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K. Nackaerts
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MINI 01 - Pathology (ID 93)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:W.A. Franklin, A.G. Nicholson
- Coordinates: 9/07/2015, 10:45 - 12:15, Mile High Ballroom 2c-3c
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MINI01.11 - Transcriptome Sequencing of Tumor vs. Surrounding Non-Malignant Lung Tissue in Non-Small Cell Lung Cancer (ID 1765)
10:45 - 12:15 | Author(s): K. Nackaerts
- Abstract
Background:
Both the response and the therapeutic ratio of targeted agents in NSCLC may depend on the expression of the target molecules in the tumor and the surrounding non-malignant lung tissue. We therefore performed transcriptome analysis and investigated correlations with histology, gender, age, CRP level and smoking status as well as evaluated the differential pathway expression in primary resected NSCLC and the surrounding non-malignant lung of the same patient.
Methods:
Transcriptome sequencing was performed on the primary tumor and distant lung tissue of the same patient from resection specimens of NSCLC patients. Differential gene expression between different conditions was identified using the statistical algorithms Cufflinks, EdgeR and DeSeq. Differential expression with P-values <0.05 after Benjamini-Hochberg correction was considered significant. Pathway analysis for overall tumor versus distant lung tissue was performed with the PANTHER gene classification platform using the Cufflinks, DeSeq and EdgeR differentially expressed gene sets as input.
Results:
Twenty-five patients were studied, 19 males and 6 females, with a median age of 69 years. Ten were current smokers, 14 former smokers (>4 weeks before surgery) and 1 non-smoker. Eleven patients had squamous cell carcinoma, 14 adenocarcinoma. A heat map with the results for the most commonly targeted genes in NSCLC is represented in figure 1. When compared to distant lung tissue, PD-L1 was downregulated in tumor tissue of adenocarcinoma and active smokers, but not in squamous cell carcinoma or ex-smokers. Internal control of tumor tissue of squamous vs. adenocarcinoma and ex-smokers vs. active smokers shows an important trend towards a higher expression of PD-L1 in squamous cell carcinoma and ex-smokers in both Cufflinks and EdgeR algorithms. Additional pathway analysis revealed 188 differentially regulated pathways. The most notable were downregulation of VEGF signaling, angiogenesis and B and T cell activation in tumor tissue when compared to distant lung tissue. Figure 1
Conclusion:
Our first results show a higher expression of PD-L1 in squamous tumors than in adenocarcinoma and a higher expression in tumors of ex-smokers than in those of active smokers. This may have consequences for the therapeutic ratio with anti-PD-L1 treatment. Downregulation of VEGFR-genes in tumor tissue was observed across almost all conditions. We will make this data more complete by adding methylation data as well as immunohistochemistry for protein localization.
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MINI 22 - New Technology (ID 134)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
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MINI22.06 - The Challenge of Molecular Testing for Clinical Trials in Advanced Non-Small Cell Lung Cancer Patients: Analysis of a Prospective Database (ID 1240)
16:45 - 18:15 | Author(s): K. Nackaerts
- Abstract
- Presentation
Background:
Molecular testing has become important in managing advanced non-small cell lung cancer (NSCLC), both in clinical practice, as well as in clinical trials. For the latter, tissue samples often have to be analysed in a central laboratory. We evaluated the turnaround time and possible delay in start of therapy in this process.
Methods:
We reviewed our prospective database on all molecular testing cases for clinical trial suitability in patients with advanced NSCLC between March 1, 2011 (start) and October 31, 2014. The following time points were considered: T1 (request for tissue sections from the pathology lab); T2 (receipt of sections and shipment); T3 (arrival of sections in central lab (CL)); T4 (receipt of biomarker result from CL).
