, a clinically available anti-diabetes drug, protected against benzene induced central and peripheral metabolic imbalance. Acarbose imitates the slowing of dietary carbohydrate digestion, suggesting that choosing a diet with a low glycemic index might be a potential strategy for reducing the negative metabolic effect of chronic exposure to benzene for smokers or people living/working in urban environments with high concentrations of exposure to automobile exhausts.

Pembrolizumab monotherapy for previously treated metastatic triple-negative breast cancer: cohort A of the phase II KEYNOTE-086 study.

BACKGROUND: Treatment options for previously treated metastatic triple-negative breast cancer (mTNBC) are limited. In cohort A of the phase II KEYNOTE-086 study, we evaluated pembrolizumab as second or later line of treatment for patients with mTNBC. PATIENTS AND METHODS: Eligible patients had centrally confirmed mTNBC, ≥1 systemic therapy for metastatic disease, prior treatment with anthracycline and taxane in any disease setting, and progression on or after the most recent therapy. Patients received pembrolizumab 200 mg intravenously every 3 weeks for up to 2 years. Primary end points were objective response rate in the total and PD-L1-positive populations, and safety. Secondary end points included duration of response, disease control rate (percentage of patients with complete or partial response or stable disease for ≥24 weeks), progression-free survival, and overall survival. RESULTS: All enrolled patients (N = 170) were women, 61.8% had PD-L1-positive tumors, and 43.5% had received ≥3 previous lines of therapy for metastatic disease. ORR (95% CI) was 5.3% (2.7-9.9) in the total and 5.7% (2.4-12.2) in the PD-L1-positive populations. Disease control rate (95% CI) was 7.6% (4.4-12.7) and 9.5% (5.1-16.8), respectively. Median duration of response was not reached in the total (range, 1.2+-21.5+) and in the PD-L1-positive (range, 6.3-21.5+) populations. Median PFS was 2.0 months (95% CI, 1.9-2.0), and the 6-month rate was 14.9%. Median OS was 9.0 months (95% CI, 7.6-11.2), and the 6-month rate was 69.1%. Treatment-related adverse events occurred in 103 (60.6%) patients, including 22 (12.9%) with grade 3 or 4 AEs. There were no deaths due to AEs. CONCLUSIONS: Pembrolizumab monotherapy demonstrated durable antitumor activity in a subset of patients with previously treated mTNBC and had a manageable safety profile. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02447003.

Predictive factors for cancer-associated thrombosis in a large retrospective single-center study.

BACKGROUND: The relationship between cancer and thrombosis has been studied for years, but reliable guidelines for thromboprophylaxis in that situation are still unclear. METHODS: We retrospectively reviewed the files of 3159 consecutive patients with newly diagnosed solid tumors at Jules Bordet Institute from January 2008 to December 2011. Among them, 99 developed a symptomatic thromboembolic episode and were matched with 2 controls (nested case control). The aim was to identify risk factors of thromboembolic events and to validate in our setting the Khorana score. RESULTS: In the cohort study, nodal status ≥ 2, presence of metastases, and primary tumor site were found to be the most significant predictive factors of a thromboembolic event (n = 99; 3.1%) in the multivariate analysis. In the nested study (n = 265), hemoglobin < 13 g/dL or treatment with a red cell growth factor, CRP ≥ 31.6 mg/L, creatinine level > 0.96 mg/dL, chronic inflammatory disease, and personal or familial history of thromboembolic events were found to be the most significant predictive factors of a thromboembolic event in the multivariate analysis. In our population, the sensitivity, specificity, positive predictive value, and negative predictive value of the Khorana score were respectively 29%, 93%, 15%, and 96%. CONCLUSION: We confirm the value of the risk factors identified in the literature with the additional presence of nodal involvement, elevated CRP, and creatinine levels, which may be helpful for patient risk stratification and should be considered in future clinical trials. Our results also suggest that the Khorana score might help to identify patients who can safely be spared of thromboprophylaxis.

