Phase II trial of dasatinib for recurrent or metastatic c-KIT expressing adenoid cystic carcinoma and for nonadenoid cystic malignant salivary tumors.

BACKGROUND: Adenoid cystic carcinoma (ACC) is a subtype of malignant salivary gland tumors (MSGT), in which 90% of cases express cKIT. Dasatinib is a potent and selective inhibitor of five oncogenic protein tyrosine kinases (PTKs)/kinase families including cKIT. We conducted a phase II study to determine the antitumor activity of dasatinib in ACC and non-ACC MSGT. PATIENTS AND METHODS: In a two-stage design, patients with progressive, recurrent/metastatic ACC (+cKIT) and non-ACC MSGT (separate cohort) were treated with dasatinib 70 mg p.o. b.i.d. Response was assessed every 8 weeks using RECIST. RESULTS: Of 54 patients: 40 ACC, 14 non-ACC (1, ineligible excluded); M:F = 28 : 26, median age 56 years (range 20-82 years), ECOG performance status 0 : 1 : 2 = 24 : 28 : 2, prior radiation: 44, prior chemotherapy: 21. The most frequent adverse events (AEs) (as % of patients, worst grade 2 or higher) were: fatigue (28%), nausea (19%), headache (15%), lymphopenia (7%), dyspnea (11%), alanine aminotransferase increased (7%), anorexia (7%), vomiting (7%), alkaline phosphatase increased (6%), diarrhea (6%), neutropenia (6%), and noncardiac chest pain (6%). No grade 4 AE occurred, 15 patients experienced a grade 3 AE, primarily dyspnea (5) and fatigue (4), and cardiac toxicity (1 prolonged QTc). Among ACC patients, best response to dasatinib: 1 patient (2.5%) had partial response, 20 patients (50%) had stable disease (SD) (3-14 months), 12 patients (30%) had PD, 2 withdrew, 3 discontinued therapy due to AE, and 2 died before cycle 2. Median progression-free survival was 4.8 months. Median overall survival was 14.5 months. For 14 assessable non-ACC patients, none had objective response, triggering early stopping rule. Seven had SD (range 1-7 months), 4 PD, 2 discontinued therapy due to AE, and 1 died before cycle 2. CONCLUSION: Although there was only one objective response, dasatinib is well tolerated, with tumor stabilization achieved by 50% of ACC patients. Dasatinib demonstrated no activity in non-ACC MSGT.

Designs of preoperative biomarkers trials in oncology: a systematic review of the literature.

BACKGROUND: The identification of predictive and pharmacodynamics (PD) biomarkers of efficacy of anticancer-targeted therapies is not always straightforward. To address this problem, preoperative trials have been set up. The present study aimed at evaluating how these trials are designed. DESIGN: We retrieved all preoperative oncology trials, defined as preoperative trials having a PD end point. RESULTS: Only 56 trials met our selection criteria. Of these, 27 trials (48%) were randomized. Forty-nine trials (88%) evaluated at least a noncytotoxic agent. In 37 trials (66%), a single agent was administered. The most prevalent tumor type was breast cancer (59%). Median duration of accrual was 28 months (range: 9-98). In these trials, there was a mean of two patients included per month (range: 0-7). The date of surgery was fixed before study entry in 35 trials (62%), while surgery was set up after preoperative therapy in the remaining 21 trials (38%). In the former trials, median duration of preoperative therapy was 17 days (range: 1-112), whereas in the latter trials it ranged from 4 to 29 weeks. The primary end point was a PD end point in 26 of the 45 trials (58%) in which it was mentioned. One percent of patients could not undergo surgery as per protocol due to an adverse event. Statistically significant predictive and PD biomarkers were identified in 17 (30%) and 27 trials (48%), respectively. CONCLUSION: Preoperative biomarkers trials are infrequent but safe and feasible. These trials often permit the identification of predictive and PD biomarkers.

A phase I study of the combination of ro4929097 and cediranib in patients with advanced solid tumours (PJC-004/NCI 8503).