Results:
251 patients were considered for biomarker-driven trials. Twenty-three cases did not have further analysis, as the request for central molecular testing was cancelled: insufficient tissue (n=11); exclusion criterion (n=10); patient refusal (n=2). Results for the remaining 228 patients were: failure of central biomarker analysis due to insufficient quantity of tissue (n=18), or quality of tissue (n=3, i.e. decalcification or poor fixation). Valuable results were obtained for 207 patients. In 91 of 228 (39.9%) samples sent, a biomarker of interest was documented. This led to 34 clinical trial inclusions. Other patients were no longer eligible due to loss of performance status (n=20), loss of contact (n=14), no trial slot available at the appropriate time (n=18), or exclusion criteria (n=5). The mean waiting time between signing informed consent (T1) and receiving results of the biomarker analysis (T4) was 25.1 calendar (SD 17.3) days (Table). The preparation of the unstained slides by the pathology lab took about 9.1 (SD 6.8) days, the time of the biomarker testing itself accounted for 12.8 (SD 7.3) days. For 18 of 228 (7.9%) patients, repeated sample shipments were needed because of insufficient tumor cells, their mean waiting time between informed consent and receiving the biomarker result was 62.2 (SD 38.4) days. Table: Waiting times (t) in molecular testing for 228 patients.Time interval Mean StDev Median Range Pathology lab (T2-T1) 9.1 6.8 7.0 1 - 70 Shipment (T3-T2) 1.8 1.6 1.0 0 - 17 Analysis (T4-T3) 12.8 7.3 12.0 2 - 58 Request to result (T4-T1) 25.1 17.3 22.0 7 - 184
Conclusion:
While molecular testing is important in many NSCLC trials, our results show that waiting times for central laboratory analysis can cause an important delay in treatment initiation, and even ineligibility for the trial(s) under consideration. Start of therapy based on properly validated local testing, with a posteriori central biomarker testing to guarantee the integrity of the trial, would be more rewarding for quite some patients.
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MINI 24 - Epidemiology, Early Detection, Biology (ID 140)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:J. Creaney, M. Carbone
- Coordinates: 9/08/2015, 16:45 - 18:15, 102+104+106
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MINI24.08 - Breath Analysis by Ion Mobility Spectrometry Allows Discrimination of Pleural Mesothelioma Patients From Controls (ID 1508)
16:45 - 18:15 | Author(s): K. Nackaerts
- Abstract
Background:
Despite the use of asbestos has been banned in many countries, 125 million people worldwide are still exposed to asbestos and at risk for developing malignant pleural mesothelioma (MPM). Since MPM is a lethal tumor, with diagnosis mainly at advanced stage due to non-specific symptoms and investigations, it is thought that only an early diagnosis will improve patient’s outcome (van Meerbeeck et al., 2011). Breathomics has emerged as a new research field, allowing to detect volatile organic compounds (VOCs) in breath which can be used as non-invasive markers for disease (Lamote et al., 2014). We investigated if asbestos induces VOCs and how breath VOCs could help discriminating MPM patients from occupational asbestos-exposed and non-exposed controls.
Methods:
Twenty-three MPM patients, ten healthy asbestos-exposed (AEx) individuals and twelve healthy non-exposed (HC) persons were included. After a fasting period of 2 hours before the breath sampling, participants breathed tidally for 3 minutes through a mouthpiece connected to a bacteria filter. Subsequently, ten ml alveolar air was sampled via a CO~2~-controlled ultrasonic sensor and analyzed using the BioScout Multicapillary Column/Ion Mobility Spectrometer (MCC/IMS, B&S Analytik, Dortmund, Germany). Per subject a background sample was taken. VOCs were visually selected and their intensity (V) was calculated via on-board VisualNow 3.7 software. After calculating the alveolar gradient, we performed a lasso regression in R to search for peaks that have the most discriminative power to distinguish MPM patients from controls. Predictions were made by leave-one-out cross-validation. The use of breath VOCs on the diagnostic performance was investigated by ROC-analysis.
Results:
Eighty-nine VOCs were selected in breath and background samples. The VOCs P25, P8 and P7 were able to discriminate HC from AEx controls with 91% accuracy (AUC~ROC~=0.95), yielding a sensitivity, specificity and positive (PPV) and negative predictive value (NPV) of respectively 90%, 92%, 90% and 92%. MPM patients were discriminated from AEx by the VOCs P5, P3, P30, P1 and P54 with 82% accuracy (AUC~ROC~=0.73), yielding a sensitivity, specificity and PPV and NPV of respectively 91%, 60%, 84% and 75%. When discriminating MPM patients from pooled HC and AEx controls, the VOCs P5, P3 and P1 were found to be important, yielding 73% accuracy (AUC~ROC~=0.71) and a sensitivity, specificity and PPV and NPV of respectively 70%, 77%, 76% and 71%.