[Retroperitoneal mixed malignant mullerian tumor : exceptional localisation and prognosis]. / Une tumeur mullérienne mixte maligne rétropéritonéale de localisation et pronostic exceptionnels.

Primary retroperitoneal carcinosarcoma or mixed malignant mullerian tumor (MMMT) is an extremely rare clinical entity. These aggressive tumors arise most commonly from genital tract. The retroperitoneal location is exceptional. Here we report the case of a 63-years old female diagnosed with heterologous, extra-genital, retroperitoneal carcinosarcoma, with malignant cells in the ascitic fluid and extra-ovarian metastatic implants. She was treated with complete radical surgical treatment consisting of resection of the retroperitoneal tumor, with omentectomy, hysterectomy, bilateral salpingooophorectomy and lumbo-aortic and pelvic lymphadenectomy. She received adjuvant chemotherapy with 6 cycles of Carboplatin and Paclitaxel. She is in complete clinical and radiological remission since the end of chemotherapy, for a total of 113 months. To our knowledge, this is the longest reported disease free survival of the extra-genital retroperitoneal MMMT. This case and the review of the literature illustrate the importance of surgical treatment. However, there are no evidence-based guidelines for the systemic management of these tumors.

Le carcinosarcome rétropéritonéal ou tumeur mullérienne mixte maligne (TMMM) est une entité clinique extrêmement rare. Ce sont des tumeurs agressives du tractus génital provenant des tissus mullériens. Les localisations rétropéritonéale et extra-génitale sont exceptionnelles. Ce cas clinique concerne une patiente de 63 ans atteinte d'un carcinosarcome extra-génital, retropéritonéal, hétérologue associé à des cellules malignes dans le liquide péritonéal et des implants métastatiques extra-ovariens. Elle a bénéficié d'une laparotomie de résection de la masse rétropéritonéale avec hystérectomie, annexectomie bilatérale, omentectomie et lymphadénectomie pelvienne et lombo-aortique, et a reçu une chimiothérapie adjuvante par 6 cycles de Carboplatine et Paclitaxel. Elle est en rémission clinique et radiologique complète depuis la fin de sa chimiothérapie, soit une durée de 113 mois. A notre connaissance, il s'agit de la durée de suivi sans récidive la plus longue rapportée dans la littérature. Ce cas, ainsi que la revue de littérature, mettent en évidence l'importance du traitement chirurgical. Par contre, il n'existe pas de standard thérapeutique pour la prise en charge adjuvante ou systémique de ces tumeurs.

TPF plus cetuximab induction chemotherapy followed by biochemoradiation with weekly cetuximab plus weekly cisplatin or carboplatin: a randomized phase II EORTC trial.

BACKGROUND: Our aim was to test the safety of cetuximab added to chemoradiation with either cisplatin or carboplatin after prior induction chemotherapy. METHODS: Patients with stage III/IV unresectable, squamous cell carcinoma of the head and neck received up to four cycles of TPF-E (cisplatin and docetaxel 75 mg/m2 on day 1 followed by 5-FU 750 mg/m2/day as a continuous infusion on days 1-5 plus cetuximab at a loading dose of 400 mg/m2 followed by a weekly dose of 250 mg/m2), with prophylactic antibiotics but no growth factors. Patients not progressing after four cycles of TPF-E were randomly assigned to radiotherapy (70 Gy over 7 weeks in 2 Gy fractions) and weekly cetuximab with either weekly cisplatin 40 mg/m2 or carboplatin, AUC of 1.5 mg/ml/min. Primary endpoint was feasibility. RESULTS: Forty-seven patients were recruited. One patient did not start TPF (hypersensitivity reaction during the cetuximab loading dose). Induction TPF-E was discontinued in 12 patients due to toxicity (6 patients), medical decision (2), death (1), patient refusal (1), protocol violation (1), co-morbidity (1). Three further patients were not randomized [progressive disease (1), protocol violation (1), toxicity and co-morbidity (1)]. Of particular interest are three patients who suffered from bowel perforation, one patient who died as results of pneumonia and septic shock, and a second patient who was found dead at home 12 days after starting TPF-E (cause of death unknown). Weekly cisplatin and carboplatin was stopped early in seven and four patients, respectively. Radiotherapy was stopped in two patients with cisplatin and interrupted in one patient with cisplatin and four patients with carboplatin. CONCLUSIONS: The addition of cetuximab to full dose TPF induction chemotherapy led to unacceptable complications and premature closing of the study. Only 34 out of 46 patients completed four cycles of TPF-E and only 30 started biochemoradiation.

