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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]