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D. Potvin
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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: 4
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.06-001 - A Study of MGCD516, a Receptor Tyrosine Kinase (RTK) Inhibitor, in Molecularly Selected Patients with NSCLC or Other Advanced Solid Tumors (ID 4109)
14:30 - 14:30 | Author(s): D. Potvin
- Abstract
Background:
MGCD516 (Sitravatinib), is an oral, potent small molecule inhibitor of a closely related spectrum of RTKs including RET, the split RTKs (VEGFR, PDGFR and KIT), TRK family, DDR2, MET and AXL. RTKs inhibited by sitravatinib are genetically altered in NSCLC and other cancers, where they function as oncogenic drivers, promoting cancer development and progression. Alterations in these RTKs have also been implicated in tumor resistance mechanisms. Sitravatinib has demonstrated antitumor activity in nonclinical cancer models harboring genetic alterations of sitravatinib targets, including rearrangement of RET, NTRK, or CHR4q12 amplification. Phase 1 dose escalation has been completed, showing dose proportional increases in exposure. PK and preliminary PD data indicate inhibition of the targets at the 150 mg dose administered orally once per day.
Methods:
This phase 1b study includes enrollment of molecularly selected patients (pts) with unresectable or metastatic NSCLC or other advanced solid tumor malignancies in patient cohorts characterized by activating alterations in sitravatinib RTK targets (RET, KDR, PDGFRA, KIT, TRK, DDR2, MET, AXL) or by loss of function mutations in CBL, a negative regulator for MET, AXL and PDGFR/KIT signaling. Pts receive sitravatinib at 150 mg once daily in 21-day cycles. Study endpoints include safety and tolerability, PK/PD, and clinical activity assessed by objective disease response per RECIST 1.1, duration of response and survival. A two stage optimal Simon design of up to 24 pts (8 pts in first stage and 16 pts in second stage) will be applied to those cohorts defined by a specific tumor gene alteration assuming p~0~=0.15 and p~1~=0.35, with an additional expansion of a cohort up to a total of 70 pts in order to provide a more precise estimate of ORR. PD biomarkers, including sMET, sVEGFR2, VEGFA and sAXL, are being explored in plasma samples for prognostic potential and possible relationship with clinical outcome. The study is open for enrollment, and recruitment is ongoing. Clinical trial information: NCT02219711
Results:
Section not applicable
Conclusion:
Section not applicable
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P2.06-008 - Phase 1/2 Study of Mocetinostat and Durvalumab (MEDI4736) in Patients with Advanced Solid Tumors and Non Small Cell Lung Cancer (NSCLC) (ID 5521)
14:30 - 14:30 | Author(s): D. Potvin
- Abstract
Background:
Immune checkpoint inhibitors produce durable clinical responses in a subset of patients, however strategies are needed to improve clinical efficacy of these agents and overcome innate or acquired resistance to therapy. Growing evidence suggests that tumors evade immune detection through modulation of intrinsic immunogenicity and inhibition of both innate and adaptive anti-tumor immune responses. Mocetinostat, a class I histone deacetylase inhibitor, has multiple potential immunomodulatory features including: 1) induction of tumor associated antigens and major histocompatibility complex Class I and Class II expression on tumor cells, 2) induction of immunogenic cell death via activation and cross-presentation of tumor antigens by antigen presenting cells, 3) enhanced function of T effector cells, and 4) decreased function of immunosuppressive cell subsets including regulatory T cells and myeloid derived suppressor cells. Given these pleiotropic immune activating effects, combination therapy of mocetinostat and PD-L1 blocking mAb, durvalumab, is a rational approach to restoring or enhancing the clinical activity of immune checkpoint blockade in patients with NSCLC.