Evaluation of the impact of tumor HPV status on outcome in patients with locally advanced unresectable head and neck squamous cell carcinoma (HNSCC) receiving cisplatin, 5-fluorouracil with or without docetaxel: a subset analysis of EORTC 24971 study.

BACKGROUND: EORTC 24971 was a phase III trial demonstrating superiority of induction regimen TPF (docetaxel, cisplatin, 5-fluorouracil) over PF (cisplatin/5-fluorouracil), in terms of progression-free (PFS) and overall survival (OS) in locoregionally advanced unresectable head and neck squamous cell carcinomas. We conducted a retrospective analysis of prospectively collected data aiming to evaluate whether only HPV(-) patients (pts) benefit from adding docetaxel to PF, in which case deintensifying induction treatment in HPV(+) pts could be considered. PATIENTS AND METHODS: Pretherapy tumor biopsies (blocks or slides) were assessed for high-risk HPV by p16 immunohistochemistry, PCR and quantitative PCR. HPV-DNA+ and/or p16+ tumors were subjected to in situ hybridization (ISH) and HPV E6 oncogene expression qRT-PCR analysis. Primary and secondary objectives were to evaluate the value of HPV/p16 status as predictive factor of treatment benefit in terms of PFS and OS. The predictive effect was analyzed based on the model used in the primary analysis of the study with the addition of a treatment by marker interaction term and tested at two-sided 5% significance level. RESULTS: Of 358, 119 pts had available tumor samples and 58 of them had oropharyngeal cancer. Median follow-up was 8.7 years. Sixteen of 119 (14%) evaluable samples were p16+ and 20 of 79 (25%) evaluable tumors were HPV-DNA+. 13 of 40 pts (33%) assessed with HPV-DNA ISH and 12 of 28 pts (43%) assessed for HPV E6 mRNA were positive. The preplanned analysis showed no statistical evidence of predictive value of HPV/p16 status for PFS (P = 0.287) or OS (P = 0.118). CONCLUSIONS: The incidence of HPV positivity was low in the subset of EORTC 24971 pts analyzed. In this analysis only powered to detect a large treatment by marker interaction, there was no statistical evidence that treatment effect found overall was different in magnitude in HPV(+) or HPV(-) pts. These results do not justify selection of TPF versus PF according to HPV status.

Molecular imaging as a tool to investigate heterogeneity of advanced HER2-positive breast cancer and to predict patient outcome under trastuzumab emtansine (T-DM1): the ZEPHIR trial.

