Sorafenib Tosylate and Hypoxia-Activated Prodrug TH-302 in Treating Patients With Advanced Kidney Cancer or Liver Cancer That Cannot Be Removed By Surgery

OBJECTIVES:

Primary

- To determine the maximum-tolerated dose (MTD) and recommended Phase II dosing (RP2D)
for the combination of sorafenib tosylate and hypoxia-activated prodrug TH-302 (TH-302)
in patients with hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC; non-HCC)
advanced solid tumors. (Phase I)

- To evaluate the overall response rate (RR) determined based on modified RECIST criteria
(Lencioni and Llovet 2010) in patients with advanced HCC receiving sorafenib tosylate
with TH-302. (Phase II)

Secondary

- To characterize overall toxicity profile of sorafenib tosylate + TH-302 within patients
with HCC and RCC (non-HCC) advanced solid tumors. (Phase I)

- To characterize the responses of sorafenib tosylate + TH-302 within patients with HCC
and RCC (non-HCC) advanced solid tumors. (Phase I)

- To assess the adverse events (AEs) profile and safety profile of sorafenib tosylate in
combination with TH-302 in patients with advanced HCC. (Phase II)

- To estimate the overall response rate based on standard RECIST criteria in the study
population. (Phase II)

- To estimate the duration of response based on modified (standard) RECIST criteria in
the study population. (Phase II)

- To estimate the progression free survival (PFS) in the study population. (Phase II)

- To estimate the overall survival (OS) in the study population. (Phase II)

- To estimate the alpha-fetoprotein (AFP) response rate (defined as > 20% decrease of AFP
from baseline) in the study population. (Phase II)

OUTLINE: This is a multicenter, phase I dose-escalation study followed by a phase II study.

Patients receive sorafenib tosylate orally (PO) twice daily (BID) on days 1-28 and
hypoxia-activated prodrug TH-302 IV over 30 minutes on days 8, 15, and 22. Courses repeat
every 28 days in the absence of disease progression or unacceptable toxicity.

Some patients undergo blood sample collection periodically during study for
alpha-fetoprotein analysis.

After completion of study treatment, patients are followed up for 3 years.

Phase I Registration - Inclusion Criteria

- Age ≥18 years

- Cytological or histological confirmed diagnosis of advanced hepatocellular or renal
cell carcinoma. HCC patients should not be amenable to treatment with surgery or to
orthotopic liver transplant.

- Patients must have measurable disease as defined in the protocol.

- RCC patients only: Tumor progression after receiving standard/approved chemotherapy
and/or targeted agent, where there is no approved therapy or for tumors where
sorafenib based therapy would be standard therapy.

- HCC patients only:

- First line (i.e., no prior systemic therapy) or second line (with prior first
line sorafenib therapy only) advanced HCC.

- Child Pugh class A or B7 liver disease

- Prior chemoembolization, radioembolization, radiofrequency ablation (RFA), or
other local ablative therapies are permissible if ≥6 weeks from procedure with
evidence of progression or new metastatic disease, if applicable.

- ECOG Performance Status (PS) 0 or 1.

- The following laboratory values obtained ≤14 days prior to registration.

- Absolute neutrophil count (ANC) ≥1200/mm3

- Peripheral Platelet Count (PLT) ≥75,000/mm3

- Hemoglobin (HgB) >8.5 g/dL

- Bilirubin ≤3.0 x upper limit of normal (ULN)

- SGOT (AST) ≤2.5 x ULN, if subject has HCC or liver metastases ≤5 x UL

- SGPT (ALT) ≤2.5 x ULN, if subject has HCC or liver metastases ≤5 x ULN

- Creatinine ≤1.5 x ULN

- INR ≤1.5 x ULN. Patients receiving anti-coagulation therapy are permitted as
long as they have a stable INR≤3.0.

- Negative pregnancy test done ≤7 days prior to registration, for women of childbearing
potential only.

- Provide informed written consent.

- Willing to return to Alliance enrolling institution for follow-up.

- Life expectancy ≥3 months.

Phase I Registration - Exclusion Criteria

- Any of the following because this study involves an investigational agent whose
genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are
unknown.

- Pregnant women

- Nursing women

- Men or women of childbearing potential who are unwilling to employ adequate
contraception for the duration of study participation. Men and women should
continue to use adequate birth control after the last administration of
sorafenib and TH-302 under the guidance of their treating physician.

- Co-morbid systemic illnesses or other severe concurrent disease which, in the
judgment of the investigator, would make the patient inappropriate for entry into
this study or interfere significantly with the proper assessment of safety and
toxicity of the prescribed regimens.

- Receiving any other investigational agent.

- Other active malignancy ≤3 years prior to registration. EXCEPTIONS: Non-melanotic
skin cancer or carcinoma-in-situ of the cervix. NOTE: If there is a history or prior
malignancy, they must not be receiving other specific treatment (other than hormonal
therapy) for their cancer.

- Inadequately controlled hypertension (systolic blood pressure of >150 mmHg or
diastolic pressure >100 mmHg on anti-hypertensive medications).

- Major surgical procedures, or significant traumatic injury ≤14 days prior to
registration or anticipation of need for elective or planned major surgical procedure
during the course of the study.

- New York Heart Association (NYHA) classification III or IV congestive heart failure.

- Received treatment with radiation therapy or investigational therapy ≤28 days prior
to registration.

- RCC patients only: Having received chemotherapy prior to study entry within 5
half-lives of the agent (as described in the package insert), or 4 weeks prior to
registration (whichever is shorter) with resolution of side effects from therapy to
≤grade 1.