Conclusion:
Breath analysis can discriminate MPM patients from healthy asbestos-exposed persons with 82% accuracy and from combined asbestos-exposed and non-exposed controls with 73% accuracy while healthy asbestos-exposed persons can be discriminated from non-exposed persons with 91% accuracy. The VOCs P25, P8 and P7 seem markers for asbestos-exposure while VOCs P5, P1 and P3 seem linked to MPM pathogenesis after exposure. For screening and to rule out diagnosis, a high sensitivity and NPV are mandatory and to rule in diagnosis, a high specificity and PPV are mandatory, which can enrich a population at risk for follow-up with (annual) CT scans or chest radiography. Hence, our results hold promise to use the breath test for screening of asbestos-exposed healthy seniors.
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MINI 25 - Trials, Radiation and Other (ID 142)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:J.M. Clavero, R. Hassan
- Coordinates: 9/08/2015, 16:45 - 18:15, 702+704+706
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MINI25.11 - Optimization of Gross Tumour Volume Definition in Lung-Sparing Volumetric Modulated Arc Therapy for Pleural Mesothelioma (ID 2860)
16:45 - 18:15 | Author(s): K. Nackaerts
- Abstract
- Presentation
Background:
High dose lung-sparing pleural radiotherapy for malignant pleural mesothelioma (MPM) is difficult. Given the steep dose gradient with volumetric modulated arc therapy (VMAT), accurate target delineation is critical. The optimal imaging modality to define radiotherapy target volumes has not been studied in depth. This is the aim of the present study.
Methods:
Twelve consecutive patients with a histopathological diagnosis of stage I-IV MPM (6 left-sided and 6 right-sided) were included. CT scans with intravenous (IV) contrast, [18]F-FDG PET/CT scans, MRI scans (post-contrast T1-weighted and T2-weighted) and diffusion-weighted images (DWI) were obtained and downloaded from the institutional database onto a standalone image fusion workstation (MIM Software Inc., Cleveland, OH, USA) for image registration and contouring. CT scans were rigidly co-registered with ~18~FDG-CT-PET, with MRI scans and with DWI scans. Four sets of pleural GTVs were defined: 1) a CT-based GTV (GTV~CT~); 2) a PET/CT-based GTV (GTV~CT+PET/CT~); 3) a T1/T2-weighted MRI-based GTV (GTV~CT+MRI~); 4) a DWI-based GTV (GTV~CT+DWI~). Only the pleural tumor was contoured; mediastinal nodes were excluded. In each of the 4 co-registrations, a “quantitative” and a “qualitative” (visual) evaluation of the volumes were performed. “Quantitative” evaluation was carried out through the coefficient of variation (COV; the ratio between the standard deviation [SD] and the mean: a measure of the dispersion of a distribution) and the Jaccard index (the ratio between the union and the intersection between two volumes: a measure of overlap). “Qualitative” evaluation consisted of a visual identification of any additional tumor site in each of the 4 obtained co-registrations.
Results:
Compared to CT-based GTV definition, PET/CT identified additional tumour sites in 12/16 patients. Compared to either CT or PET/CT, MRI and DWI identified additional tumour sites in 15/16 patients. Additional tumour sites were mainly the parietal pleura, the diaphragm and the chest wall. Mean GTV~CT~, GTV~CT+PET/CT~, GTV~CT+MRI~ and GTV~CT+DWI~ (+SD) were respectively 630.1 mL (+302.81), 640.23 (+302.83), 660.8 (+290.8) and 655.2 mL (+290.7). Mean Jaccard index was lower in MRI-based contours versus all the others.
Conclusion:
To the best of our knowledge, this is the first study showing that the integration of the MRI (T1/T2-weighted) and DWI into the target volume definition in lung-sparing hemi-thoracic VMAT in MPM may allow to improve the accuracy of target delineation and reduce the likelihood of geographical misses.