BACKGROUND: Only human epidermal growth factor receptor (HER)2 status determined by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) has been validated to predict efficacy of HER2-targeting antibody-drug-conjugate trastuzumab emtansine (T-DM1). We propose molecular imaging to explore intra-/interpatient heterogeneity in HER2 mapping of metastatic disease and to identify patients unlikely to benefit from T-DM1. PATIENTS AND METHODS: HER2-positive mBC patients with IHC3+ or FISH ≥ 2.2 scheduled for T-DM1 underwent a pretreatment HER2-positron emission tomography (PET)/computed tomography (CT) with (89)Zr-trastuzumab. [(18)F]2-fluoro-2-deoxy-D-glucose (FDG)-PET/CT was performed at baseline and before T-DM1 cycle 2. Patients were grouped into four HER2-PET/CT patterns according to the proportion of FDG-avid tumor load showing relevant (89)Zr-trastuzumab uptake (>blood pool activity): patterns A and B were considered positive (>50% or all of the tumor load 'positive'); patterns C and D were considered negative (>50% or all of the tumor load 'negative'). Early FDG-PET/CT was defined as nonresponding when >50% of the tumor load showed no significant reduction of FDG uptake (<15%). Negative (NPV) and positive predictive values (PPV) of HER2-PET/CT, early FDG response and their combination were assessed to predict morphological response (RECIST 1.1) after three T-DM1 cycles and time-to-treatment failure (TTF). RESULTS: In the 56 patients analyzed, 29% had negative HER2-PET/CT while intrapatient heterogeneity (patterns B and C) was found in 46% of patients. Compared with RECIST1.1, respective NPV/PPV for HER2-PET/CT were 88%/72% and 83%/96% for early FDG-PET/CT. Combining HER2-PET/CT and FDG-PET/CT accurately predicted morphological response (PPV and NPV: 100%) and discriminated patients with a median TTF of only 2.8 months [n = 12, 95% confidence interval (CI) 1.4-7.6] from those with a TTF of 15 months (n = 25, 95% CI 9.7-not calculable). CONCLUSIONS: Pretreatment imaging of HER2 targeting, combined with early metabolic response assessment holds great promise for improving the understanding of tumor heterogeneity in mBC and for selecting patients who will/will not benefit from T-DM1. CLINICALTRIALSGOV IDENTIFIER: NCT01565200.

Role of corticosteroids in prostate cancer progression: implications for treatment strategy in metastatic castration-resistant patients.

Corticosteroid agents (CA) are widely used in the treatment of metastatic castration-resistant prostate cancer (mCRPC) either as concomitant treatment with active agents such as docetaxel, cabazitaxel and abiraterone or in a palliative setting, predominantly due to their anti-inflammatory activity. However, the chronic use of CA has numerous side effects, especially in case of steroid-induced adrenal insufficiency. Furthermore, the latest clinical and preclinical data demonstrate that CA themselves are likely to promote tumour progression in certain populations of patients with mCRPC. Therefore, the role of CA in advanced disease should be carefully weighed for each patient and their withdrawal should be considered in some patients. This is necessary, especially in clinical trials that need good performance status patients to evaluate the activity and the safety of emerging drugs in mCRPC that do not require the concurrent use of CA. In oncology, there is no consensus on an algorithm of gradual steroid tapering and frequently the approach to this procedure is empirical. An algorithm is presented in this article based on clinical observations. Prospective studies are necessary to evaluate the efficacy and safety of the above-proposed algorithm in metastatic castration-resistant prostate cancer.

SNPs at miR-155 binding sites of TYRP1 explain discrepancy between mRNA and protein and refine TYRP1 prognostic value in melanoma.

BACKGROUND: We previously demonstrated an inverse correlation between tyrosinase-related protein 1 (TYRP1) mRNA expression in melanoma metastases and patient survival. However, TYRP1 protein was not detected in half of tissues expressing mRNA and did not correlate with survival. Based on a study reporting that 3' untranslated region (UTR) of TYRP1 mRNA contains two miR-155-5p (named miR-155) binding sites exhibiting single-nucleotide polymorphisms (SNPs) that promote (matched miRNA-mRNA interaction) mRNA decay or not (mismatched), we aimed to investigate the role of miR-155 in the regulation of TYRP1 mRNA expression and protein translation accounting for these SNPs. METHODS: The effect of miR-155 on TYRP1 mRNA/protein expression was evaluated in two melanoma cell lines harbouring matched or mismatched miR-155-TYRP1 mRNA interaction after transfection with pre-miR-155. In parallel, 192 skin and lymph node melanoma metastases were examined for TYRP1 mRNA/protein, miR-155 and SNPs and correlated with patient survival. TYRP1 mRNA, SNPs at its 3'UTR and miR-155 were analysed by RT-qPCR, whereas TYRP1 protein was evaluated by western blot in cell lines and by immunohistochemistry in metastatic tissues. RESULTS: The miR-155 induced a dose-dependent TYRP1 mRNA decay and hampered its translation into protein in the line with the 'match' genotype. In melanoma metastases, TYRP1 mRNA inversely correlated with miR-155 expression but not with TYRP1 protein in the 'match' group, whereas it positively correlated with protein but not with miR-155 in the 'mismatch' group. Consequently, in the latter group, TYRP1 protein inversely correlated with survival. CONCLUSION: Polymorphisms in 3'UTR of TYRP1 mRNA can affect TYRP1 mRNA regulation by miR-155 and its subsequent translation into protein. These SNPs can render TYRP1 mRNA and protein expression nonsusceptible to miR-155 activity and disclose a prognostic value for TYRP1 protein in a subgroup of melanoma patients. These data support the interest in the prognostic value of melanogenic markers and propose TYRP1 to refine prognosis in patients with advanced disease.

