A Phase 1 Dose Escalation Study of Hepatic Intra-Arterial Administration of TKM 080301 (Lipid Nanoparticles Containing siRNA Against the PLK1 Gene Product) in Patients With Colorectal, Pancreas, Gastric, Breast, Ovarian and Esophageal Cancers With Hepatic
- Metastatic liver disease is a life-limiting factor for patients with a variety of cancers.
unresectable liver metastases, the 5-year survival is < 5%.
- For selected histologies the 5-year survival of resectable hepatic metastases ranges
from 20-60%, suggesting that control of liver metastases could result in prolonged
- Phase I through III trials have shown that Hepatic Arterial Infusion (HAI) is safe.
However, agents used thus far in HAI have limited efficacy.
- TKM-080301 is a lipid nanoparticle (LNP) formulation containing siRNA against the PLK1
(polo-like kinase-1) gene product. More specifically, TKM-080301 is a type of LNP
formulation, referred to as SNALP (Stable Nucleic Acid Lipid Particles). PLK1 has been
validated as a molecular target and a prognostic factor in a variety of cancers.
Inhibition of PLK1 activity in proliferating cancer cells rapidly induces mitotic
arrest and apoptosis.
- This study will offer HAI with TKM-080301 to patients with unresectable and/or life
threatening primary liver cancer or liver metastases.
- To evaluate feasibility of administering TKM-080301 via HAI and to characterize the
pharmacokinetics (PK) and pharmacodynamics of TKM-080301 administered by HAI.
- To establish the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of
- To evaluate response rate using RECIST, PET and EASL criteria.
- To evaluate the conversion rate from unresectable to resectable disease.
- Patients with unresectable colorectal, pancreas, gastric, breast, ovarian and
esophageal cancers with hepatic metastases; or primary liver cancer patients who have
demonstrated progressive disease following standard of care treatment.
- 18 years old or greater with an ECOG 0-2
- Laboratory and physical examination parameters within acceptable limits by standard of
practice guidelines prior to surgery or chemotherapy.
- This is a dose escalation phase-I study testing HAI of TKM-080301 for patients with
unresectable colorectal, pancreas, gastric, breast, ovarian and esophageal cancers with
hepatic metastases, or primary liver cancers.
- Up to 54 patients who meet eligibility criteria will receive HAI with TKM-080301.
- Initial dose will be 4 mg/m(2); treatment will be given every 2 weeks for up to 12
- Patients will be evaluated every 6 weeks. Patients whose tumors become resectable will
be offered this option; patients who show progressive disease will be taken off
treatment. All patients will be followed for survival.
Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
To evaluate feasibility of administering TKM-080301 via HAI, and establish MTD and DLT.
Thomas S Uldrick, M.D.
National Cancer Institute (NCI)
United States: Federal Government
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