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MS 19 - Global Nursing Issues in Lung Cancer (ID 37)
- Event: WCLC 2015
- Type: Mini Symposium
- Track: Nursing and Allied Professionals
- Presentations: 1
- Moderators:P. Hollen, B. Ivimey
- Coordinates: 9/08/2015, 14:15 - 15:45, 708+710+712
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MS19.01 - Nursing Challenges in Clinical Trials (ID 1931)
14:15 - 15:45 | Author(s): K. Nackaerts
- Abstract
- Presentation
Abstract:
Background: The model of clinical trials in lung cancer has evolved quite dramatically over the past years. Expanded phase I trials in biomarker-driven populations are a new paradigm of accelerated drug approval. Enrolling patients in these clinical trials creates several new challenges. Clinical Research Nurses (CRNs) play an important role in recruitment, actual drug delivery, and monitoring of this whole process. Methods: Identify the different barriers to recruitment that CRNs face with these clinical trials. Barriers to participation can be patient-related, physician-related or tissue-related. Review of literature was the basis for the patient- and physician-related barriers. To identify the tissue barriers, we studied our own database. We also present practical tips to overcome these barriers out of own expertise in the field. Results: Patients’ barriers to participate in clinical trials include individual characteristics, practical issues, and attitudes. The most common barriers are the individual characteristics: cultural background, health literacy, ethnicity, and age. Lack of knowledge, insurance coverage, extra appointments, reimbursement, and patient ineligibility are typical practical barriers. Attitudinal barriers are reluctance to randomisation, fear for side effects, and efficacy concerns (e.g. allocation to placebo) (1-3). To overcome these barriers the trial should be explained clearly. Patient should be supported in what may be a difficult decision and should not be pressured to do so. Dedicated CRNs may help with monitoring the recruitment process, providing additional information, and obtaining informed consent (1). The process of informed consent is the optimal time to define clearly the terms of the clinical trial, and to explain the sometimes difficult to understand medical and legal terms in the informed consent document. Optimally, this should lead to good understanding by the patient of the potential benefits and risks (4). Main physicians’ barriers are lack of time due to competing priorities, insufficient staff and training to meet the ever increasing procedures from competent authorities or institutional review boards and finance departments, worry about the impact on the doctor-patient relation, concern for patients, and lack of reward and recognition. Lack of time is considered a major barrier. Doctors experience time pressure from their usual clinical practice and management duties. Recruitment, the consent process, and the follow up of clinical trials on top of that demand a large piece of extra time (1;4;5). Lack of support staff, for example CRNs, can also account for poor recruitment. A stable clinical research team is likely to be advantageous. CRNs should not only have expert clinical and well developed critical thinking skills, but be well acquainted with the complex scientific, regulatory, and ethical aspects of clinical research (6). Well trained and experienced CRNs truly are “PI-extensions”. By monitoring the clinical activity to find possible candidates for trials, they support the physician with recruitment, and later on with the follow-up of included patients. Over the last years, we saw a major progress in the treatment of advanced non-small cell lung cancer, largely due to new targeted agents, monoclonal antibodies, and immunomodulatory agents. Both in clinical practice, as well as in clinical trials, the availability of tissue for biomarker analysis – in order to make the best choice for the patient – is crucial. Tissue availability is a new important barrier to clinical trials, as we noted from our own experience (7). Moreover, central lab confirmation of an already known biomarker, is often requested before the patient is allowed to start therapy, leading to sometimes important delays. In our respiratory oncology trial unit, we analysed of our molecular database regarding this barrier (7). The mean waiting time between signing informed consent and receiving results of the biomarker analysis from the central laboratory turned out to be 25 calendar days! While delivering a tissue sample for central