A randomized controlled phase II trial of a novel composition of paclitaxel embedded into neutral and cationic lipids targeting tumor endothelial cells in advanced triple-negative breast cancer (TNBC).

BACKGROUND: EndoTAG-1, composed of paclitaxel embedded in liposomal membranes targeting tumor endothelial cells, was evaluated for safety and efficacy in advanced triple-negative breast cancer (TNBC). PATIENTS AND METHODS: One hundred and forty patients were treated with weekly EndoTAG-1 (22 mg/m(2)) plus paclitaxel (70 mg/m(2)), twice weekly EndoTAG-1 (2× 44 mg/m(2)), or weekly paclitaxel (90 mg/m(2)) for greater than or equal to four cycles (3-week treatment + 1-week rest) or until progression/toxicity. Primary end point was progression-free survival (PFS) rate evaluated centrally after four cycles of therapy (week 16). The study was not powered for intergroup comparisons. RESULTS: The PFS rate at week 16 was 59.1% [one-sided 95% CI: 45.6, ∞] on combination treatment, 34.2% [21.6, ∞] on EndoTAG-1, and 48.0% [30.5, ∞] on paclitaxel. Median PFS reached 4.2, 3.4, and 3.7 months, respectively. After complete treatment (week 41 analysis), median overall survival (OS) was 13.0, 11.9, and 13.1 months for the modified Intention-to-Treat (ITT) population and 15.1, 12.5, and 8.9 months for the per-protocol population, respectively. The clinical benefit rate was 53%, 31%, and 36% for the treatment groups. Safety analysis revealed known toxicities of the drugs with slight increases of grade 3/4 neutropenia on combination therapy. CONCLUSION: Treatment of advanced TNBC with a combination of EndoTAG-1 and standard paclitaxel [Taxol® (Bristol-Myers Squibb GmbH), or equivalent generic formulation] was well tolerated and showed antitumor efficacy. The positive trend needs to be confirmed in a randomized phase III trial. STUDY REGISTRATION: European Clinical Trials Database: EudraCT number 2006-002221-23. ClinicalTrials.gov identifier: NCT00448305.

Plasma circulating tumor DNA as an alternative to metastatic biopsies for mutational analysis in breast cancer.

BACKGROUND: Molecular screening programs use next-generation sequencing (NGS) of cancer gene panels to analyze metastatic biopsies. We interrogated whether plasma could be used as an alternative to metastatic biopsies. PATIENTS AND METHODS: The Ion AmpliSeq™ Cancer Hotspot Panel v2 (Ion Torrent), covering 2800 COSMIC mutations from 50 cancer genes was used to analyze 69 tumor (primary/metastases) and 31 plasma samples from 17 metastatic breast cancer patients. The targeted coverage for tumor DNA was ×1000 and for plasma cell-free DNA ×25 000. Whole blood normal DNA was used to exclude germline variants. The Illumina technology was used to confirm observed mutations. RESULTS: Evaluable NGS results were obtained for 60 tumor and 31 plasma samples from 17 patients. When tumor samples were analyzed, 12 of 17 (71%, 95% confidence interval (CI) 44% to 90%) patients had ≥1 mutation (median 1 mutation per patient, range 0-2 mutations) in either p53, PIK3CA, PTEN, AKT1 or IDH2 gene. When plasma samples were analyzed, 12 of 17 (71%, 95% CI: 44-90%) patients had ≥1 mutation (median 1 mutation per patient, range 0-2 mutations) in either p53, PIK3CA, PTEN, AKT1, IDH2 and SMAD4. All mutations were confirmed. When we focused on tumor and plasma samples collected at the same time-point, we observed that, in four patients, no mutation was identified in either tumor or plasma; in nine patients, the same mutations was identified in tumor and plasma; in two patients, a mutation was identified in tumor but not in plasma; in two patients, a mutation was identified in plasma but not in tumor. Thus, in 13 of 17 (76%, 95% CI 50% to 93%) patients, tumor and plasma provided concordant results whereas in 4 of 17 (24%, 95% CI 7% to 50%) patients, the results were discordant, providing complementary information. CONCLUSION: Plasma can be prospectively tested as an alternative to metastatic biopsies in molecular screening programs.

