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J.D. Maltzman



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    O22 - Mesothelioma III (ID 122)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Mesothelioma
    • Presentations: 1
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      O22.05 - Exposure-response Relationship of Amatuximab (AMA) in Combination with Pemetrexed and Cisplatin (P/C) in Patients with Unresectable Pleural Mesothelioma (ID 1609)

      16:15 - 17:45  |  Author(s): J.D. Maltzman

      • Abstract
      • Presentation
      • Slides

      Background
      AMA is chimeric monoclonal antibody that binds to mesothelin, which is highly expressed in malignant mesothelioma and largely absent from normal tissue. In vitro studies indicate that AMA potentially has anti-tumor activity via antibody-dependent cellular cytotoxicity. AMA was studied in a Phase 2 mesothelioma trial.

      Methods
      This was a global, single arm, open label Phase 2 trial in 89 patients with previously untreated epithelial or mixed histology unresectable malignant pleural mesothelioma. Subjects received P/C every three weeks for 4 to 6 cycles combined with AMA 5mg/kg on days 1 and 8 of each 21 day cycle. All patients were fully supplemented with folate and B12 as per pemetrexed label requirements. Single agent AMA was then continued in the same schedule until disease progression. The primary endpoint was progression-free survival (PFS) at 6 months with a secondary end point of overall survival (OS).

      Results
      Median PFS was 6.1 months while median OS was 14.8 months. An evaluation of serum drug concentration relationship with clinical response noted that those subjects who achieved a median trough serum concentration of 32.9 µg/mL had an improved median PFS over those whose trough serum concentration was below the median (238 days vs 115 days, p<0.001). Similarly those subjects with a serum trough concentration of AMA above a median of 38.2 µg /mL had a median OS of 583 days while those with a median serum concentration of AMA below 38.2 µg /mL had a median OS of 375 days, p=0.0202. The most commonly reported adverse event was that of hypersensitivity to the chimeric antibody at first dose second cycle.

      Conclusion
      The safety profile of AMA in combination with P/C was consistent with that seen previously for the PC regimen. Although PFS is not significantly different from historical results of P/C alone, the median OS was 14.8 months (as compared to 13.3 months for P/C[1]). PK/PD analysis demonstrated that AMA trough concentrations were a significant predictor of both PFS and OS where higher concentrations were associated with longer OS and PFS. [1]Reference: Vogelzang NJ, Rusthoven JJ, Symanowski J, et al. Phase III Study of Pemetrexed in Combination With Cisplatin Versus Cisplatin Alone in Patients With Malignant Pleural Mesothelioma. J Clin Oncol, 2003; 21:2636-2644.

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    P1.11 - Poster Session 1 - NSCLC Novel Therapies (ID 208)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P1.11-019 - Phase 2 double-blind, placebo-controlled study of three-weekly farletuzumab with a platinum containing doublet in subjects with previously untreated folate receptor alpha (FRA) expressing non-small-cell lung cancer (NSCLC) (ID 1616)

      09:30 - 16:30  |  Author(s): J.D. Maltzman

      • Abstract

      Background
      Farletuzumab (FAR) is a humanized monoclonal antibody that binds to folate receptor alpha, which is highly expressed in NSCLC, specifically adenocarcinoma. FAR potentially has anti-tumor activity via antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity, and was studied in a Phase 2 NSCLC trial.

      Methods
      This was a global, double-blind, randomized Phase 2 trial in 130 patients with previously untreated FRA-expressing NSCLC. Patient tumors were screened using a FRA immunohistochemical diagnostic assay at a central pathology lab. Subjects could receive carboplatin and paclitaxel, carboplatin and pemetrexed, or cisplatin and pemetrexed for 4 to 6 cycles combined with randomized test product (FAR 7.5 mg/kg every three weeks with chemotherapy, or placebo). Cycle 1 included a loading dose on Day 1 of Week 2. Single agent test product was then continued every three weeks until disease progression. The primary endpoint was progression-free survival (PFS) by Response Evaluation Criteria in Solid Tumors, 1.1.

      Results
      One hundred and thirty patients were randomized. All had adenocarcinoma with one patient having a mixed adeno-squamous histology. All subjects had some expression of FRA in their tumor tissue as assessed by IHC. Median PFS as determined by primary investigator was 5.9 (placebo) and 4.7 (FAR) months with no statistically significant difference between arms (HR=1.22 [95% CI: 0.78, 1.89]). PFS as assessed by an independent evaluator showed a median PFS of 5.9 (placebo) and 6.7 (FAR) months with a HR of 0.91 (95% CI: 0.54, 1.51). The most commonly reported adverse events across arms were those known to be associated with chemotherapy such as hematologic toxicities occurring during combination therapy phase of the study. Preliminary analysis showed that subjects whose serum farletuzumab concentration level was in the top quartile did not reach a median PFS compared to those on placebo. Further investigation is currently on-going.

      Conclusion
      The study did not meet its primary PFS endpoint. The secondary end point of OS was immature at the time of this analysis. The most commonly reported adverse events across arms were those known to be associated with the study chemotherapy agents. Preliminary pharmacokinetic / pharmacodynamic analysis identified patients with a high serum concentration of FAR that may have benefited from treatment.