TKM 080301 for Primary or Secondary Liver Cancer

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.

-INCLUSION CRITERIA:

1. Histologically or cytologically confirmed colorectal, pancreas, gastric, breast,
ovarian and esophageal cancers with hepatic metastases, or primary liver cancers
(Hepatocellular carcinoma and Cholangiocarcinoma).

2. Hepatic disease must be measurable per RECIST Criteria (version 1.1).

3. Hepatic disease should be deemed unresectable as per standard of care criteria.

Note: Evidence of limited unresectable extrahepatic disease on preoperative
radiological studies is acceptable if the life-limiting component of progressive
disease is in the liver.

4. All patients must have failed to respond to standard regimens or therapies known to
provide clinical benefit. For example:

- Patients with metastatic colorectal cancer must have received 5-FU and

leucovorin in combination with either oxaliplatin and/or irinotecan, since level

1 evidence support increase survival with these regimens, compared to 5-FU and
leucovorin alone.

- Patients with hepatocellular carcinoma must have received sorafenib, since level 1
evidence support increase survival.

5. Greater than or equal to 18 years of age

6. Must be able to understand and sign the Informed Consent Document

7. Clinical performance status of ECOG less than or equal to 2

8. Life expectancy of greater/equal than two months

9. Patients of both genders must be willing to practice birth control during and for four
months after receiving chemotherapy

10. Hematology:

- Absolute neutrophil count greater than or equal to 1500/mm(3) without the support
of filgrastim.

- Platelet count greater than or equal to 100,000/mm(3).

- Hemoglobin greater than or equal to 9.0 g/dl.

11. Chemistry:

- Serum ALT/AST less than or equal to 2.5 times the upper limit of normal.

- Serum Albumin greater than or equal to 3.0 g/dL

- Serum creatinine less than or equal to 1.5 times ULN unless the measured

creatinine clearance is greater than 60 mL/min/1.73 m(2)

- Total bilirubin less than or equal to 1.2 mg/dl

12. International Normalized Ratio (INR) less than or equal to 1.5

13. Seronegative for HIV antibody

14. No chemotherapy or any other investigational drugs within 4 weeks of treatment

15. LVEF greater than or equal to 50 percent

16. QT/QTc interval less than 450 ms

EXCLUSION CRITERIA:

1. Any known brain metastases (prior or current regardless of treatment status)

2. Women of child-bearing potential who are pregnant or breastfeeding, because of the
potentially dangerous effects of the chemotherapy on the fetus or infant.

3. Active systemic infections, coagulation disorders or other major medical illnesses of
the cardiovascular, respiratory or immune systems, recent myocardial infarction or
heart failure (within 6 months of enrollment).

4. NYHA greater than or equal to 2

5. Childs B or C cirrhosis or with evidence of severe portal hypertension by history,
endoscopy, or radiologic studies

6. Weight less than 40 kg

7. Significant ascites, greater than 1000cc in the absence of peritoneal disease

8. Concomitant medical problems that would place the patient at an unacceptable risk for
the procedure/drug

9. Patient has known hypersensitivity or previous severe reactions to oligonucleotideor
lipid-based products, including liposomal drug products (e.g. Doxil) and
phospholipid-based products (parenteral nutrition, Intralipid)

10. Discretion of the PI