Present and future breast cancer management--bench to bedside and back: a positioning paper of academia, regulatory authorities and pharmaceutical industry.

Insights into tumour biology of breast cancer have led the path towards the introduction of targeted treatment approaches; still, breast cancer-related mortality remains relatively high. Efforts in the field of basic research revealed new druggable targets which now await validation within the context of clinical trials. Therefore, questions concerning the optimal design of future studies are becoming even more pertinent. Aspects such as the ideal end point, availability of predictive markers to identify the optimal cohort for drug testing, or potential mechanisms of resistance need to be resolved. An expert panel representing the academic community, the pharmaceutical industry, as well as European Regulatory Authorities met in Vienna, Austria, in November 2012, in order to discuss breast cancer biology, identification of novel biological targets and optimal drug development with the aim of treatment individualization. This article summarizes statements and perspectives provided by the meeting participants.

A phase I schedule dependency study of the aurora kinase inhibitor MSC1992371A in combination with gemcitabine in patients with solid tumors.

INTRODUCTION: MSC1992371A is an aurora kinase inhibitor with potential antitumor activity. METHODS: This trial established the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of oral MSC1992371A given before or after gemcitabine (1,000 mg/m(2)) in a 21-day cycle in patients with advanced malignancies. In schedule 1 (n = 31), gemcitabine was administered on days 1 and 8 followed by escalating doses of MSC1992371A on days 2 and 9. In schedule 2 (n = 35), MSC1992371A was given on days 1 and 8 followed by gemcitabine on days 2 and 9. Patients had a range of solid tumors, the most frequent of which was colorectal (n = 19). RESULTS: In both schedules, the 37 mg/m(2) dose level was defined as the MTD. The main DLT was grade 4 neutropenia. Adverse events consisted of neutropenia, thrombocytopenia, asthenia, fatigue, nausea, vomiting, anorexia, and diarrhea. Administration of MSC1992371A prior to gemcitabine had no effect on the metabolism or elimination of gemcitabine. Time to reach maximum plasma concentration and area under the plasma concentration-time curve for MSC1992371A increased proportionally with dose. Exploration of drug-target-related and tumor biomarkers did not identify predictors of biologic activity or response. Two patients (1 with lung carcinoma and 1 with hepatocellular carcinoma) had durable partial responses in schedule 2, and 5 patients had stable disease (SD) lasting 6 - 14 months. CONCLUSION: Oral MSC1992371A can be administered at a MTD of 37 mg/m(2) in combination with the standard 1,000 mg/m(2) dose of gemcitabine, but hematologic toxicity requires careful monitoring. Preliminary signs of efficacy were indicated by durable responses and SD.

[Cardiac metastase of a soft tissue sarcoma: a case report and a review of the literature]. / Métastase cardiaque d'un sarcome des tissus mous: cas clinique et revue de la literature.

Soft tissue sarcomas represent rare tumors. They recur most often locally and in the lungs. We report the case of a 58-year woman who was treated for awith chemotherapy and then surgery. About a year after the end of the treatment an intracardiac mass was identified during a follow up chest CT-scan. The patient underwent a surgical resection of that mass found to bel myxoid chondrosarcoma metastasis. Only 2 cases of cardiac dissemination of extraskeletal myxoid chondrosarcoma have been described. The differential diagnosis of intracardiac masses is discussed. In some carefully selected cases atrisks of obstructive shock or embolization and unique metastatic location, cardiac surgery should be considered.

