Author of

• 17842

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  P2.06 - Poster Session with Presenters Present (ID 467)

  • Event: WCLC 2016
  • Type: Poster Presenters Present
  • Track: Scientific Co-Operation/Research Groups (Clinical Trials in Progress should be submitted in this category)
  • Presentations: 1
  • Moderators:
  • Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)

  • 17851

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    P2.06-009 - Combined PKCι and mTOR Inhibition in Advanced or Recurrent Lung Cancer, Preliminary Report of an Ongoing Phase I/II Trial (ID 6251)

    14:30 - 14:30  |  Author(s): H.J. Ross
    • Abstract

    Background:
    Cancer stem cells may be responsible for initiation, maintenance, progression and metastatic spread of lung cancers and may contribute to native or acquired drug resistance. We (APF, VJ) showed that PKCι is an oncogene for NSCLC and is amplified in many NSCLC including in most squamous lung cancer cells (LSCC). PKCι is required for LSCC cell proliferation in vitro and tumorigenicity in vivo and for maintenance of the lung cancer tumor initiating cell (TIC) phenotype. The PKCι-Rac1-Ect2-MMP10 signaling axis is activated in LSCC TICs and PKCι knock down impairs soft agar growth, clonal expansion and tumorigenicity. The gold salt auranofin (ANF) reproduces the effects of PKCi knock down on the PKCι-Rac1-Ect2-MMP10 signaling pathway and on clonal expansion and tumorigenicity by potently and selectively inhibiting oncogenic PKCι signaling. Combined PKCι and mTOR inhibition synergistically reduces lung cancer cell proliferation and tumor growth in vivo and in vitro.
    
    Methods:
    A phase I/II clinical trial is accruing patients to evaluate safety and preliminary efficacy of combined inhibition of PKCι and mTOR in lung cancer patients. Adults with confirmed diagnosis of lung cancer (squamous, RAS-mutated adenocarcinoma or small cell lung cancer), PS 0-2, adequate organ function, no significant comorbidities and completion of at least one prior course of platinum doublet chemotherapy were enrolled. Patients received oral ANF 3mg (dose level 0) or 6mg (dose level 1) once daily + sirolimus 5 mg once daily in 28 day continuous cycles. Primary endpoints are to establish the maximum tolerated dose (phase I) and to assess progression free survival at 4 months (phase I/II). Tumor biopsies for biomarker assessment focus on the PKCι-Rac1-Ect2-MMP10 pathway. Secondary endpoints are safety, survival, response rate and duration, and biomarker development.
    
    Results:
    6 patients were enrolled in the phase I portion of the trial, 3 each at dose level 0 & 1. All pts were evaluable. No DLTs were seen during the dose escalation phase. On dose level 0, 1 pt died with pneumonia during cycle 5. On dose level 1, 1 pt had grade 4 hyponatremia during cycle 4. At median follow up of 7.1 months (1.8 - 23.9) and median 6 cycles (2-25), responses were: PR 1 (16.7%), SD 3 (50%), PD 2 (33%). The phase II trial is ongoing at dose level 1.
    
    Conclusion:
    Phase I analysis suggested safety of auranofin plus sirolimus at doses that were effective against NSCLC in preclinical models. Biomarker analysis is ongoing. NCT01737502, funding R21 CA153000 (APF)