BACKGROUND: The Notch signalling pathway has been implicated in tumour initiation, progression, angiogenesis and development of resistance to vascular endothelial growth factor (VEGF) targeting, providing a rationale for the combination of RO4929097, a γ-secretase inhibitor, and cediranib, a VEGF receptor tyrosine kinase inhibitor. METHODS: Patients received escalating doses of RO4929097 (on a 3 days-on and 4 days-off schedule) in combination with cediranib (once daily). Cycle 1 was 42 days long with RO4929097 given alone for the first 3 weeks followed by the co-administration of both RO4929097 and cediranib starting from day 22. Cycle 2 and onwards were 21 days long. Soluble markers of angiogenesis were measured in plasma samples. Archival tumour specimens were assessed for expression of three different components of Notch signalling pathway and genotyping. RESULTS: In total, 20 patients were treated in three dose levels (DLs). The recommended phase II dose was defined as 20 mg for RO4929097 on 3 days-on and 4 days-off schedule and 30 mg daily for cediranib. The most frequent treatment-related adverse events (AEs) were diarrhoea, hypertension, fatigue and nausea. Eleven patients had a best response of stable disease and one patient achieved partial response. We did not detect any correlation between tested biomarkers of angiogenesis or the Notch pathway and treatment effect. There was no correlation between mutational status and time to treatment failure. CONCLUSION: RO4929097 in combination with cediranib is generally well tolerated at the DLs tested. Preliminary evidence of antitumour efficacy with prolonged disease stabilisation in some patients with progressive malignancies warrants further clinical investigation of this treatment strategy.

A phase I dose-escalation study of aflibercept administered in combination with pemetrexed and cisplatin in patients with advanced solid tumours.

BACKGROUND: To evaluate the safety, pharmacokinetics (PKs), and pharmacodynamics of aflibercept, and to identify the recommended phase II dose (RP2D) of aflibercept in combination with pemetrexed and cisplatin. METHODS: Aflibercept was administered at escalating doses of 2, 4, or 6 mg kg(-1) in combination with fixed doses of pemetrexed (500 mg m(-2)) plus cisplatin (75 mg m(-2)) every 3 weeks. Blood samples were collected for PK analyses. Serum antiaflibercept antibodies were quantified to assess their impact on systemic aflibercept concentrations. RESULTS: Eighteen patients were enrolled. One patient dosed at 4 mg kg(-1) experienced grade 3 hypophosphatemia (dose-limiting toxicity; DLT), which prompted a cohort expansion. No further DLTs were observed in the 4 mg kg(-1) cohort or the 6 mg kg(-1) dose cohort. Most common adverse events (AEs) of all grades included (%): fatigue (89), anaemia (89), nausea (83), hyponatremia (78), and neutropenia (72). Grade ≥ 3 AEs consistent with anti-vascular endothelial growth factor therapy included (%): hypertension (22), pulmonary embolism (11), and deep vein thrombosis (6). Five patients (28%) experienced mild neurocognitive disturbance. No episodes of reversible posterior leukoencephalopathy syndrome (RPLS) were noted. CONCLUSION: The results of this phase I study allowed further evaluation of the combination of aflibercept with pemetrexed and cisplatin in a phase II study. The RP2D of aflibercept was 6 mg kg(-1), to be administered intravenously every 3 weeks in combination with pemetrexed and cisplatin.

Phase I clinical, pharmacokinetic and pharmacodynamic study of SB939, an oral histone deacetylase (HDAC) inhibitor, in patients with advanced solid tumours.

