Virtual Library

 x 
My Library Virtual Library FAQ

Start Your Search

H. Kindler



Author of

  • +

    MO09 - Mesothelioma I (ID 120)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track:
    • Presentations: 2
    • +

      MO09.01 - Evaluation of tolerability and anti-tumor activity of GDC-0980, an oral PI3K/mTOR inhibitor, administered to patients with advanced malignant pleural mesothelioma (MPM) (ID 1712)

      16:15 - 16:20  |  Author(s): H. Kindler

      • Abstract
      • Presentation
      • Slides

      Background
      The PI3K-AKT-mTOR signaling pathway is dysregulated in a wide variety of cancers. Pathway activation in mesothelioma may occur through diverse cellular mechanisms, including activation of receptor tyrosine kinases that signal through Ras and PI3K/Akt/mTOR, and loss of PTEN expression. GDC-0980 is a potent and selective oral dual inhibitor of class I PI3K and mTOR kinases that has demonstrated broad activity in various xenograft cancer models.

      Methods
      A phase I dose-escalation study was conducted in 2 Stages: Stage 1 evaluated oral, daily (QD) doses of 2-70 mg GDC-0980 given 21/28 or 28/28 days in a 3+3 dose escalation design. Stage 2 evaluated disease specific cohorts at the recommended phase 2 dose (RP2D), including a MPM cohort at 30 mg GDC-0980 QD 28/28 days. Safety and tolerability of GDC-0980 was assessed as well as pharmacokinetics (PK) and pharmacodynamics (PD) assessment of PI3K pathway inhibition by FDG-PET. Anti-tumor activity was assessed by modified RECIST; CT scans were centrally reviewed retrospectively by a radiologist with MPM expertise. Archival tumor tissue was evaluated for PIK3CA mutation by allele specific PCR or Sanger sequencing and PTEN expression was assessed by immunohistochemistry.

      Results
      33 MPM patients were enrolled: 6 in Stage 1 at 8-70 mg and 27 in Stage 2 at 30mg GDC-0980. Safety and tolerability of GDC-0980 in Stage 1 was similar in MPM compared to other solid tumor patients, with the exception of a Grade 5 pneumonitis that occurred in a MPM patient at 40 mg GDC-0980 QD. Based on Stage 1 tolerability data, a RP2D of 30 mg QD was evaluated in Stage 2 for MPM patients. The most frequent Grade ≥3 drug-related adverse events (AEs) at 30 mg GDC-0980 were rash (19%), with one patient (4%) having to discontinue GDC-0980. Other AEs were fatigue (15%), and hyperglycemia, diarrhea, and colitis (7% each). Reversible Grade 2 pneumonitis was reported for 2 patients (7%). Population PK analysis was used to assess the behavior of GDC‑0980 in MPM patients. Additionally, PK/PD relationships will be discussed for efficacy and safety, including exposure‑response, where appropriate. Archival tissue was analyzed for 29 MPM patients. Two samples had PIK3CA mutations (R88Q and E545G) and one sample showed loss of PTEN expression. PI3K pathway inhibition by FDG-PET responses was observed in 8 of 24 MPM patients with available scans. Anti-tumor activity was observed in both stages. Two patients achieved a partial response (PR) in Stage 1, one patient at 50 mg and one patient with the PIK3CA mutation R88Q at 8 mg GDC-0980. Two PRs were observed at the RP2D of 30 mg in Stage 2. Eleven (41%) MPM patients at the RP2D remained on study for >6 months, and 2 (7%) patients remained on study >12 months.

      Conclusion
      GDC-0980 was generally well tolerated in MPM patients at the RP2D. Anti-tumor activity, evidenced by tumor regression and prolonged disease control, has been observed. PIK3CA mutations and PTEN loss were uncommon.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

    • +

      MO09.10 - Volumetric Response Classification Criteria in Mesothelioma (ID 3302)

      17:10 - 17:15  |  Author(s): H. Kindler

      • Abstract
      • Presentation
      • Slides

      Background
      Tumor response criteria provide a framework for therapeutic decisions and clinical trials management in oncology. The standard response classification categories (partial response (PR), stable disease (SD), and progressive disease (PD)) were defined by the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines based on relative changes in linear measurements of tumor diameter on computed tomography (CT) scans. An increase in linear dimension of at least 20% is categorized as PD, a decrease in linear dimension of at least 30% is categorized as PR, and a change in linear dimension not great enough to exceed either of these thresholds is categorized as SD. With improvements in imaging technology and enhancements in computer algorithms, the extraction of tumor volume from CT scans has become more practical. The possibility that tumor volume may eventually become the preferred tumor measurement metric rather than linear dimension necessitates the development of volumetric response criteria. Although extrapolation of the RECIST response criteria to volume is straightforward for spherical nodules, tumors as non-spherical as mesothelioma likely will require unique volumetric response criteria.

