Study of Sorafenib + TH-302: Phase I in Advanced Renal Cell Carcinoma (RCC) and Advanced Hepatocellular Carcinoma (HCC) and Phase II in 1st Line Advanced HCC


Rochester, Minn., Phoenix/Scottsdale, Ariz.

Trial status:

Open for Enrollment

Why is this study being done?

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.

Who is eligible to participate?

DISEASE CHARACTERISTICS: - Cytologically or histologically confirmed diagnosis of advanced hepatocellular carcinoma (HCC) or renal cell carcinoma; HCC patients should not be amenable to treatment with surgery or to orthotopic liver transplant (phase I) - Cytologically or histologically confirmed diagnosis of hepatocellular carcinoma that is locally advanced or metastatic and is not amenable to treatment with surgery or to orthotopic liver transplant (phase II) - Patients must have measurable disease - HCC patients only: - Advanced HCC after first-line (i.e., no prior systemic therapy) or second-line (with prior first-line sorafenib tosylate therapy only) treatment (phase I) - Advanced HCC after first-line treatment (i.e., no prior systemic therapy) (phase II) - 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 - No known central nervous system (CNS) or brain metastasis that is either symptomatic or untreated - Patients with neurological symptoms must undergo a computed tomography (CT) scan/magnetic resonance imaging (MRI) of the brain to exclude brain metastasis - Patients 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 not allowed - No fibrolamellar histology HCC, mixed hepatocholangiocarcinoma, hepatic sarcomas, and other non-HCC primary liver tumors PATIENT CHARACTERISTICS: - ECOG performance status 0 or 1 - Life expectancy ≥ 3 months - Absolute neutrophil count ≥ 1,200/mm³ - Peripheral platelet count ≥ 75,000/mm³ - Hemoglobin > 8.5 g/dL - Total bilirubin ≤ 3.0 times upper limit of normal (ULN) - AST and ALT ≤ 2.5 times ULN (if patient has HCC or liver metastases, then ≤ 5 times ULN) (phase I) - Creatinine ≤ 1.5 times ULN - International normalized ratio (INR) ≤ 1.5 times ULN - Negative pregnancy test done ≤ 7 days prior to registration, for women of childbearing potential only - Willing to return to North Central Cancer Treatment Group (NCCTG) enrolling institution for follow-up - Ability to receive intravenous contrast for the purpose of imaging (phase II) - None of the following: - 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 tosylate and hypoxia-activated prodrug TH-302 (TH-302) under the guidance of their treating physician - No 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 - No 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 - No inadequately controlled hypertension (systolic blood pressure of > 150 mm Hg or diastolic pressure > 100 mm Hg on anti-hypertensive medications) - No New York Heart Association (NYHA) classification III or IV congestive heart failure - No known or suspected allergy or hypersensitivity to any component of TH-302, sorafenib tosylate, or any of the sorafenib tosylate excipients - No condition that severely impairs patient's ability to swallow whole pills - No QTc interval > 500 msec on baseline electrocardiogram (EKG) - No documented history of prolonged QTc interval ≤ 6 months prior to registration - No traumatic injury in the past 14 days PRIOR CONCURRENT THERAPY: - See Disease Characteristics - Not receiving any other investigational agent - No major surgical procedures prior to registration or anticipation of need for elective or planned major surgical procedure during the course of the study - No treatment with radiation therapy or investigational therapy ≤ 28 days prior to registration - RCC patients only: No 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 - No medication that has documented data or is generally accepted as having increased risk of QT prolongation and/or Torsades de Pointes - Not receiving any medications or substances that are inducers or strong or moderate inhibitors of CYP3A4 ≤ 7 days prior to registration - Patients receiving anti-coagulation therapy are permitted as long as they have a stable INR ≤ 3.0

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