Tyrosinase-related protein 1 mRNA expression in lymph node metastases predicts overall survival in high-risk melanoma patients.

BACKGROUND: Clinical outcome of high-risk melanoma patients is not reliably predicted from histopathological analyses of primary tumours and is often adjusted during disease progression. Our study aimed at extending our previous findings in skin metastases to evaluate the prognostic value of tyrosinase-related protein 1 (TYRP1) in lymph node metastases of stages III and IV melanoma patients. METHODS: TYRP1 mRNA expression in 104 lymph node metastases was quantified by real-time PCR and normalised to S100 calcium-binding protein B (S100B) mRNA expression to correct for tumour load. TYRP1/S100B ratios were calculated and median was used as cutoff value. TYRP1/S100B mRNA values were correlated to clinical follow-up and histopathological characteristics of the primary lesion. RESULTS: A high TYRP1/S100B mRNA ratio significantly correlated with reduced disease-free (DFS) and overall survival (OS; Cox regression analysis, P=0.005 and 0.01, respectively), increased Breslow thickness (Spearman's rho test, P<0.001) and the presence of ulceration (Mann-Whitney test, P=0.02) of the primaries. Moreover, high TYRP1/S100B was of better prognostic value (lower P-value) for OS than Breslow thickness and ulceration. Finally, it was well conserved during disease progression with respect to high/low TYRP1 groups. CONCLUSION: High TYRP1/S100B mRNA expression in lymph node metastases from melanoma patients is associated with unfavourable clinical outcome. Its evaluation in lymph node metastases may refine initial prognosis for metastatic patients, may define prognosis for those with unknown or non-evaluable primary lesions and may allow different management of the two groups of patients.

Safety and efficacy of neratinib (HKI-272) plus vinorelbine in the treatment of patients with ErbB2-positive metastatic breast cancer pretreated with anti-HER2 therapy.

BACKGROUND: Neratinib (HKI-272) is a potent irreversible pan-ErbB tyrosine kinase inhibitor with clinical activity in patients with ErbB2/HER2-positive breast cancer. PATIENTS AND METHODS: Phase I of this open-label, phase I/II study investigated the maximum tolerated dose (MTD) of oral neratinib (160 or 240 mg/day) plus vinorelbine (25 mg/m2; days 1 and 8 of each 21-day cycle) in patients with solid tumors. Phase II assessed the safety, clinical activity, and pharmacokinetics of the combination in patients with HER2-positive metastatic breast cancer; the primary efficacy end point was objective response (OR). RESULTS: In phase I (n=12), neratinib (240 mg) plus vinorelbine (25 mg/m2) was established as the MTD. In phase II, 79 patients with HER2-positive metastatic breast cancer were treated at the MTD. The most common treatment-related adverse events were diarrhea (96%), neutropenia (54%), and nausea (50%). Three patients discontinued treatment due to diarrhea. No clinically important skin side-effects were observed. The OR rate in assessable phase II patients was 41% (no prior lapatinib) and 8% (prior lapatinib). There was no evidence of pharmacokinetic interaction between neratinib and vinorelbine. CONCLUSION: Neratinib plus vinorelbine showed promising antitumor activity and no unexpected toxic effects in HER2-positive metastatic breast cancer patients. Trial registration ClinicalTrials.gov #NCT00706030.

Phase I trial combining temozolomide plus lapatinib for the treatment of brain metastases in patients with HER2-positive metastatic breast cancer: the LAPTEM trial.