Methods:
This open-label Phase 1/2 study is evaluating the tolerability and clinical activity of mocetinostat in combination with durvalumab. Secondary objectives include pharmacokinetics, incidence of anti-drug antibodies, and changes in tumor PD-L1 expression. Exploratory objectives evaluate changes in circulating and tumor cell PD-L1, circulating and tumor infiltrating immune cell populations and cytokines. Phase 1 explores increasing doses of mocetinostat administered orally (50, 70, 90 mg three times weekly [TIW]) in combination with durvalumab in patients with advanced solid tumors. The regimen begins with a 7-Day Lead-in Period of mocetinostat single agent TIW followed by the combination regimen with durvalumab (1500 mg intravenously every 28 days). Phase 2 evaluates the clinical activity of mocetinostat and durvalumab, as assessed by Objective Response Rate (ORR) by RECIST 1.1., in patients with NSCLC who have previously received at least one platinum containing doublet chemotherapy regimen for advanced disease. Four population cohorts are included: 1) immunotherapy naïve, no/low PD-L1 expression, 2) immunotherapy naïve, high PD-L1 expression, 3) prior clinical benefit with PD-L1 or PD-1 inhibitor treatment followed by progression, 4) prior treatment with PD-L1 or PD-1 inhibitor with progression within 16 weeks of initiation of treatment. Tumor PD-L1 expression will be determined by the SP263 assay. The sample sizes for the populations are based on two-stage Simon Optimal Designs. Status: Enrollment into the study opened in June 2016. Clinical Trial Information: NCT02805660
Results:
Section not applicable
Conclusion:
Section not applicable
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P2.06-014 - Phase 2 Study of Glesatinib or Sitravatinib with Nivolumab in Non-Small Cell Lung Cancer (NSCLC) after Checkpoint Inhibitor Therapy (ID 4795)
14:30 - 14:30 | Author(s): D. Potvin
- Abstract
Background:
Combination therapy with agents that target the molecular and cellular mechanisms of resistance to checkpoint inhibitor therapy (CIT) is a rational approach to restoring or improving the efficacy of CIT in patients with immunotherapy resistant NSCLC. Glesatinib, a tyrosine kinase inhibitor (TKI), which targets Axl, MER and MET RTKs expressed on macrophages and antigen-presenting-cells within the tumor microenvironment (TME), may reverse the immunosuppressive TME and enhance anti-tumor T and NK cell responses by enhancing antigen presentation and T cell effector function. Sitravatinib, also a TKI, which targets VEGFR2 and KIT as well as Axl, MER and MET, may further enhance anti-tumor activity by VEGFR2 and KIT inhibition mediated reduction of regulatory T cells and myeloid-derived suppressor cells (MDSCs). Given these pleiotropic immune activating effects, the combination of glesatinib or sitravatinib with nivolumab is a rational approach to restoring or enhancing the clinical activity of CIT in patients with immunotherapy resistant NSCLC.
Methods:
This open-label Phase 2 study evaluates the tolerability and clinical activity of the investigational agents, glesatinib or sitravatinib in combination with nivolumab in separate cohorts of patients with non-squamous NSCLC who have experienced progression of disease on or after treatment with CIT. The study begins with a limited dose escalation evaluation of each investigational agent in combination with nivolumab to determine the dose levels to be used in Phase 2. The primary objective is to assess the clinical activity of the combination regimens using the Objective Response Rate (ORR) by RECIST 1.1. Other objectives include safety, tolerability, pharmacokinetics and changes in circulating and tumor cell PD-L1, circulating and tumor infiltrating immune cell populations, cytokines and gene expression signatures. Enrollment into each Phase 2 treatment arm is stratified by prior outcome of CIT (e.g., clinical benefit versus progression of disease in ≤12 weeks). The investigational agents are administered orally in continuous regimens; nivolumab is administered intravenously, 3 mg/kg every 2 weeks. The sample sizes for the treatment arms are based on two-stage Simon Optimal Designs. Status: The US IND opened in June 2016.
Results:
Section not applicable
Conclusion:
Section not applicable
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P2.06-017 - Amethyst NSCLC Trial: Phase 2 Study of MGCD265 in Patients with Advanced or Metastatic NSCLC with Activating Genetic Alterations in MET (ID 5384)
14:30 - 14:30 | Author(s): D. Potvin
- Abstract
Background:
MGCD265 is a potent, orally available, small molecule RTK inhibitor of MET and Axl, both of which mediate signals for cell growth, survival, and migration. The Amethyst NSCLC trial is designed to evaluate the activity of MGCD265 in patients with NSCLC exhibiting genetic alterations involving MET. Alterations in MET, including gene amplification and/or genetic mutations, occur in approximately 7% of NSCLC cases converting MET to an oncogene capable of driving cancer development and progression. Amplification of MET has been associated with a poor prognosis in NSCLC. In addition, various genetic mutations result in the deletion of exon 14 in MET mRNA (METex14del) and the subsequent loss of the Y1003 regulatory binding site for CBL ubiquitin ligase, required for MET degradation and signal attenuation. Loss of the Y1003 binding site of MET results in sustained MET signaling, which has been implicated as an oncogenic driver in a subset of NSCLC. The importance of MET as a driver is demonstrated in xenograft models of NSCLC with METex14del and MET amplification, and where MGCD265 induces tumor regression. Additionally, confirmed partial responses have been observed in pts with NSCLC characterized by METex14del who were treated with MGCD265 in the Phase 1 setting.
Methods:
Pts with platinum pre-treated NSCLC characterized by activating genetic MET alterations identified in tumor tissue or circulating tumor DNA (ctDNA) are eligible for this multi-center, global, Phase 2 trial. Pts are assigned to one of four cohorts based on the type of MET dysregulation and detection method: 1) mutations in tissue, 2) amplification in tissue, 3) mutations in ctDNA, and 4) amplification in ctDNA. The primary endpoint is Objective Response Rate (ORR) in accordance with RECIST 1.1; a Bayesian Predictive Probability Design is applied independently to each cohort. Secondary objectives include safety, tolerability, response duration, survival, correlation between tissue and ctDNA testing, and PK/PD. This study is currently open globally, and recruitment is ongoing.
Results:
Section not applicable.
Conclusion:
Section not applicable.
