A randomized, placebo-controlled phase III trial of masitinib plus gemcitabine in the treatment of advanced pancreatic cancer.

BACKGROUND: Masitinib is a selective oral tyrosine-kinase inhibitor. The efficacy and safety of masitinib combined with gemcitabine was compared against single-agent gemcitabine in patients with advanced pancreatic ductal adenocarcinoma (PDAC). PATIENTS AND METHODS: Patients with inoperable, chemotherapy-naïve, PDAC were randomized (1 : 1) to receive gemcitabine (1000 mg/m(2)) in combination with either masitinib (9 mg/kg/day) or a placebo. The primary endpoint was overall survival (OS) in the modified intent-to-treat population. Secondary OS analyses aimed to characterize subgroups with poor survival while receiving single-agent gemcitabine with subsequent evaluation of masitinib therapeutic benefit. These prospectively declared subgroups were based on pharmacogenomic data or a baseline characteristic. RESULTS: Three hundred and fifty-three patients were randomly assigned to receive either masitinib plus gemcitabine (N = 175) or placebo plus gemcitabine (N = 178). Median OS was similar between treatment-arms for the overall population, at respectively, 7.7 and 7.1 months, with a hazard ratio (HR) of 0.89 (95% CI [0.70; 1.13]. Secondary analyses identified two subgroups having a significantly poor survival rate when receiving single-agent gemcitabine; one defined by an overexpression of acyl-CoA oxidase-1 (ACOX1) in blood, and another via a baseline pain intensity threshold (VAS > 20 mm). These subgroups represent a critical unmet medical need as evidenced from median OS of 5.5 months in patients receiving single-agent gemcitabine, and comprise an estimated 63% of patients. A significant treatment effect was observed in these subgroups for masitinib with median OS of 11.7 months in the 'ACOX1' subgroup [HR = 0.23 (0.10; 0.51), P = 0.001], and 8.0 months in the 'pain' subgroup [HR = 0.62 (0.43; 0.89), P = 0.012]. Despite an increased toxicity of the combination as compared with single-agent gemcitabine, side-effects remained manageable. CONCLUSIONS: The present data warrant initiation of a confirmatory study that may support the use of masitinib plus gemcitabine for treatment of PDAC patients with overexpression of ACOX1 or baseline pain (VAS > 20mm). Masitinib's effect in these subgroups is also supported by biological plausibility and evidence of internal clinical validation. TRIAL REGISTRATION: ClinicalTrials.gov:NCT00789633.

Masitinib in advanced gastrointestinal stromal tumor (GIST) after failure of imatinib: a randomized controlled open-label trial.

BACKGROUND: Masitinib is a highly selective tyrosine kinase inhibitor with activity against the main oncogenic drivers of gastrointestinal stromal tumor (GIST). Masitinib was evaluated in patients with advanced GIST after imatinib failure or intolerance. PATIENTS AND METHODS: Prospective, multicenter, randomized, open-label trial. Patients with inoperable, advanced imatinib-resistant GIST were randomized (1 : 1) to receive masitinib (12 mg/kg/day) or sunitinib (50 mg/day 4-weeks-on/2-weeks-off) until progression, intolerance, or refusal. Primary efficacy analysis was noncomparative, testing whether masitinib attained a median progression-free survival (PFS) (blind centrally reviewed RECIST) threshold of >3 months according to the lower bound of the 90% unilateral confidence interval (CI). Secondary analyses on overall survival (OS) and PFS were comparative with results presented according to a two-sided 95% CI. RESULTS: Forty-four patients were randomized to receive masitinib (n = 23) or sunitinib (n = 21). Median follow-up was 14 months. Patients receiving masitinib experienced less toxicity than those receiving sunitinib, with significantly lower occurrence of severe adverse events (52% versus 91%, respectively, P = 0.008). Median PFS (central RECIST) for the noncomparative primary analysis in the masitinib treatment arm was 3.71 months (90% CI 3.65). Secondary analyses showed that median OS was significantly longer for patients receiving masitinib followed by post-progression addition of sunitinib when compared against patients treated directly with sunitinib in second-line [hazard ratio (HR) = 0.27, 95% CI 0.09-0.85, P = 0.016]. This improvement was sustainable as evidenced by 26-month follow-up OS data (HR = 0.40, 95% CI 0.16-0.96, P = 0.033); an additional 12.4 months survival advantage being reported for the masitinib treatment arm. Risk of progression while under treatment with masitinib was in the same range as for sunitinib (HR = 1.1, 95% CI 0.6-2.2, P = 0.833). CONCLUSIONS: Primary efficacy analysis ensured the masitinib treatment arm could satisfy a prespecified PFS threshold. Secondary efficacy analysis showed that masitinib followed by the standard of care generated a statistically significant survival benefit over standard of care. Encouraging median OS and safety data from this well-controlled and appropriately designed randomized trial indicate a positive benefit-risk ratio. Further development of masitinib in imatinib-resistant/intolerant patients with advanced GIST is warranted.

