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M. Saleh



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

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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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): M. Saleh

      • 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.

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    P3.10 - Poster Session 3 - Chemotherapy (ID 210)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P3.10-053 - Phase II study of a novel taxane (Cabazitaxel-XRP 6258) in previously treated advanced non-small cell lung cancer (NSCLC) patients: toxicity report (ID 3362)

      09:30 - 09:30  |  Author(s): M. Saleh

      • Abstract

      Background
      Cabazitaxel-XRP6258 is a novel semisynthetic taxane derived from the European yew. In vitro, it has similar microtubules stabilization properties to docetaxel, even against resistant cell lines, due to its lower affinity for P-glycoprotein. Additionally, preclinical models indicated that cabazitaxel was able to cross the blood brain barrier. In addition to prostate cancer, data available from completed phase I, II and III trials showed activity in lung cancer. Based on these data we designed and conducted a phase II trial of Cabazitaxel in the second line treatment of NSCLC.

      Methods
      In this open-label, pilot Phase II trial, subjects with stage IV NSCLC [7[th] Edition of the TNM staging classification, 2009], who have failed first line chemotherapy (platinum doublet or non-platinum doublets, including previous taxane exposure) were randomly treated with either treatment Schedule A (20 mg/m2 every 3 weeks as a 1 hour IV infusion, f/b 25 mg/m2, if no DLTs) or B (8.4 mg/m2 as a 1 hour IV infusion on days 1, 8, 15, and 22 of a 5 week cycle, f/b 10mg/m2, if no DLTs). The primary endpoint was to assess the objective response rate (ORR) of Cabazitaxel-XRP6258. Secondary Objectives were to assess the time to progression (TTP), progression free survival (PFS), overall survival (OS) and safety.

      Results
      Overall the treatment was well tolerated. Among the so far 22 patients enrolled onto the trial, the most commonly found side effects to cabazitaxel were fatigue (18%), anemia (9%), hematuria (8%), neuropathy (6.5%), neutropenia (6%), nausea (6%), and dyspnea (6%), reported as a percentage of the total 141 censored events, compared with the previously most commonly described side effects to cabazitaxel of neutropenia, leukopenia, anemia, diarrhea, fatigue, and asthenia. Most side effects (76%) were grade 1/2 while 23% were grade 3/4; only one patient (4.5%) experienced grade 5 toxicity and succumb to sepsis. The most common adverse effects leading to treatment discontinuation were hematuria and sepsis. Often reported toxicities (over 10%) not found in this cohort includes diarrhea, vomiting, constipation, alopecia, arthralgia and mucosal inflammation. Inversely, the report of hematuria in almost one third of the patients (73% grade 1/2 and 27% grade 3/4) was significant, even more because contrary to the experience with prostate cancer (17% incidence) our population of patients lack the presence of blood in urine at baseline.

      Conclusion
      This Phase II study of cabazitaxel in second line advanced NSCLC showed good tolerance to the drug when administered in two different schedules. The observed side effects are in general consistent with prior reports but hematuria, developed upon exposure to the drug in almost one third of patients. We speculate that cabazitaxel may induce hematuria in cancer patients by direct injury of the urothelial mucosa.