confirmation of molecular testing is crucial in biomarker-driven NSCLC trials, the mandatory waiting of patients to start therapy is to be discussed. Waiting times for central laboratory analysis not only lead to an important delay in treatment initiation, but even ineligibility for the trial(s) under consideration. Start of therapy based on a properly validated local test, with a posteriori central biomarker testing to guarantee the integrity of the trial, would be more rewarding for quite some patients (8). Conclusion: Recruitment in lung cancer clinical trials is a complex and vulnerable process with different types of barriers. Identifying such barriers can help clinical trial staff to develop strategies to optimize participation and cooperation. Well-trained CRNs have a unique knowledge and set of skills that allows them to make a significant contribution to the clinical research team. CRNs should follow the rapid change in clinical trials closely, so that they can be a guide for patients in their clinical trial journey. Moreover, they have an important role in minimising the patient barriers, give support in physician barriers, and facilitating tissue barriers. References (1) Ross S, Grant A, Counsell C et al. Barriers to participation in randomised controlled trials: A systematic review. J Clin Epidemiol 1999;52:1143-1156. (2) Manne S, Kashy D, Albrecht T et al. Attitudinal barriers to participation in oncology clinical trials: Factor analysis and correlates of barriers. Eur J Cancer Care 2015;24:28-38. (3) Kaplan CP, Napoles AM, Dohan D et al. Clinical trial discussion, referral, and recruitment: Physician, patient, and system factors. Cancer Causes Control 2013;24:979-988. (4) Mills EJ, Seely D, Rachlis B et al. Barriers to participation in clinical trials of cancer: A meta-analysis and systematic review of patient-reported factors. Lancet Oncol 2006;7:141-148. (5) Seruga B, Sadikov A, Cazap EL et al. Barriers and challenges to global clinical cancer research. Oncologist 2014;19:61-67. (6) Hastings CE, Fisher CA, McCabe MA et al. Clinical research nursing: A critical resource in the national research enterprise. Nurs Outlook 2012;60:149-156. (7) Lepers S, Ottevaere A, Oyen C et al. The challenge of molecular testing for clinical trials in advanced non-small cell lung cancer patients: analysis of a prospective database. J.Thorac.Oncol. 2015; 10 Suppl: Mini Oral presentation WCLC 2015. (8) Adam V, Dooms C, Vansteenkiste J. Lung cancer at the intensive care unit: The era of targeted therapy. Lung Cancer 2015;E-pub May 18.
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P1.08 - Poster Session/ Thymoma, Mesothelioma and Other Thoracic Malignancies (ID 224)
- Event: WCLC 2015
- Type: Poster
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.08-006 - Lung Toxicity after Post-Operative Radiotherapy after EPP for Mesothelioma and Pneumonectomy for Non-Small Cell Lung Cancer (ID 2863)
09:30 - 17:00 | Author(s): K. Nackaerts
- Abstract
Background:
Our hypothesis is that MPM patients treated with post-operative RT after EPP are more prone to develop lung toxicity compared to non-small cell lung cancer (NCSLC) patients treated with post-operative RT after pneumonectomy, since their higher baseline inflammation status.
Methods:
We retrospectively reviewed the records of 39 consecutive patients with MPM who received post-operative RT after extrapleural pneumonectomy (EPP), and of 10 consecutive patients with non-small cell lung cancer who received post-operative RT after pneumonectomy between March 2003 and March 2012 at the University Hospitals of Leuven. For MPM patients, the planning target volume was defined as the entire hemi-thorax, chest wall incisions, drain sites, and involved nodal stations. Prescription dose was 54 Gy in 2-Gy fractions delivered to the planning target volume (PTV). For NSCLC patients, the planning target volume was defined as mediastinal nodal stations according to the pathologic nodal involvement. Prescription dose was 54-66 Gy in 2-Gy fractions delivered to the PTV. Both cohorts received induction systemic chemotherapy before surgery. Primary endpoint was lung toxicity. Dyspnea was graded using the Common Toxicity Criteria (CTC) v. 4.03 and was recorded before RT, 45 days after the completion of RT and every 3 months thereafter until the completion of the follow up. Dosimetric dose-volume parameters (lung V5, lung V20, mean lung dose [MLD], mean heart dose, heart V45) were retrieved for both cohorts. The correlation between the dosimetric parameters and the toxicity (dyspnea score) was investigated.