BACKGROUND: SB939 is an orally available, competitive histone deacetylase (HDAC) inhibitor selective for class I, II and IV histone deacetylases. Preclinical evaluation of SB939 revealed a profile suggesting improved efficacy compared to other HDAC inhibitors. This phase I study was carried out to determine the safety, dose-limiting toxicity, recommended phase II dose (RPTD), as well as pharmacokinetic (PK) and pharmacodynamic (PD) profiles of SB939 in a daily × 5 schedule in advanced solid tumours. METHODS: Sequential dose-escalating cohorts of patients were enrolled into 8 dose levels. At dose level 1, SB939 was taken on days 1-3 and 15-17 every 4 weeks, then on days 1-5 and 15-19 for other dose levels. Detailed PK sampling was performed in cycle 1, days 1 and 5. Peripheral blood mononuclear cells (PBMCs) were collected on cycle 1 at various time points for determination of acetylated histone H3 (AcH3) levels. RESULTS: In total, 38 patients received a total of 96 cycles of treatment. The maximal administered dose was 90 mg and the RPTD was 60 mg given 5 consecutive days every 2 weeks. The most frequent non-hematologic adverse events (AEs) of at least possible attribution to SB939 were fatigue, nausea, vomiting, anorexia and diarrhoea. Pharmacokinetic analysis showed dose-proportional increases in AUC across the doses evaluated. Elimination half-life was 5.6-8.9 h. There was no clear relationship between AcH3 changes and dose level or anti-tumour response. CONCLUSIONS: SB939 is well tolerated in patients with advanced solid tumours. The RPTD of this drug is 60 mg on a schedule of 5 consecutive days every 2 weeks. The toxicities of SB939 are consistent with other HDAC inhibitors.

The role of folate receptor alpha (FRalpha) in the response of malignant pleural mesothelioma to pemetrexed-containing chemotherapy.

BACKGROUND: The standard treatment of choice for malignant pleural mesothelioma is chemotherapy with pemetrexed and platinum, but the clinical outcome is poor. This study investigates the response to pemetrexed in a panel of eight mesothelioma cell lines and the clinical outcome for patients treated with pemetrexed in relation to folate receptor alpha (FRalpha). METHODS: Cell lines were treated with pemetrexed to determine the concentration that reduced growth to 50% (GI(50)). FRalpha expression was determined by western blotting and that of FRalpha, reduced folate carrier (RFC) and proton-coupled folate transporter (PCFT) by real-time quantitative RT-PCR. Immunohistochemistry for FRalpha was carried out on 62 paraffin-embedded samples of mesothelioma from patients who were subsequently treated with pemetrexed. RESULTS: A wide range of GI(50) values was obtained for the cell lines, H2452 cells being the most sensitive (GI(50) 22 nM) and RS5 cells having a GI(50) value greater than 10 microM. No FRalpha protein was detected in any cell line, and there was no relationship between sensitivity and expression of folate transporters. FRalpha was detected in 39% of tumour samples, generally in a small percentage of cells. There was no correlation between the presence of FRalpha and the outcome of pemetrexed treatment, and no significant difference between histological subtypes. CONCLUSION: Response to treatment with pemetrexed does not depend on the presence of FRalpha.

Mesenchymal chondrosarcoma of the orbit: an unusual site for a rare tumour.

Mesenchymal chondrosarcoma is a rare tumour with orbital involvement being an exceptional occurrence. We present a case of a 22-year old man with such disease, together with details of his management. A brief literature review of this uncommon tumour was also enclosed.

Removal of endocrine disrupting chemicals (EDCs) using low pressure reverse osmosis membrane (LPROM).

Endocrine disrupting chemicals (EDCs) are the focus of current environmental issues, as they can cause adverse health effects to animals and human, subsequent to endocrine function. The objective of this study was to remove a specific compound of EDCs (i.e. pentachlorophenol, C(6)OCL(5)Na, molecular weight of 288 g/mol) using low pressure reverse osmosis membrane (LPROM). A cross flow module of LPROM was used to observe the effects of operating parameters, i.e. pH, operating pressure and temperature. The design of the experiment was based on MINITAB(TM) software, and the analysis of results was conducted by factorial analysis. It was found that the rejection of pentachlorophenol was higher than 80% at a recovery rate of 60 to 70%. The rejection was subjected to increase with the increase of pH. The flux was observed to be increased with the increase of operating pressure and temperature. This study also investigated the interaction effects between operating parameters involved.

Phase 1 study of nab-paclitaxel, cisplatin and 5-fluorouracil as induction chemotherapy followed by concurrent chemoradiotherapy in locoregionally advanced squamous cell carcinoma of the oropharynx.