Masitinib as a chemosensitizer of canine tumor cell lines: a proof of concept study.

Masitinib, a selective tyrosine kinase inhibitor, has previously been shown to enhance the antiproliferative effects of gemcitabine in human pancreatic cancer, demonstrating potential as a chemosensitizer. This exploratory study investigated the ability of masitinib to sensitize various canine cancer cell lines to doxorubicin, vinblastine, and gemcitabine. Masitinib strongly sensitized histiocytic sarcoma cells to vinblastine (>70-fold reduction in IC(50) at 5 µM masitinib), as well as osteosarcoma and mammary carcinoma cells to gemcitabine (>70-fold reduction at 5-10 µM). In addition, several cell lines were sensitized to doxorubicin (2-10-fold reduction at 10 µM). These data establish proof-of-concept that masitinib in combination with chemotherapeutic agents can generate synergistic growth inhibition in various canine cancers, possibly through chemosensitization. The findings justify further investigation into those combinations that may potentially yield therapeutic benefit.

Phase 1 dose-escalation study of oral tyrosine kinase inhibitor masitinib in advanced and/or metastatic solid cancers.

BACKGROUND: Masitinib is a tyrosine kinase inhibitor with a pre-clinical profile suggesting greater affinity and selectivity in vitro for the wild-type c-Kit receptor and its juxtamembrane mutation than imatinib. METHODS: This dose-escalation study was conducted in patients with advanced and/or metastatic cancer to determine the maximum tolerated dose (MTD) for orally administered masitinib over a 12-week period. Secondary objectives were a clinical assessment of masitinib's activity in cancer patients and establishment of a pharmacokinetic profile. RESULTS: Forty patients with various solid tumours (predominantly GIST, 19 patients) were treated with masitinib at doses ranging between 0.7 and 17.2mg/kg/day. Although the MTD was not formally reached, an acceptable dose for chronic use was identified at 12 mg/kg/day. Treatment-related AEs were frequent (38/40 patients), however, the majority were grade 1 or 2 and demonstrated dose dependency at higher concentrations. Pharmacokinetic results showed a linear, dose-dependent increase of C(max) and AUC. One of two GIST patients with imatinib intolerance had a partial response at 11.1mg/kg/day. About 29% of the imatinib-resistant GIST population and 38% of the overall population had stable disease. CONCLUSIONS: The safety profile of masitinib at 12 mg/kg/day b.i.d. for the treatment of solid cancers appears favourable and compatible with a long-term regimen. Tumour control rate in imatinib-resistant patients was encouraging, hence, the activity of masitinib in c-Kit expressing tumours, such as GIST, warrants further exploration as first-line anticancer therapy as well as for imatinib-resistant patients.

Integration of microfluidics with biomedical infrared spectroscopy for analytical and diagnostic metabolic profiling.

