The purpose of this study is to evaluate the safety and tolerability of dalantercept plus sorafenib in patients with advanced hepatocellular carcinoma (HCC) to determine the recommended dose level of dalantercept in combination with sorafenib.

The initial design of the study was a dose escalating approach in which dalantercept in combination with sorafenib, would be administered at increasing dose levels among 3 cohorts of subjects with HCC in order to determine the Maximum Tolerated Dose (MTD) of the combination. Once the MTD was determined, a forth expansion cohort of subjects would be enrolled at the MTD to assess safety. A total of up to 38 subjects were planned.

The initial cohort (Cohort 1) enrolled 5 subjects at a dalantercept dose level of 0.6 mg/kg once every 3 weeks (Q3W) in combination with sorafenib (400 mg PO once daily). Following an assessment of safety/tolerability by a Safety Review Team, it was recommended to de-escalate the dalantercept dose for Cohort 2 to 0.4 mg/kg Q3W in combination with sorafenib (400 mg PO once daily); 6 subjects were enrolled.

The 0.4 mg/kg dose level was determined to be the MTD, and an additional 10 subjects were enrolled at that dose level in the expansion cohort (Cohort 3).

A formal Statistical Analysis Plan was initially planned for this study. However, due to its early termination, only cursory descriptive statistics were carried out on the available data; no formal SAP was prepared.

Inclusion Criteria:

• Histologically confirmed, locally advanced or metastatic HCC.
• Child-Pugh Score A (5-6)
• At least one target lesion that has not been treated with local therapy and is measurable by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
• Life expectancy of at least 12 weeks.
• Able to tolerate oral therapy.
• Appropriate clinical laboratory values within 72 hours prior to study day 1:
• Females of child bearing potential (defined as sexually mature women who have not undergone hysterectomy or bilateral oophorectomy, or are not naturally postmenopausal ≥ 24 consecutive months) must have negative urine or blood pregnancy test prior to enrollment and use adequate birth control methods (abstinence, oral contraceptives, barrier method with spermicide, or surgical sterilization) during study participation. Males must agree to use a latex condom during any sexual contact with females of child bearing potential while participating in the study and for 12 weeks following the last dose of dalantercept, even if he has undergone a successful vasectomy. Patients must be counseled concerning measures to be used to prevent pregnancy and potential toxicities prior to the first dose of dalantercept.

Exclusion Criteria:

• Mixed tumor histology

• Prior systemic therapy for metastatic disease.

• Adjuvant therapy < 6 months prior to study day 1.

• Prior treatment with dalantercept or other agent targeting the ALK1 pathway.

• Prior treatment with sorafenib or other RAF/VEGF targeted therapies.

• Hepatic radiation, chemoembolization, and radiofrequency ablation < 4 weeks prior to study day 1.

• Palliative radiation therapy to metastatic sites of disease < 2 weeks prior to study day 1.

• Interferon therapy < 4 weeks prior to study day 1.

• Uncontrolled Hepatitis B despite appropriate therapy.

• Clinically significant pulmonary, endocrine, neurologic, hematologic, gastrointestinal (GI), autoimmune, psychiatric or genitourinary disease unrelated to HCC that in the judgment of the investigator should preclude treatment with dalantercept or sorafenib.

• Known HIV infection.

• Clinically significant cardiovascular risk

• Clinically significant active pulmonary risk

• Known active gastrointestinal (GI) bleeding.

• Known bleeding diathesis Known history of hereditary hemorrhagic telangiectasia (HHT).

• History of another primary cancer, with the exception of:

  1. Curatively resected non melanoma skin cancer.
  2. Curatively treated cervical carcinoma in situ.
  3. Other primary solid tumor with no known active disease in the opinion of the investigator that will not affect patient outcome in the setting of current HCC diagnosis.

• Major surgery within 4 weeks prior to study day 1 Active infection Anti-coagulation therapy Concomitant treatment with potent CYP3A4 inducers

• Peripheral edema ≥ grade 2 within 2 weeks prior to study day 1.

• History of recurrent ascites requiring paracentesis within 4 weeks of study day 1.

• History of severe (using the National Cancer Institute Common Toxicity Criteria for Adverse Events, version 4.0 [NCI-CTCAE] v4 current minor version ≥ grade 3) allergic or anaphylactic reaction or hypersensitivity to recombinant proteins or excipients