Author of

• 10874

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  P1.13 - Poster Session 1 - SCLC (ID 200)

  • Event: WCLC 2013
  • Type: Poster Session
  • Track: Medical Oncology
  • Presentations: 1
  • Moderators:
  • Coordinates: 10/28/2013, 09:30 - 16:30, Exhibit Hall, Ground Level

  • 10880

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    P1.13-006 - Phase I/IIa study of the novel combination of bendamustine plus irinotecan followed by etoposide plus carboplatin in untreated patients with extensive stage small cell lung cancer (ID 2567)

    09:30 - 09:30  |  Author(s): D.J. Allendorf
    • Abstract

    Background
    Standard therapy for extensive stage small cell lung cancer (ES-SCLC) with etoposide (VP16) plus cisplatin or carboplatin (Carbo) results in median time to progression (TTP) of 4 months with overall survival (OS) of 9 months. Bendamustine (B) induced DNA damage is repaired by excision repair and irinotecan (I), a topoisomerase-1 inhibitor (Top-1), leads to increases in topoisomerase-2 (Top-2), the target of VP16. Therefore, the sequence B+I → VP16+Carbo was hypothesized to increase TTP by exploiting mitotic catastrophe, with subjects with low ERCC-1 expression and high Top-1 or Top-2 expression having longer TTP and OS compared to those with high ERCC-1 expression

    Methods
    This is an open label trial enrolling patients (pts) with evaluable ES-SCLC. Phase I primary endpoint was to determine the maximum tolerated dose (MTD) of B+I; the phase IIa primary endpoint was TTP after B+I→E+C. Secondary endpoints were objective response rate (ORR) and OS. In the phase I (N=15), pts received I (150 mg/m[2], d 1) with B at 80, 100, or 120 mg/m[2]/day (d 1,2) every 3 weeks for 3 cycles. Phase IIa pts were treated at the selected phase II dose of B+I for 3 cycles, followed by E (100 mg/m[2], d 1-3) + Carbo (AUC 6, d 1) for 3 cycles. Restaging was performed after 3 cycles of each regimen. The phase IIa was powered to detect a 30% increase in TTP from 4 to 5.2 m with a of 0.1. The Kaplan-Meier method was used to calculate TTP and OS. Toxicities were evaluated using the NCI CTCAE.

    Results
    The MTD of B was not reached and a dose of 100 mg/m[2 ]was selected as the phase IIa dose, with dose-escalation allowed in subsequent cycles of therapy for ≤ grade 2 toxicity. Dose limiting toxicities were diarrhea, nausea, and vomiting. Two treatment-related deaths, from metabolic encephalopathy and from neutropenic sepsis, occurred in the Phase IIa portion. The commonest grade 3/4 hematologic toxicity was neutropenia. Fatigue, nausea, vomiting, and diarrhea were common non-hematologic toxicities. Efficacy Parameters (N=28): Median TTP 6.0 m (95% CI 4.8-7.2); Median OS 10.0 m (95% CI 8.4-11.6); ORR 83% (4% CR); Median tumor reduction after B+I 65%; Median tumor reduction after E+C 73%. Statistically significant prognostic factors for TTP were sex, LDH, Top-1 and Top-2 and for OS were Top-2 and LDH. The predictive significance of Top-1 for TTP is confounded by insufficient samples with no expression of Top-1 and failure to demonstrate correlation with ERCC1 levels may have been related to antibody selection – reanalysis in in progress.

    Conclusion
    B+I is an active regimen in ES-SCLC and the treatment sequence B+I→E+C seems to improve the TTP and OS in ES-SCLC compared to historic results for E+C. Toxicities were increased compared to historic results for E+C, but were manageable. Correlative studies with pre-treatment assessment of tumor ERCC-1 and Top-2 as predictors of response are ongoing.