Study of CVM-1118 for Patients With Advanced Neuroendocrine Tumors

CVM-1118 (TRX-818) 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 is evaluated from the phase 1 study. The objectives of the phase 2 study is to further investigate the efficacy of CVM-1118 for patients with advanced neuroendocrine tumors.

Neuroendocrine tumors (NETs) are a group of uncommon heterogeneous malignancies originating from neuroendocrine cells localized throughout the body. Approximately 50% of patients with NETs would have metastatic cancer, where 65% of patients with metastatic cancer would result in mortality within 5 years of diagnosis.

The current treatments of NETs do not follow single discipline and the effective agents are largely still under clinical investigations. Apparent formation of vasculogenic mimicry (VM) has been reported in at least two types of NETs. Moreover, VM has been found as part of multiple microvascular alterations in mouse models of pancreatic neuroendocrine tumors.

Wih the high potential of inhibiting VM formation, CVM-1118 is considered to have therapeutic potentials in treating NET tumors.

Eligibility Criteria:
Inclusion Criteria:

Patients eligible for inclusion in this study must meet ALL of the following criteria:

1. \[Tumor eligibility\] Histologically or cytologically confirmed advanced (unresectable and/or metastatic) neuroendocrine tumors that are well-differentiated, low or intermediate grade (WHO Grade 1 or 2) of pancreatic or gastrointestinal, or low/ intermediate grade of lung origin, that are refractory to standard of care therapy, or for whom no standard of care therapy is available.
2. Patients must have measurable or evaluable disease as per RECIST criteria v1.1. Target lesions that have been previously irradiated will not be considered measurable (lesion) unless increase in size is observed following completion of radiation therapy.
3. Patients must have documented progressive disease within 6 months prior enrollment after prior therapy.
4. Patients who are on therapy with a somatostatin analog are eligible but progressive disease must be demonstrated subsequent to establishment for at least 3 months of a stable dose.
5. Male or female, 20 years of age or older.
6. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2.
7. Resolution of all acute toxic effects of prior therapy or surgical procedures to Grade 1 (except alopecia).
8. Adequate organ function as defined by the following criteria:

   * Serum aspartate transaminase (AST) and serum alanine transaminase (ALT) ≦ 3 x upper limit of normal (ULN), or AST and ALT ≦ 5 x ULN if liver function abnormalities are due to underlying malignancy
   * Total serum bilirubin ≦ 1.5 x ULN (except for patients with documented Gilbert's syndrome)
   * Absolute neutrophil count (ANC) ≧ 1500/µL
   * Platelets ≧ 90,000/µL
   * Hemoglobin ≧ 9.0 g/dL
   * Serum creatinine ≦ 2.0 x ULN or creatinine clearance of ≧ 50 mL/min
9. Signed and dated informed consent document indicating that the patient (or legally acceptable representative) has been informed of all the pertinent aspects of the trial prior to enrollment.
10. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures.

Exclusion Criteria:

Patients eligible for this study must not meet ANY of the following criteria:

1. Poorly differentiated neuroendocrine carcinoma, or high grade neuroendocrine tumor.
2. Active, uncontrolled bacterial, viral, or fungal infection(s) requiring systemic therapy.
3. Major surgery, radiation therapy, or systemic anti-cancer therapy within 4 weeks of starting study treatment.
4. Prior high-dose chemotherapy requiring hematopoietic stem cell rescue.
5. Current treatment on another clinical trial.
6. Patients who are using other investigational agents or who had received investigational drugs within 4 weeks prior to study enrollment.
7. Brain metastases, spinal cord compression, carcinomatous meningitis, or leptomeningeal disease unless appropriately treated and neurologically stable for at least 4 weeks.
8. Any of the following within the 12 months prior to starting study treatment:

   myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, congestive heart failure, or cerebrovascular accident including transient ischemic attack; within 6 months prior to starting study treatment for pulmonary embolus. However, upon agreement between the investigator and sponsor, the 6-month post-event-free period for a patient with a pulmonary embolus can be waived if due to advanced cancer. Appropriate treatment with anticoagulants is permitted.
9. Hypertension that cannot be controlled by medications (\> 160/100 mmHg despite optimal medical therapy).
10. Current treatment with therapeutic doses of warfarin (low dose warfarin up to 2 mg PO daily for deep vein thrombosis prophylaxis is allowed).
11. Known history of human immunodeficiency virus (HIV) seropositivity and/or is receiving anti-retroviral therapy.
12. Hepatitis B virus (HBV) or hepatitis C virus (HCV) with evidence of chronic active disease or receiving/requiring antiviral therapy.
13. History of receiving organ transplantation or immune disorders that require continuous immunosuppressant agent therapy.
14. Pregnancy or breastfeeding. Female patients must be surgically sterile or be postmenopausal or must agree to the use of effective contraception during the period of therapy. All female patients with reproductive potential must have a negative pregnancy test (serum or urine) prior to enrollment. Male patients must be surgically sterile or must agree to use effective contraception during the period of therapy. The definition of effective contraception will be based on the judgment of the Investigator or a designated associate.
15. Other severe acute or chronic medical or psychiatric conditions or laboratory abnormalities that would impart, in the judgment of the investigator and/or Sponsor, excess risk associated with study participation or study drug administration, which would make the patient inappropriate for entry into this study.