Results:
In MPM patients, the dyspnea score was 0-1 in 24/39 patients (61.5%), 2 in 11/39 patients (28.2%), 3 in 3/39 patients (7.7%) and 4 in 1/39 patients (2.5%). No grade 5 toxicity was recorded. In NSCLC patients, only grade 0-1 dyspnea was registered (grade 0: 4/10 patients; grade 1: 6/10 patients). Mean MLD was 7.56 Gy (range: 1.60-14.80; SD: 3.65) for the MPM group and 5.96 Gy (range: 3.2-14.5; SD: 3.57) for the NSCLC group. Univariate analysis showed a significant correlation between grade > 2 dyspnea and MLD, lung V5 and lung V20.
Conclusion:
Post-operative radiotherapy after EPP is well-tolerated, with 10% of patients experiencing grade > 3 dyspnea. Strict dose-constraints should be applied when radiotherapy is administered in multimodality treatment.
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P2.07 - Poster Session/ Small Cell Lung Cancer (ID 222)
- Event: WCLC 2015
- Type: Poster
- Track: Small Cell Lung Cancer
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.07-010 - Alisertib (MLN8237)+Paclitaxel versus Placebo+Paclitaxel for Relapsed SCLC (ID 1158)
09:30 - 17:00 | Author(s): K. Nackaerts
- Abstract
Background:
Small cell lung cancer (SCLC) is an aggressive malignant disease comprising approximately 14% of all lung cancers, with approximately 31,000 new diagnoses each year in the USA. SCLC has a very poor prognosis, particularly in patients presenting with extensive stage disease. Platinum-based combinations are standard first-line therapy for SCLC; however, relapse is almost universal (≥85%) and patients require further treatment in subsequent lines. Effective new targeted therapies are needed to improve the poor outcomes observed in SCLC. Alisertib is an investigational, orally available, selective inhibitor of Aurora A kinase. Alisertib has shown single-agent antitumor activity in preclinical in vivo models of SCLC and has demonstrated synergism with paclitaxel in this setting. Single-agent alisertib has demonstrated promising efficacy in patients with relapsed/refractory SCLC (Melichar B, et al. Lancet Oncol 2015;16[4]:395–405). Further, phase 1 and 2 evaluation of alisertib+paclitaxel in patients with relapsed ovarian cancer and breast cancer has suggested the antitumor activity of this combination (Falchook G, et al. Int J Gynecol Cancer 2013;23[8] Suppl_1:abstract; Coleman R, et al. Ann Oncol 2014;25[Suppl_4]:abstract 876O). Here we describe the design and objectives of an ongoing phase 2, randomized, double-blind, placebo-controlled study of alisertib+paclitaxel versus placebo+paclitaxel in patients with relapsed SCLC and previously treated with only one line of platinum-based therapy (NCT02038647).
Methods:
Approximately 166 adult patients with relapsed SCLC after standard first-line platinum-based therapy, measurable disease by RECIST v1.1, and Eastern Cooperative Oncology Group performance status 0 or 1 will be enrolled at approximately 80 sites in the USA and Europe. Patients will be randomized 1:1 (stratified by type of relapse [sensitive vs resistant/refractory] and presence of brain metastases) to receive 28-day cycles of either alisertib 40 mg or matched placebo PO twice daily on days 1−3, 8−10, and 15−17, plus paclitaxel 60 or 80 mg/m[2 ]IV, respectively, on days 1, 8, and 15, until disease progression or unacceptable toxicity. The primary endpoint of the trial is progression-free survival (PFS). Assuming a hazard ratio of 0.6 for PFS, a total of 138 progression/death events will be required to provide 85% power (two-sided alpha=0.05). Secondary endpoints include: overall and complete response rates; disease control rate; duration of response; overall survival; safety (NCI-CTCAE v4.03); alisertib pharmacokinetics; and symptom-related endpoints (symptom score, time to symptom relief, time to symptom progression). Evaluation of candidate biomarkers in tumor tissue specimens and in circulating tumor cells (CTC)/circulating tumor DNA, change from baseline in CTC numbers, and health-related quality of life (EORTC QLQ-C30/QLQ-LC13 instruments) are exploratory endpoints. As of 10 April 2015, there are 60 sites open in 6 countries with 90 patients randomized. The study continues to enroll patients.
Results:
not applicable
Conclusion:
not applicable