      Methods
      A semi-automated computerized method was used to determine the mesothelioma tumor volume from CT scans (baseline and all available follow-up scans) retrospectively collected from 70 patients undergoing standard-of-care chemotherapy. Relative changes in tumor volume from baseline were categorized as PR, SD, or PD based on different combinations of percent change thresholds. Overall patient survival was correlated with best response using Harrell’s C statistic. The response criteria for PD and PR were each varied in 1% increments to obtain optimized classification criteria.

      Results
      The process that systematically evaluated various combinations of response criteria identified an increase in tumor volume of at least 58% and a decrease in tumor volume of at least 17% for PD and PR, respectively, as the criteria that were best correlated with patient survival. These criteria yielded a C statistic of 0.76, where a C statistic value of 1.0 would indicate perfect separation of response groups with respect to subsequent survival times. This result may be compared with the C statistic value of 0.61 obtained when volumetric response criteria extrapolated directly from the RECIST criteria (+73% for PD and -66% for PR) were applied to this cohort.

      Conclusion
      The evolution toward volumetric assessment of tumor burden and response to therapy necessitates the derivation and validation of volume-specific tumor response criteria to distinguish among PR, SD, and PD. The present study motivates such response criteria for mesothelioma and indicates that mesothelioma volumetric response criteria differ substantively from a simplistic extension of the RECIST criteria to three dimensions. Future prospective studies will be required to validate these criteria.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

  • +

    O22 - Mesothelioma III (ID 122)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Mesothelioma
    • Presentations: 1
    • +

      O22.06 - Quality of Life Measurement Parallel Changes in Pulmonary Function in Patients Undergoing Pleurectomy and Decortication for Malignant Pleural Mesothelioma (ID 3444)

      17:10 - 17:20  |  Author(s): H. Kindler

      • Abstract
      • Presentation
      • Slides

      Background
      The role of maximal cyto-reductive surgery in malignant pleural mesothelioma (MPM) remains controversial. Although selected patients achieve long-term disease control following extended pleurectomy and decortication (PD), not all patients benefit. In addition surgical complications and side effects may adversely affect quality of life (QoL). We previously observed significant improvement in the quality of life following PD in patients who were symptomatic at baseline (Mollberg et al, Ann Thorac Surg 2012). In this study, we further examined the effects of PD on pulmonary function and correlated changes in pulmonary function with QOL.

      Methods
      Consecutive patients with MPM undergoing PD were prospectively enrolled at a single center. The primary endpoint was to determine the effects of PD on QoL. Health related QoL was assessed using the European Organization for Research and Treatment of Cancer Core Quality of Life Questionaire-C30 (EORTC QLQ-C30) before operation and at one,4-5, 7-8 , 10-11 and 12-13monthsmonths postoperatively. Pulmonary function testing was performed (PFTs) were measured immediately before the operation and at 6-7 months postoperatively. Patients were grouped according to the World Health Organization baseline performance status (PS) and compared.

      Results
      Twenty-seven patients with a median age of 71 years old (range 59 to 91 years), 19 males and 8 females, were enrolled in the study from March 2010 to October 2012. At the time of the operation, 17 patients were WHO PS 0, 10 were PS 1. At baseline, the PS 1 patients had a significantly worse global QoL (p<.0001), functional (p<0.0001) and symptoms scores (p<0.0001). PS 0 patients had not significant change in global QoL or functional) and symptoms scores (except for emotional function and insomnia p<0.01) following the operation. In addition they demonstrated a significant decrease in FVC (p<0.003), FEV1 (p<0.005), TLC (<0.001) and DLCO (<0.009) following PD. PS 1 patients showed significant improvements in Global Health (p=0.05) functional measures (p< 0.01) and symptoms scores (p <0.03) at 4-5 months and this was maintained at 6-7 months following PD. Improvement also was noted in the FVC (p=0.09), FEV1(p=0.04) and DLCO (p=0.09) in these patients.

