Author of

• 25943

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  P2.06 - Mesothelioma (Not CME Accredited Session) (ID 955)

  • Event: WCLC 2018
  • Type: Poster Viewing in the Exhibit Hall
  • Track:
  • Presentations: 1
  • Moderators:
  • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall

  • 27020

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    P2.06-11 - A Phase I/II Study of Intrapleural Ad-SGE-REIC Administration in Patients with Refractory Malignant Pleural Mesothelioma (ID 11328)

    16:45 - 18:00  |  Author(s): Takashi Nakano
    • Abstract

    Background
    

    Reduced expression in immortalized cell (REIC)/Dickkopf-3 (Dkk-3) is a tumor-suppressor gene and REIC/Dkk-3 expression was markedly downregulated in various human cancer cells. REIC/Dkk-3 protein is also known as a key player, namely an antagonist of the Wnt signaling pathway. Ad-SGE-REIC is an adenoviral vector carrying REIC/Dkk-3 that mediates cancer cell death induction and anti-cancer immunity augmentation.

    a9ded1e5ce5d75814730bb4caaf49419 Method
    

    We conducted a phase I/II, 3+3 design, dose escalation study in malignant pleural mesothelioma (MPM) patients (pts) with measurable lesions. Pts with refractory to or unsuitable for standard chemotherapy received 2 intrapleural administrations of Ad-SGE-REIC on days1 and 4. Three escalating doses of level (DL) 1: 3.0×10¹¹, DL2: 1.0×10¹² and DL3: 3.0×10¹² viral particles were employed. This dosage and regimen were set by considering the reason of manufacturing and neutralizing anti-body for adenovirus. The safety and dose-limiting toxicities (DLTs) of Ad-SGE-REIC were evaluated for 32 days. Continuous safety and efficacy were assessed for 172 days using modified RECIST (mRECIST). The concentrations of REIC/Dkk-3 in pleural fluid also were measured as indirect indication of targeted gene expressions.

    4c3880bb027f159e801041b1021e88e8 Result
    

    From 07/2015 to 09/2017, a total of 13 pts have been treated at DL1 (n=4 included one fatal case within 32 days), DL2 (n=3) and DL3 (n=6). Male: 100%; median age 70; PS 0: 23%, 1: 69%, 2: 8%; epithelial/biphasic histology: 69%/15%; Stage III-IV: 77%; previous chemotherapy use with platinum-pemetrexed: 92%. Treatment-related AEs (TRAEs) were all Grade 1-2 and no DLTs occurred. The most frequent TRAEs were fever and CRP increase based on adenovirus infection. Tumor responses assessed by independent central review showed that there was no objective response and DCR was 62% (8/13 pts). Median PFS was 3.4 months at all groups and 5.7 months at DL3. A remarkable increase of REIC/Dkk-3 concentration in pleural fluid was determined (6/13 pts, prominently high in DL3).

    8eea62084ca7e541d918e823422bd82e Conclusion
    

    The intrapleural administration of Ad-SGE-REIC up to 2 cycles was safe and well tolerated in MPM pts and promising results of efficient REIC/Dkk-3 expression and durable disease control were obtained. We are planning phase II study using repeated intrapleural or intratumoral administration.

    6f8b794f3246b0c1e1780bb4d4d5dc53

• 25088

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  PL02 - Presidential Symposium - Top 5 Abstracts (ID 850)

  • Event: WCLC 2018
  • Type: Plenary Session
  • Track: Advanced NSCLC
  • Presentations: 1
  • Moderators:
  • Coordinates: 9/25/2018, 08:15 - 09:45, Plenary Hall

  • 27893

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    PL02.09 - Nintedanib + Pemetrexed/Cisplatin in Patients with Unresectable MPM: Phase III Results from the LUME-Meso Trial (ID 11192)

    09:15 - 09:25  |  Author(s): Takashi Nakano
    • Abstract
    • Presentation
    • Slides

    Background
    

    Nintedanib targets VEGFR 1–3, PDGFR α/β, FGFR 1–3, Src and Abl kinases, all implicated in malignant pleural mesothelioma (MPM) pathophysiology. This global Phase II/III, randomised, double-blind study investigated pemetrexed/cisplatin in combination with nintedanib or pemetrexed/cisplatin in combination with placebo, followed by nintedanib or placebo maintenance, in patients with unresectable MPM. In the double-blind, randomised Phase II part, nintedanib plus pemetrexed/cisplatin improved PFS vs placebo (HR=0.56; 95% CI: 0.34–0.91; p=0.017; median 9.4 vs 5.7 months).

    In Phase III, chemotherapy-naïve patients with epithelioid MPM (ECOG PS 0–1) were randomised 1:1 to receive up to six cycles of pemetrexed (500 mg/m²)/cisplatin (75 mg/m²) on Day 1, plus nintedanib (200 mg bid) or matched placebo on Days 2–21. After combination treatment, patients without disease progression received nintedanib or placebo maintenance. The primary endpoint (PFS by investigator assessment) and key secondary endpoint (OS) were planned to be analysed by hierarchical testing, with an interim OS analysis at the time of the primary PFS analysis. PFS was also assessed by independent central review. Based on the assumed treatment effect (HR=0.63), the study had 90% power to detect a statistically significant and clinically meaningful improvement in PFS.

    In total, 458 patients were randomised. Baseline patient characteristics and oncological history were similar between treatment arms. Median duration of nintedanib or placebo administration was 5.3 and 5.1 months, respectively. After 250 events, there was no difference in PFS between nintedanib and placebo arms (HR=1.01; 95% CI: 0.79–1.30; p=0.91; median 6.8 vs 7.0 months, respectively). PFS by central independent review was similar (242 events; HR=0.99; 95% CI: 0.77–1.28; p=0.96; median 6.8 months in each arm). In the interim OS analysis (127 deaths [28% of events]), median OS was 14.4 vs 16.1 months (nintedanib vs placebo; HR=1.12; 95% CI: 0.79–1.58; p=0.54). There were no unexpected safety findings. The proportion of patients with Grade ≥3 AEs was higher with nintedanib than with placebo (72% vs 62%). The most frequently reported Grade ≥3 AE by medical concept in both treatment arms was neutropenia (nintedanib: 32%; placebo: 24%). The proportion of deaths due to serious AEs was 4.0% (nintedanib) and 7.5% (placebo).

    The primary endpoint of the Phase III part of LUME-Meso was not met ‒ Phase II findings were not confirmed. The reported safety profile was consistent with the known safety profiles of nintedanib and pemetrexed/cisplatin.

    a9ded1e5ce5d75814730bb4caaf49419

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