We describe how infrared spectroscopy of dry films (IRDF) can provide diagnostic information, and how we expect integration with laminar fluid diffusion interface (LFDI) sample pre-processing to generate new analytical and diagnostic tests. LFDI pre-processing provides sample clean-up and analyte separation. The sensitivity of IRDF to certain analytes is enhanced through the depletion of sample constituents that otherwise obscure relevant spectral features, permitting the deposition of films with larger sample volumes and, hence, of greater effective optical pathlength for the targeted analytes. An integrated LFDI-IRDF technology holds promise both as a method for rapid point-of-care quantitative analysis of biological fluids and as the engine of discovery for a wide range of novel diagnostic methods based upon metabolic profiling. In particular, successful integration will provide a versatile and cost effective technology platform that will allow for the accurate quantification of low-concentration analytes that are otherwise inaccessible and will provide the basis for diagnostic and prognostic methods that would otherwise be impossible. The specific question addressed by the proof-of-concept study summarised here is whether the spectra of LFDI processed samples can provide analytical methods that are more accurate than otherwise possible without LFDI pre-processing. The enrichment of serum creatinine is accomplished, with subsequent enhancement of its spectral contribution permitting quantification of this clinically important analyte beyond that achievable with no pre-processing. Finally, to illustrate the potential in diagnostic applications, two recently initiated studies are outlined, one involving chronic kidney disease and the other for chronic and acute coronary artery disease.

A quantitative evaluation of spurious results in the infrared spectroscopic measurement of CO2 isotope ratios.

The possible generation of spurious results, arising from the application of infrared spectroscopic techniques to the measurement of carbon isotope ratios in breath, due to coincident absorption bands has been re-examined. An earlier investigation, which approached the problem qualitatively, fulfilled its aspirations in providing an unambiguous assurance that 13C16O2/12C16O2 ratios can be confidently measured for isotopic breath tests using instruments based on infrared absorption. Although this conclusion still stands, subsequent quantitative investigation has revealed an important exception that necessitates a strict adherence to sample collection protocol. The results show that concentrations and decay rates of the coincident breath trace compounds acetonitrile and carbon monoxide, found in the breath sample of a heavy smoker, can produce spurious results. Hence, findings from this investigation justify the concern that breath trace compounds present a risk to the accurate measurement of carbon isotope ratios in breath when using broadband, non-dispersive, ground state absorption infrared spectroscopy. It provides recommendations on the length of smoking abstention required to avoid generation of spurious results and also reaffirms, through quantitative argument, the validity of using infrared absorption spectroscopy to measure CO2 isotope ratios in breath.

Evaluation of spurious results in the infrared measurement of CO2 isotope ratios due to spectral effects: a computer simulation study.

The application of infrared spectroscopy to the measurement of carbon isotope ratio breath tests is a promising alternative to conventional techniques, offering relative simplicity and lower costs. However, when designing such an instrument one should be conscious of several spectral effects that may be misinterpreted as changes in the isotope concentration and which therefore lead to spurious results. Through a series of computer simulations which model the behaviour of the CO2 absorption spectrum, the risk these effects pose to reliable measurement of 13CO2/12CO2 ratios and the measures required to eliminate them are evaluated. The computer model provides a flexible high-resolution spectrum of the four main isotopomer fundamental transitions and fifteen of their most significant hotband transitions. It is demonstrated that the infrared source, infrared windows and breath sample itself all exhibit strong temperature induced errors but pressure effects do not produce significant errors. We conclude that for reliable measurement of 13CO2/12CO2 ratios using infrared spectroscopy no pressure controls are required. window effects are eliminated using windows wedged at a minimum angle of 0.8-2.2 mrad, depending on the material, and the temperature sensitivity of source and gas cells necessitates stabilization to an accuracy of at least 0.2 K.

The application of infrared spectroscopy to breath CO2 isotope ratio measurements and the risk of spurious results.