      Conclusion
      At intermediate follow-up, extended PD for MPM had a negative impact on pulmonary function in minimally symptomatic patients without any significant improvement in QoL. In contrast, patients who were symptomatic at baseline significantly improved in QoL and showed a modest improvement in pulmonary function after PD. The change in pulmonary function may be partially responsible for the observed QoL in symptomatic patients undergoing PD.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

  • +

    P2.14 - Poster Session 2 - Mesothelioma (ID 196)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Mesothelioma
    • Presentations: 2
    • +

      P2.14-002 - Validation of the CALGB and EORTC Prognostic Models for Mesothelioma Based on Multiple CALGB Trials (Alliance) (ID 922)

      09:30 - 09:30  |  Author(s): H. Kindler

      • Abstract

      Background
      Prognostic models play an important role in the design and analysis of mesothelioma treatment trials. The European Organisation for Research and Treatment of Cancer (EORTC) and the Cancer and Leukemia Group B (CALGB) prognostic models are two well-known tools to predict survival in patients with malignant mesothelioma. In this retrospective validation study, we aim to assess the performance of these two mesothelioma prognostic models for overall survival (OS) with multiple clinical trials data from CALGB.

      Methods
      Using 204 patients with malignant pleural mesothelioma, the EORTC model (Curran et al 1998) was developed using a Cox regression with white blood cell (WBC) count, ECOG performance status (PS), diagnosis, histological type, and gender as prognostic variables. Using 337 patients with malignant mesothelioma, the CALGB model (Herndon et al 1998) was developed using a cross-validated exponential regression tree with PS, age, haemoglobin (Hgb) level, WBC count, chest pain indicator, and weight loss indicator as prognostic variables. In this validation study, 602 mesothelioma patients from fifteen completed CALGB treatment trials accrued between June 1984 and August 2009 were included. As the CALGB model was developed using the seven earlier studies, 266 patients from eight recent studies were included in the validation. For the EORTC model, we analysed all studies as well as just those eight recent studies. The concordance of predicted survival times and risk scores was estimated by c-index (Harrell et al 1996). Secondary endpoint of interest includes progression-free survival (PFS). Sensitivity analysis and multiple imputations were used to handle missing data. We also compared our results with PS alone.

      Results
      (1) For OS, the EORTC model produced c-indices equal to 0.592 and 0.610 for the fifteen and eight studies respectively. For the eight recent studies, the CALGB model produced c-indices equal to 0.618 and 0.593 without and with imputation respectively. PS alone produced c-indices equal to 0.591 and 0.564 for the fifteen and eight studies respectively. (2) For PFS, the EORTC model produced c-indices equal to 0.569 and 0.598 for the fifteen and eight studies respectively. For the eight recent studies, the CALGB model produced c-indices equal to 0.585 and 0.560 without and with imputation respectively. PS alone produced c-indices equal to 0.568 and 0.553 for the fifteen and eight studies respectively. See Table 1. Figure 1

      Conclusion
      The EORTC and CALGB models perform similarly, with little improvement in prognostic ability from either compared to using PS alone. Further improvement on these existing prognostic models is warranted.

    • +

      P2.14-014 - A Phase 2 Randomized, Double-blind, Placebo-Controlled, Multicenter Study of VS-6063 as Maintenance Therapy in Subjects with Malignant Pleural Mesothelioma which has Not Progressed on at least 4 Cycles of Pemetrexed/Platinum therapy (ID 3375)

      09:30 - 09:30  |  Author(s): H. Kindler

      • Abstract

      Background
      Malignant pleural mesothelioma (MPM) is an aggressive tumor in the pleural lining of the lung usually caused by asbestos exposure. Median OS following frontline chemotherapy with pemetrexed/cisplatin is ~12 months. There is no established second line therapy. Approximately 50% of MPM patients exhibit homozygous disruption of the NF2 tumor suppressor gene by mutation and/or deletion resulting in lack of expression of functional merlin protein. Preclinical data have indicated that mesothelioma cell lines that lack NF2/Merlin are especially sensitive to focal adhesion kinase (FAK) inhibition in both cellular and animal models. Interestingly, pemetrexed and cisplatin increase cancer stem cells (CSCs), while FAK inhibitors have been found to decrease CSCs in mesothelioma models. Given the sensitivity of mesothelioma cells lacking NF2/Merlin and the effect on CSCs, the use of a FAK inhibitor in a maintenance setting after first line chemotherapy may be an attractive strategy to extend survival of MPM patients. VS-6063 is an orally bioavailable selective inhibitor of FAK. In a phase 1 trial VS-6063 was generally well tolerated, with grade 1/2 nausea, vomiting and fatigue as the most frequent adverse events (Jones SF J Clin Oncol 2011 29:1 suppl; abstr 3002).

