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Chi et al. J Cancer Metastasis Treat 2020;6:43  I  http://dx.doi.org/10.20517/2394-4722.2020.90                             Page 11 of 17

               Table 4. Ongoing clinical trials investigating novel targeting agents
                                                                                               Clinicaltrials.
                Study drug       Combination     Study phase Treatment setting  Sponsor
                                                                                               gov identifier
                PARP inhibitors
                 Olaparib  None                     II      Any         AstraZeneca            NCT01078662
                           None                     III     Maintenance  AstraZeneca           NCT02184195
                           None                     II      Second line  AstraZeneca           NCT02677038
                           Cediranib (VEGF inhibitor)  II   Second line  National Cancer Institute  NCT02498613
                 Rucaparib  None                    II      Maintenance  Abramson Cancer Center, UPenn NCT03140670
                           Liposomal irinotecan,    I/II    Any         Academic and Community   NCT03337087
                           5-fluorouracil and leucovorin                Cancer Research United
                 Niraparib  Ipilimumab or nivolumab  I/II   Second line  Upenn                 NCT03404960
                           None                     III     Any         Anup Kasi              NCT03553004
                 Veliparib  FOLFIRI or mFOLFIRI     II      Second line  National Cancer Institute  NCT02890355
                           mFOLFOX6                 I/II    Any         Georgetown University  NCT01489865
                           ± Cisplatin and gemcitabine  II  Any         National Cancer Institute  NCT01585805
                 Talazoparib  Avelumab and binimetinib  Ib/II  Any      Pfizer                 NCT03637491
                NTRK inhibitors
                 Larotrectinib None                 II      Any         Bayer                  NCT 02576431
                 Entrectinib  None                  II      Any         Hoffmann-La Roche      NCT02568267
                Mitochondrial inhibitor
                 Devimistat  Gemcitabine plus nab-paclitaxel  I  First line  Atlantic Health System  NCT03435289
                           mFOLFIRINOX              III     Any         Rafael Pharmaceuticals  NCT03504423
                FAK inhibitor
                 PF-00562271 None                   I       Second line  Verastem              NCT00666926
                Connective tissue growth factor inhibitor
                 Pamrevlumab Gemcitabine plus nab-paclitaxel  I/II  Neoadjuvant  FibroGen      NCT02210559
                           Gemcitabine plus nab-paclitaxel  III  First line  FibroGen          NCT03941093
               NTRK: Neurotrophic tropomyosin-related kinase; FOLFIRINOX: leucovorin, fluorouracil, irinotecan, oxaliplatin; FAK: focal adhesion kinase


               NTRK inhibitors
               Topomyosin receptor kinase (TRK) transmembrane proteins plays an important role in neural
               development. When different partners fuse with TRK encoding genes (NTRK1, NTRK2 or NTRK3) the
               resulting gene encode for oncogenic proteins that constitutively activate the RAS-MEK-ERK, PI3k-AKT,
                                                                        [88]
               and diacyleglycerol-inositol-1,4,5-triphosphate signaling pathways . NTRK fusions are found in < 1% of
               PDAC. In the STARTRK-2 trial (NCT02568267) with entrectinib, a TRK A/B/C inhibitor, 3 patients with
               PDAC had PR based on RECIST criteria. Another ongoing trial NAVIGATE (NCT 02576431) showed
               response rate was as high as 75% among 55 patients with NTRK fusion positive solid tumors treated with
               larorectinib. However, only one patient with PDAC was included in the cohort. Currently, entrectinib and
               larorectinib are approved by FDA for a tissue-agnostic indication in solid tumors that harbor NRTK fusion
               gene.

               Devimistat
               Devimistat selectively inhibits the tricarboxylic acid cycle in the mitochondria and is hypothesized
               to work synergistically with cytotoxic agents by decreasing mitochondria metabolism, impairing
               production of intermediates required for DNA damage repair. Devimistat was studied in a phase I trial in
               combination with mFOLFIRINOX in 20 patients with metastatic PDAC. The response rate was 61% with
                                    [89]
               3 patients achieving CR . Currently Devimistat is being studied in a phase III trial in combination with
               mFOLFIRINOX (NCT03504423) and in a phase I trial in combination with gemcitabine and nab-paclitaxel
               (NCT03435289).

               Focal adhesion kinase inhibitors
               Focal adhesion kinase (FAK) is a tyrosine kinase that promotes tumor growth, invasion and metastasis by
               interacting with tumor cells and stromal cells in various types of cancer . In preclinical research, FAK
                                                                              [90]
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