Stable CO2 isotope breath tests are established as a valuable tool in diagnostic and investigative medicine with the potential to become more prominent in the future. However, their development and widespread clinical use is limited by the requirement of isotope ratio mass spectroscopic analysis. To overcome this restriction alternative analytical techniques have been developed; the most promising, offering relative simplicity and lower costs, are those instruments using infrared spectroscopy. Clinical investigations using such instruments show them to perform well but very little attention has been given to the possibility of interference from the infrared absorption spectrum of other compounds in the breath. To provide an unambiguous answer to this concern we have analysed literature on over 200 detected breath compounds and their infrared absorption spectra to identify any absorption bands coincident with the nu3 absorption band of CO2. It was found that only five breath trace compounds possess coincident fundamental absorption bands, none of which pose the risk of spurious results. We conclude that the 13C16O2/12C16O2 ratio can confidently be measured for isotopic breath tests using an infrared spectrometer, the position of the nu3 absorption band of CO2 in the infrared spectrum precluding any discernible risk of spurious measurements due to coincidental absorption bands.

A survey of teaching and the use of clinical guidelines in accident and emergency departments.

OBJECTIVE: To investigate organised teaching in accident and emergency (A&E) departments in England and Wales. METHODS: A survey was carried out by postal questionnaire. Directed to senior house officers (SHOs), the questionnaire examined the nature and extent of departmental teaching, and measured the availability, suitability, and actual use made of guidelines. Of 231 questionnaires sent, 164 were returned (response rate 71%). RESULTS: The results show that most SHOs attended A&E induction courses at the beginning of their attachments, although the scope of these coursed varied widely. Most SHOs also received regular teaching, although the programmes were generally of less than 3 h in duration. The majority of respondents were well supported with written documentation in a variety of formats. However, a significant minority (29%) of SHOs requested more detailed clinical guidance, and these tended to be the respondents who received the most departmental teaching. CONCLUSIONS: More time could be allocated to structured teaching than at present, and greater use made of complementary educational methods such as practical skill teaching, case presentation, clinical audit, and involvement in journal clubs. More extensive departmental teaching should also be supported by making available more detailed and comprehensive clinical guidelines.

Attitudes and behaviors towards clinical guidelines: the clinicians' perspective.

Objectives--To find out what attitudes hospital doctors have towards the culture of clinical guidelines; to ascertain perceived knowledge and use of clinical guidelines; and to investigate why hospital doctors think that clinical guidelines may not be used and how they think that the use of guidelines can be encouraged. Design--Postal questionnaire survey be tween October 1993 and January 1994. Setting--Hospitals within Oxford region. Subjects--409 doctors of all grades working in one of six specialties (anaesthetics, paediatrics, general surgery, general medicine, obstetrics and gynaecology and accident and emergency medicine). 47 were randomly picked as part of the pilot study, 362 were extracted from hospital staffing lists. Results--268 clinicians (66%) responded to the questionnaire. Most respondents (77%, 208) expressed welcoming attitudes towards guidelines but 51%(136) perceived the attitudes of their colleagues as being less favourable. Over three quarters of respondents claimed to use guidelines at least once a month. Most respondents learnt about guidelines from discussions with their peers (50%, 134 respondents) or senior doctors 37%, 99) or from journals (39%, 105). Reasons why guidelines may not be used included being unaware of particular guidelines (80%, 213 respondents) and the fact that guidelines had been poorly developed (64%, 171) or were impractical (49%, 132). The best ways to encourage the use of guidelines were thought to be encouragement from senior doctors (72%, 193 respondents) and peers (59%, 157) and by monitoring behaviour and providing feedback (68%, 181). Conclusion--The decision to use a guide line was based on the perceived value of each guideline and was influenced by other clinicians' behaviour. The results provide an insight into aspects of dissemination and implementation which are perceived as influential by the recipients of guidelines.