BACKGROUND: Brain metastases (BMs) pose a clinical challenge in breast cancer (BC). Lapatinib or temozolomide showed activity in BM. Our study assessed the combination of both drugs as treatment for patients with HER2-positive BC and BM. METHODS: Eighteen patients were enrolled, with sixteen of them having recurrent or progressive BM. Any type of previous therapy was allowed, and disease was assessed by gadolinium (Gd)-enhanced magnetic resonance imaging (MRI). The primary end points were the evaluation of the dose-limiting toxicities (DLTs) and the determination of the maximum-tolerated dose (MTD). The secondary end points included objective response rate, clinical benefit and duration of response. RESULTS: The lapatinib-temozolomide regimen showed a favorable toxicity profile because the MTD could not be reached. The most common adverse events (AEs) were fatigue, diarrhea and constipation. Disease stabilization was achieved in 10 out of 15 assessable patients. The estimated median survival time for the 16 patients with BM reached 10.94 months (95% CI: 1.09-20.79), whereas the median progression-free survival time was 2.60 months [95% confidence interval (CI): 1.82-3.37]. CONCLUSIONS: The lapatinib-temozolomide combination is well tolerated. Preliminary evidence of clinical activity was observed in a heavily pretreated population, as indicated by the volumetric reductions occurring in brain lesions.

Phase I study of oral CP-4126, a gemcitabine derivative, in patients with advanced solid tumors.

CP-4126 is a gemcitabine (2',2'-difluorodeoxycytidine; dFdC) 5' elaidic acid ester. The purpose of this dose-escalating study was to assess safety, pharmacokinetics (PK) and preliminary antitumor activity of the oral formulation and to determine the recommended dose (RD) for phase II studies. The study had a two-step design: a non-randomized dose-escalating step I with oral CP-4126 alone, followed by a randomized, cross-over step II that compared oral CP-4126 with dFdC i.v.. CP-4126 was given on days 1,8,15 in a 4-week schedule with increasing doses until the RD was established. 26 patients with different solid tumours were enrolled in step I at seven dose levels (100-3,000 mg/day). The most frequent drug-related AEs were fatigue and dysgeusia, the majority being grade 1-2. One patient experienced a dose limiting toxicity after one dose of CP-4126 at 1,300 mg/day (ASAT grade 3). PK of CP-4126 could not be determined. The metabolites dFdC and dFdU obeyed dose-dependent pharmacokinetics. Exposures to dFdC were about ten-fold lower compared to exposures after comparable doses of dFdC i.v.. Nine patients reached stable disease as best response, whereby in one patient with vaginal carcinoma a 25 % reduction of tumor volume was reached. This study demonstrates that CP-4126 can be safely administered orally to patients up to 3,000 mg/day in a d1,8,15 q4w schedule with a tolerable safety profile. CP-4126 acts as a prodrug for dFdC when given orally, but because of the poor absorption and the rapid pre-systemic metabolism the study was terminated early and no RD could be determined.

Phase I study of pulsatile 3-day administration of afatinib (BIBW 2992) in combination with docetaxel in advanced solid tumors.

BACKGROUND: A phase I study to assess the maximum tolerated dose (MTD) of a short course of afatinib in combination with docetaxel for the treatment of solid tumors. METHODS: Patients with advanced solid malignancies received docetaxel 75 mg/m(2) intravenously on day 1 and oral afatinib once daily on days 2-4, in 3-week treatment cycles. The afatinib dose was escalated in successive cohorts of 3-6 patients until dose-limiting toxicity (DLT). The MTD cohort was expanded to 13 patients. Pharmacokinetic parameters were assessed. RESULTS: Forty patients were treated. Afatinib doses were escalated to 160 mg/day in combination with 75 mg/m(2) docetaxel. Three patients had drug-related DLTs during cycle 1. The MTD was defined as 90 mg/day afatinib (days 2-4) with docetaxel 75 mg/m(2). The most frequent drug-related adverse events (all grades) were alopecia, diarrhea, stomatitis (all 50 %) and rash (40 %, all grade ≤ 2). Three patients had confirmed responses, two patients had unconfirmed responses and nine patients had durable stable disease >6 cycles. No pharmacokinetic interaction was observed. CONCLUSION: Afatinib 90 mg administered for 3 days after docetaxel 75 mg/m(2) is the MTD for this treatment schedule and the recommended phase II/phase III dose. This combination showed anti-tumor activity in phase I, with a manageable adverse-event profile.