Author of

• 17556

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  P2.03a - Poster Session with Presenters Present (ID 464)

  • Event: WCLC 2016
  • Type: Poster Presenters Present
  • Track: Advanced NSCLC
  • Presentations: 1
  • Moderators:
  • Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)

  • 17583

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    P2.03a-027 - A Phase I Study of the Non-Receptor Tyrsine Kinase Inhibitor (NKI) Bosutinib in Combination with Pemetrexed in Patients with Advanced Solid Tumors (ID 4408)

    14:30 - 14:30  |  Author(s): O. Gaber
    • Abstract

    Background:
    The combination of cytotoxic chemotherapy with Src signaling pathway inhibitors represents a potential novel strategy to improve tumor response. Preclinical data suggests that thymidylate synthase (TS) and Src act via a common pathway and their overexpression has prognostic significance. Ceppi et al, explored the concept that Src inhibitors could be synergistic in combination with pemetrexed. Using immunohistochemical detection, Src kinase activation, evaluated by a phosphospecific antibody, was associated with higher TS expression in tumor specimens. Src-inhibition synergistically enhanced pemetrexed-cytotoxicity in human A549 lung cancer cells. Treatment with a Src inhibitor prevented up-regulation of TS mRNA and protein levels induced by pemetrexed that increased resistance to treatment. This suggests that Src represents a potential target to improve the efficacy of TS-inhibiting agents mainly in treatment of metastatic adenocarcinoma of the lung and malignant mesothelioma. Bosutinib is a NKI that inhibits the Abelson and Src kinases approved to treat CML. Hypothesis. Bosutinib can be safely administered in combination with pemetrexed with the MTD determined. Objectives. 1) Determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of bosutinib combined with pemetrexed, 2) Estimate the tumor response rate (RR), progression-free survival (PFS) and overall survival (OS) for patients with selected advanced cancers treated with this combination, 3) Explore potential biomarkers for treatment selection and response, including expression of Src kinase, phosphorylated Src kinase, and expression of potential modifying genes including K-ras, and 4) Determine the effect on the pharmacokinetics of each drug.
    
    Methods:
    This is a single institution phase I dose-escalation study for patients with selected advanced solid malignancies eligible to receive pemetrexed and ECOG performance status 0-2. Sequential dose cohorts of 3-6 patients will be treated. The starting dose of bosutinib is 200 mg daily in addition to pemetrexed 500 mg/m2 (Table 1).

    Dose level (cohort)	number of patients	Bosutinib dose (mg)	Pemetexed dose (mg/m2)
    -2	3-6	100	400
    -1	3-6	100	500
    1	3-6	200	500
    2	3-6	300	500
    3	3-6	400	500
    4	3-6	500	500
    Expansion cohort	10-12	MTD	500

    
    
    Results:
    not applicable
    
    Conclusion:
    not applicable