      Methods
      A multinational, randomized, double-blind, placebo controlled, phase 2 clinical trial was designed to determine if VS-6063 provides superior clinical benefit compared with placebo as a maintenance treatment in patients with MPM following frontline therapy with pemetrexed/platinum therapy. The study aims to assess whether VS-6063 improves median OS and median PFS over placebo. Randomization will be stratified by Merlin status (high versus low) and patients will receive either VS-6063 400mg BID continuously or matched placebo (1:1). The study follows an adaptive enrichment design where, pending results from an interim analysis, sampling may be restricted to patients with low Merlin protein expression if promising results are observed among the subpopulation. Approximately 370 eligible patients with pathologically confirmed MPM, who have PR or SD following at least 4 cycles of pemetrexed with either cisplatin or carboplatin, Karnofsky PS ≥70%, will be enrolled. Patients will continue treatment until disease progression. Archival tumor tissue will be used for the analysis of Merlin status and is therefore required for participation. Secondary endpoints include patient-reported outcomes of health-related quality of life and disease- or treatment-related symptoms utilizing the LCSS-meso scale, objective response and safety and tolerability. Clinical trial information: NCT01870609.

      Results
      not applicable

      Conclusion
      not applicable

  • +

    P3.14 - Poster Session 3 - Mesothelioma (ID 197)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Mesothelioma
    • Presentations: 1
    • +

      P3.14-011 - Genomic profiling of Epithelial Malignant Pleural Mesothelioma (MPM) using Massively Parallel Sequencing. (ID 2855)

      09:30 - 09:30  |  Author(s): H. Kindler

      • Abstract

      Background
      Development of targeted therapies in malignant pleural mesothelioma has been limited due to the incomplete understanding of genetic aberrations occurring in this disease. We determined mutational and copy number (CN) events in a comprehensive fashion in 12 patients with epithelial malignant pleural mesothelioma in order to identify characteristic genetic aberrations and new potential treatment targets.

      Methods
      Fresh frozen tumor (≥70% tumor content) and matched normal tissue from 12 patients with treatment-naïve epithelial malignant pleural mesothelioma were evaluated using targeted, massively parallel sequencing (Illumina HiSeq) for 580 cancer-relevant genes using hybrid capture target enrichment and an established bioinformatics analysis pipeline. CN analysis was performed using sequencing data (CONTRA) and validated on the NanoString nCounter. Mutations were modeled bioinformatically using the CHASM oncogenic driver prediction algorithm and reviewed for prior occurrence in COSMIC and evidence supporting usefulness as a treatment target.

      Results
      Loss of CDKN2A was the most common genetic event occurring in 80% of samples. INPP4B and TRAF6 were lost in 20-30% of tumors. No loss of PTEN was observed in any sample. Two BAP1 small frameshift deletions were observed. Copy number aberrations, in particular amplifications, were rare. The only gene with modest increase in copy number was MET (median CN=2.8). We identified multiple somatic missense mutations including: two APC mutations (K1245E, G2502D; both predicted to be damaging), one TSC1 (K587A) and one TSC2 (P952A, predicted driver) mutation, one KIT mutation (L799F; predicted driver), one JAK2 (P953A; predicted driver), as well as single mutations in NF1 (G849R), EPHA1 (P697S), EPHA4 (T532I), and mTOR (L2208P), all of which had driver character. Specific mutations have not been reported in COSMIC. No canonical PI3K or MAPK pathway aberrations were identified.

      Conclusion
      We identified several novel and known mutations and copy number events in epithelial malignant pleural mesothelioma: deletions in CDKN2A and INPP4B were the most common copy number events. Frameshift deletions in BAP1 were identified. Overall few copy number events were observed. Potentially targetable aberrations include missense mutations in NF1, JAK2, EPHA1, TSC2, mTOR and KIT, which are predicted to have driver character and additional experimental validation is indicated. Additional tumor and cell line samples are being processed and will be available at the time of presentation.