CVM-1118 is a new small molecule chemical entity being developed as a potential anti-cancer therapeutic by TaiRx, Inc. CVM-1118 is a potent anti-cancer agent in numerous human cancer cell lines. The safety of administrating CVM-1118 on human has been evaluated from the phase 1 study. The objective of the phase 2 study is to further investigate the efficacy of CVM-1118 with nivolumab for subjects with unresectable advanced hepatoma.

Nivolumab, a human IgG4 kappa monoclonal antibody acts as a checkpoint inhibitor, blocking the interaction between PD-1 and its ligands (PD-L1 and PD-L2 ) and therefore preventing the activation of T cells from attacking the cancer. Nivolumab is currently approved for several cancer types.

To meet the medical need, TaiRx, Inc. develops a new small molecule drug, CVM-1118 can promote apoptosis and delay proliferation. Moreover, CVM-1118 targets the formation of vasculogenic mimicry (VM). VM has been associated with tumor metastasis and poor clinical outcomes. VM is reported to be particularly active in tumor under hypoxia state when patients are treated with the potent vascular endothelial growth factor (VEGF) inhibitor like sorafenib or bevacizumab. Hence, the ability of inhibiting the VM network makes CVM-1118 a potential good combination drug with Nivolumab in advanced diseases such as hepatoma where Nivolumab alone has shown activity.

The safety profile of CVM-1118 dosing has been established in the phase 1 study. The analysis of metabolism pathways further showed that the potential drug-drug interactions of CVM-1118 and Nivolumab are very low.

Based on the mechanism of actions and the safety analysis of nivolumab and CVM-1118, the design of phase 2 trial with the combination therapy might have great potential for the patients with unresectable advanced HCC.

Inclusion Criteria:

• Age 18+ (20+ for subjects in Taiwan)

• Diagnosis of hepatocellular carcinoma

  • Pathologically or cytologically-confirmed or clinically diagnosed in accordance with American Association for the Study of Liver Diseases (AASLD) criteria (i.e., radiologic imaging with cross-sectional multiphasic contrast CT or MRI showing a ≥ 1 cm liver lesion)

• Subjects with advanced-stage, unresectable hepatocellular carcinoma that is not appropriate for potentially curable therapy who have progressed from, been intolerant of prior systemic anti-cancer therapies (e.g., sorafenib, lenvatinib, atezolizumab in combination with bevacizumab).

• Barcelona Clinic Liver Cancer (BCLC) stage B not appropriate for or with disease progression after local regional therapy, or BCLC stage C

• Child-Pugh liver function class A

• Measurable disease (per mRECIST)

• ECOG performance status of 0 to 1

• Adequate laboratory parameters including:

  • AST and ALT ≤ 3.0 x ULN (≤ 5.0 x ULN if due to liver involvement)
  • Total serum bilirubin ≤ 2.0 x ULN (≤ 3.0 x ULN for subjects with documented Gilbert's syndrome)
  • ANC ≥1500/µL
  • Platelets ≥ 90,000/µL
  • HGB ≥ 9.0 g/dL
  • Serum creatinine clearance of ≥ 50 mL/min based on Cockcroft-Gault formula
  • Serum albumin ≥ 2.8 gm/dL
  • INR ≤ 2.3
  • PT/aPTT ≤ 1.2 x ULN

• QTcF ≤ 480 msec

• Subjects are eligible to enroll if they have HBV-, or HCV-HCC, defined as follows:

  • Chronic HBV infection as evidenced by detectable HBV DNA or HBsAg. Subjects with chronic HBV infection must be on antiviral therapy and have HBV DNA <500 IU/mL. If not on an antiviral therapy at screening, then subjects must be willing to start the antiviral therapy at the time of consent.
  • Active or resolved HCV infection as evidenced by detectable HCV RNA or antibody.

Exclusion Criteria:

• HCC with portal vein invasion at the main portal branch (Vp4)
• Known history of esophageal varices or gastrointestinal bleeding within the past 3 months
• Prior immunotherapy for hepatoma
• ≤ 7 days from prior limited field palliative irradiation therapy and C1D1
• ≤ 28 days from prior irradiation therapy and C1D1
• ≤ 14 days (or 5 half-lives) from prior systemic anticancer therapy and C1D1
• ≤ 28 days from local regional therapy (e.g., trans-arterial embolization, radiofrequency ablation) and C1D1
• Presence of other active cancer(s) likely to require treatment in the next two (2) years or likely to impact the assessment of any study endpoints
• Active bacterial or fungal infection(s) requiring systemic therapy within 7 days prior to C1D1
• Known CNS metastases
• Known history of HIV infection
• Females who are currently pregnant or breast-feeding
• Known gastrointestinal disease that may significantly alter the absorption of oral medications
• Psychiatric illness or social situation that would interfere with compliance with study requirements
• History of clinically significant cardiovascular abnormalities