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:

• Histologically or cytologically confirmed colorectal, pancreas, gastric, breast, ovarian and esophageal cancers with hepatic metastases, or primary liver cancers (Hepatocellular carcinoma and Cholangiocarcinoma).
• Hepatic disease must be measurable per RECIST Criteria (version 1.1).
• 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.

• 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.
• Greater than or equal to 18 years of age
• Must be able to understand and sign the Informed Consent Document
• Clinical performance status of ECOG less than or equal to 2
• Life expectancy of greater/equal than two months
• Patients of both genders must be willing to practice birth control during and for four months after receiving chemotherapy
• 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.
• 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
• International Normalized Ratio (INR) less than or equal to 1.5
• Seronegative for HIV antibody
• No chemotherapy or any other investigational drugs within 4 weeks of treatment
• LVEF greater than or equal to 50 percent
• QT/QTc interval less than 450 ms

Exclusion criteria

• Any known brain metastases (prior or current regardless of treatment status)
• Women of child-bearing potential who are pregnant or breastfeeding, because of the potentially dangerous effects of the chemotherapy on the fetus or infant.
• 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).
• NYHA greater than or equal to 2
• Childs B or C cirrhosis or with evidence of severe portal hypertension by history, endoscopy, or radiologic studies
• Weight less than 40 kg
• Significant ascites, greater than 1000cc in the absence of peritoneal disease
• Concomitant medical problems that would place the patient at an unacceptable risk for the procedure/drug
• 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)
• Discretion of the PI