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A. Horiike



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    MINI 15 - Chemotherapy Developments for Lung Cancer (ID 128)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      MINI15.01 - A Phase I/II Study Evaluating the Combination of Resminostat and Docetaxel for Platinum-Pretreated NSCLC (ID 700)

      16:45 - 18:15  |  Author(s): A. Horiike

      • Abstract
      • Presentation
      • Slides

      Background:
      Resminostat, an oral hydroxamate-type inhibitor of class I and II histone deacetylases, has shown a broad spectrum of anti-tumor activity against human cancer cell lines, and synergetic or additive effects in combination with docetaxel in non-small cell lung cancer (NSCLC) cell lines. We initiated a phase I/II study to evaluate the safety and efficacy of combining resminostat and docetaxel in patients (pts) with NSCLC pretreated with platinum-based therapy. The purpose of the phase I portion was to evaluate dose-limiting toxicities (DLTs) in the first cycle, estimate the maximum tolerated dose (MTD) of resminostat when administered in combination with docetaxel, and determine the recommended dose (RD) for the phase II portion. Here, we report the results of the phase I portion.

      Methods:
      NSCLC pts with failure of a platinum-based therapy were eligible for the study. Patients were treated with docetaxel on day 1 and resminostat on days 1 to 5 every 21 days. Phase I was an open-label, 3+3 cohort, dose-escalation study. While the docetaxel dose was fixed at 75 mg/m[2], the resminostat dose was escalated from 400mg (Dose Level 1: DL1) to 600 mg (DL2). DLT was defined as follows: grade 4 thrombocytopenia, grade 4 neutropenia lasting >7 days, febrile neutropenia lasting >3 days, and any other clinically significant grade 3/4 non-hematological toxicity.

      Results:
      A total of 9 pts (DL1: 3 pts, DL2: 6 pts) were enrolled in the phase I portion: male/female, 6/3; median age, 60 yr (50-71 yr); histologically proven adenocarcinoma/squamous cell carcinoma, 7/2; performance status, 0/1 in 7/2 pts. No DLTs were observed at DL1 or DL2. The most frequent grade 3/4 adverse events in any cycle were neutropenia (8 pts, 88.9%), leukocytopenia (8 pts, 88.9%), and febrile neutropenia (4 pts, 44.4%). These events were transient and resolved prior to the next cycle. No pharmacokinetic (PK) interaction between resminostat and docetaxel was observed. A partial response was observed in 1 pts (DL1) and stable disease in 3 pts (DL2).

      DL1 N=3 DL2 N=6
      PK parameters (Geometric Mean) Resminostat Docetaxel Resminostat Docetaxel
      C~max ~(ng/mL) 3,010 2,840 5,610 3,140
      T~max ~(h) 1.78 1.00 1.47 1.03
      AUC~inf~(h∙ng/mL) 11,800 3,030 25,500 3,280
      t~1/2~ (h) 2.98 8.21 3.02 8.73


      Conclusion:
      The combination of resminostat and docetaxel was tolerable up to DL2 (docetaxel 75 mg/m[2], resminostat 600 mg); the MTD was not reached. Dose Level 2 was determined as the RD for the phase II portion of this study, which is currently ongoing.

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    P3.07 - Poster Session/ Small Cell Lung Cancer (ID 223)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Small Cell Lung Cancer
    • Presentations: 1
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      P3.07-005 - Maintenance Irinotecan Therapy in Extensive Disease Small Cell Lung Cancer: A Feasibility Study (ID 607)

      09:30 - 17:00  |  Author(s): A. Horiike

      • Abstract
      • Slides

      Background:
      We performed a feasibility study of maintenance irinotecan therapy in patients with extensive disease small cell lung cancer (ED-SCLC) who responded to the induction irinotecan plus cisplatin (IP) therapy.

      Methods:
      The eligibility criteria included pts with ED-SCLC who responded to four cycles of induction IP therapy, ECOG performance status (PS) of 0 to 1, age of 20 to 70 years and adequate organ functions. Pts received irinotecan monotherapy at 60 mg/m2 on days 1, 8 and 15 of a 28-day cycles until disease progression. The primary endpoint was the proportion of treatment success (TS) at 6 months. Using a binomial design, a lower activity level (p0) of 0.25 and a target activity level (p1) of 0.50, the preplanned accrual of 28 patients was sufficient (alpha, 0.10 and power, 0.90).

      Results:
      Between August 2012 and August 2013, 22 pts were enrolled. However, accrual was discontinued because of the three grade 3 pneumonitis events (3 of 22 patients, 13.6%). Patient characteristics of the 22 eligible pts were as follows; the median age was 65 (54-70) years; 12 pts had a PS of 0, and 16 pts were male. The median number of cycles delivered was four (range, 1–31). Four of 22 (18.2%) patients achieved TS at 6 months. Median progression free survival and overall survival from the start of the maintenance irinotecan therapy were 3.2 months and 15.9 months, respectively. Grade ≥3 toxicities included neutropenia (4.5%), hyponatremia (4.5%), pneumonitis (13.6%) and cholangitis (4.5%). No treatment-related deaths occurred. Figure 1



      Conclusion:
      This trial was early terminated due to the unexpected toxicity, but maintenance irinotecan therapy was still active for a subset of ED-SCLC.

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