TKM 080301 for Primary or Secondary Liver Cancer
Condition: Colorectal Cancer With Hepatic Metastases; Pancreas Cancer With Hepatic Metastase; Gastric Cancer With Hepatic Metastase; Breast Cancer With Hepatic Metastase; Ovarian Cancer With Hepatic Metastase
MeSH terms: Colorectal Neoplasms; Neoplasm Metastasis; Ovarian Neoplasms; Stomach Neoplasms; Pancreatic Neoplasms
Study type: Interventional
Phase: Phase 1

Summary: 
      Background:

      Cancer in the liver can start in the liver (e.g., primary liver cancer or hepatocellular
      cancer) or spread to the liver from cancers in other parts of the body (e.g. colon, pancreas,
      gastric, breast, ovarian, esophageal cancers, cancer with metastases to the liver.) People
      who have tumors that can be removed by surgery live longer than those whose cancer cannot be
      removed. Chemotherapy can shrink some tumors in the liver, which also helps people to live
      longer, and sometimes chemotherapy can shrink tumors enough that they can be removed by
      surgery. However, most chemotherapy drugs do not work well on tumors in the liver. In this
      study we are testing a new drug, TKM-080301, given directly into the cancer blood supply in
      the liver circulation, to see if it will cause tumors to shrink.

      Objectives:

      - To test the safety and effectiveness of TKM-080301 for cancer in the liver that has not
      responded to standard treatments.

      Eligibility:

      - Individuals at least 18 years of age who have inoperable cancer that has started in or
      spread to the liver.

      Design:

        -  Participants will be screened with a medical history and physical exam. They will also
           have blood tests, and imaging studies.

        -  Participants will have a liver angiogram (type of X-ray study) to look at the blood flow
           in the liver and to place a catheter for delivery of the TKM080301.

        -  Participants will have a single dose of TKM-080301 given directly into the liver. After
           the drug has been given, the catheter will be removed. They will have frequent blood
           tests and keep a diary to record side effects.

        -  Participants may have two more doses, each dose given 2 weeks apart. {Before each dose,
           participants will have another angiogram and catheter placement.}They may also have
           liver biopsies to study the tumors.

        -  Two weeks after the third treatment (one full course), participants will have a physical
           exam, blood tests, and imaging studies. If the tumor is shrinking, they may have up to
           three more courses of the study drug.

        -  Participants will have follow up visits every 3 months for 2 years after the last course
           and then every 6 months as required.
    

Detailed description: 
      BACKGROUND:

      - Metastatic liver disease is a life-limiting factor for patients with a variety of cancers.
      For

      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
           survival.

        -  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.

      OBJECTIVES:

      Primary Objective:

      - To evaluate feasibility of administering TKM-080301 via HAI and to characterize the
      pharmacokinetics (PK) and pharmacodynamics of TKM-080301 administered by HAI.

      Secondary Objectives:

        -  To establish the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of
           TKM-080301.

        -  To evaluate response rate using RECIST, PET and EASL criteria.

        -  To evaluate the conversion rate from unresectable to resectable disease.

      ELIGIBILITY:

        -  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.

      DESIGN:

      - 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
           doses.

        -  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.
    

Intervention name(s): TKM-080301
Intervention type(s): Drug
Intervention MeSH terms: TKM-080301
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: SNALP; Regional Therapy; Stage IV Disease; Adenocarcinoma; Unresectable; Liver Metastases; Colorectal Cancer; Stomach Cancer; Gastric Cancer; Breast Cancer; Ovarian Cancer; Pancreatic Cancer; Liver Cancer