BACKGROUND: Induction chemotherapy followed by concurrent chemoradiation (CRT) (sequential therapy) has been evaluated in the treatment of locoregionally-advanced squamous cell cancer of the head and neck (LA-SCCHN), with docetaxel, cisplatin (P) and 5-flurouracil (F) shown to be superior to PF doublet. Nab-paclitaxel (A) is a novel albumin-bound paclitaxel with a superior therapeutic index to docetaxel. METHODS: A phase I trial [Clinical trials.gov identifier NCT00731380] to assess the safety and efficacy of nab-paclitaxel+cisplatin+5-fluorouracil (APF) as induction chemotherapy for three cycles, followed by concurrent carboplatin (area-under-curve (AUC) 1.5 weekly) with radiation therapy (RT) (70 Gy/35 fractions), was conducted using a 3+3 design in patients with previously untreated LA-SCCHN. Dose-limiting toxicities (DLTs) included: standard haematologic and non-haematologic toxicities, treatment delays, inability to complete ⩾95% of RT and skin/mucosal toxicity related to RT assessed from day 1 of treatment to 8 weeks after completion of CRT. RESULTS: 17 patients with oropharyngeal cancer were enrolled in three dose levels, with 15 patients evaluable for DLT. The median age was 54 years (range, 44-65 years), 14 patients were male, and 11 patients' tumours were p16 positive and four negative. Grade 3/4 adverse events during APF (%total number of cycles) were hyponatraemia (14%) neutropenia (10%), lymphopaenia (4%) and thrombocytopenia (2%) during 49 evaluable APF cycles. Febrile neutropenia occurred during one cycle of treatment. CONCLUSION: The recommended phase 2 dose of APF is nab-paclitaxel 100mg/m(2) days 1 and 8, cisplatin 75 mg/mg(2) day 1 and 5-fluorouracil 1000 mg/m(2)/day×96 h days 1-4, every 3 weeks, for three cycles prior to CRT.

Acute upper arm ischaemia: a rare presentation of non-Hodgkin's lymphoma.

Digital ischaemia has been sparsely reported in current literature. Its association with lymphomatous conditions has been described in even more exceptional occurrences. We present the first case of upper arm ischaemia associated with non-Hodgkin's lymphoma. A brief literature review of this rare phenomenon is also accompanied with it.

Life after first-line chemotherapy in malignant pleural mesothelioma: a North-East England experience.

AIMS: The benefit of first-line chemotherapy in malignant pleural mesothelioma (MPM) has been established. However, this disease invariably progresses and little is known about how this disease subsequently relapses after initial treatment. Data on second-line treatment are also scarce, especially outside the context of a clinical trial. We conducted a review to observe the presentation of MPM patients when their disease progresses after initial therapy and the use of second-line therapy and its associated outcomes. MATERIALS AND METHODS: Patients were retrospectively identified from the Sunderland Royal Hospital and the Northern Centre for Cancer Care, Newcastle upon Tyne, UK. Data, including demographics, clinical presentation and treatment details at first line and beyond, together with its associated benefits, were collected. Related times to treatment failure (TTF), rates of symptom improvement and survival data were also collated. RESULTS: There were 62 evaluable patients in our series. At the time of data collection, 58 patients (94%) had relapsed. At disease progression, symptoms were usually similar to those at initial presentation, but in patients with prolonged TTF (>9 months) they were more likely to relapse with clinical lymphadenopathy in the neck and axilla compared with patients with TTF < or =9 months (52% vs 13%, respectively, P<0.05). Second-line treatment was given in 45% of patients. Twenty-one patients (36%) received second-line chemotherapy outside the context of a clinical trial and most had retreatment with pemetrexed-based chemotherapy due to a prolonged TTF. In patients treated with second-line therapy outside the remit of a clinical trial, a disease control rate was achieved in nine patients (43%, 95% confidence interval 22-64), whereas improvement in symptoms were noted in 13 patients (62%, 95% confidence interval 41-83). The median TTF in this setting was 6.5 months. CONCLUSION: Patients with a prolonged TTF after first-line treatment are more likely to relapse with neck and axillary lymphadenopathy. The use of second-line chemotherapy, including rechallenge treatment, in this disease is a viable option for a selected group of MPM patients.