- Known central nervous system or brain metastasis that are either symptomatic or
untreated. Note: Patients with neurological symptoms must undergo a CT scan/MRI of
the brain to exclude brain metastasis.

- Note: Subjects with CNS metastases that have been treated and are stable without
symptoms for ≥ 4 weeks after completion of treatment are eligible.

- HCC patients only: Cancer potentially amenable to local modalities of therapy or
surgical resection.

- Known or suspected allergy or hypersensitivity to any component of TH-302, sorafenib,
or any of the sorafenib excipients.

- Any condition that severely impairs patient's ability to swallow whole pills.

- QTc interval >500 msec on baseline EKG.

- Documented history of prolonged QTc interval ≤ 6 months prior to registration.

- Receiving any medication that has documented data or is generally accepted as having
increased risk of QT prolongation and/or Torsades de Pointes.

- Receiving any medications or substances that are inducers or strong or moderate
inhibitors of CYP3A4, see the protocol for a complete listing.

- Fibrolamellar histology HCC, mixed hepatocholangiocarcinoma, hepatic sarcomas and
other non-HCC primary liver tumors.

- History of lobectomy involving >50% of lobe.

- Radioembolization within 8 weeks of Day 1 dosing of sorafenib.

Phase II Registration - Inclusion Criteria

- Age ≥18 years

- Cytological or histological confirmed diagnosis of hepatocellular carcinoma that is
locally advanced or metastatic and is not amenable to treatment with surgery or to
orthotopic liver transplant.

- Patients must have measurable disease as defined in Section 11.0 must have at least
one non-nodal lesion.

- First line advanced HCC (i.e., no prior systemic therapy).

- Child Pugh class A or B7 liver disease

- Prior chemoembolization, radioembolization, radiofrequency ablation (RFA), or other
local ablative therapies are permissible if ≥6 weeks from procedure with evidence of
progression or new metastatic disease, if applicable.

- ECOG Performance Status (PS) 0 or 1.

- The following laboratory values obtained ≤14 days prior to registration.

- Absolute neutrophil count (ANC) ≥1200/mm^3

- Peripheral Platelet Count (PLT) ≥75,000/mm^3

- Hemoglobin (HgB) >8.5 g/dL

- Total bilirubin ≤3.0 x upper limit of normal (ULN)

- SGOT (AST) ≤5 x ULN.

- SGPT (ALT) ≤5 x ULN.

- Creatinine ≤1.5 x ULN.

- INR ≤1.5 x ULN. Patients receiving anti-coagulation therapy are permitted as
long as they have a stable INR≤3.0.

- Negative pregnancy test done ≤7 days prior to registration, for women of childbearing
potential only.

- Provide informed written consent.

- Willing to return to Alliance enrolling institution for follow-up.

- Life expectancy ≥3 months.

- Ability to receive intravenous contrast for the purpose of imaging.

Phase II Registration - Exclusion Criteria

- Any of the following because this study involves an investigational agent whose
genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are
unknown.

- Pregnant women

- Nursing women

- Men or women of childbearing potential who are unwilling to employ adequate
contraception for the duration of study participation. Men and women should
continue to use adequate birth control after the last administration of
sorafenib and TH-302 under the guidance of their treating physician.

- Co-morbid systemic illnesses or other severe concurrent disease which, in the
judgment of the investigator, would make the patient inappropriate for entry into
this study or interfere significantly with the proper assessment of safety and
toxicity of the prescribed regimens.

- Receiving any other investigational agent.

- Other active malignancy ≤3 years prior to registration. EXCEPTIONS: Non-melanotic
skin cancer or carcinoma-in-situ of the cervix. NOTE: If there is a history or prior
malignancy, they must not be receiving other specific treatment (other than hormonal
therapy) for their cancer.

- Inadequately controlled hypertension (systolic blood pressure of >150 mmHg or
diastolic pressure >100 mmHg on anti-hypertensive medications).

- Major surgical procedures, or significant traumatic injury ≤14 days prior to
registration or anticipation of need for elective or planned major surgical procedure
during the course of the study.

- New York Heart Association (NYHA) classification III or IV congestive heart failure.

- Received treatment with radiation therapy or investigational therapy ≤28 days prior
to registration.

- Known central nervous system or brain metastasis that are either symptomatic or
untreated. Note: Patients with neurological symptoms must undergo a CT scan/MRI of
the brain to exclude brain metastasis.

- Note: Subjects with CNS metastases that have been treated and are stable without
symptoms for ≥ 4 weeks after completion of treatment are eligible.

- Fibrolamellar histology HCC, mixed hepatocholangiocarcinoma, hepatic sarcomas and
other non-HCC primary liver tumors.

- Cancer potentially amenable to local modalities of therapy or surgical resection.

- Known or suspected allergy or hypersensitivity to any component of TH-302, sorafenib,
or any of the sorafenib excipients

- Any condition that severely impairs patient's ability to swallow whole pills.

- QTc interval >500 msec on baseline EKG.

- Documented history of prolonged QTc interval ≤ 6 months prior to registration.

- Receiving any medication that has documented data or is generally accepted as having
increased risk of QT prolongation and/or Torsades de Pointes.

- Receiving any medications or substances that are inducers or strong or moderate
inhibitors of CYP3A4, please see protocol for a complete listing.

- History of lobectomy involving >50% of lobe.

- Radioembolization within 8 weeks of Day 1 dosing of sorafenib.