Phase II Study to Evaluate the Efficacy and Safety of TLC388 for Differentiated Neuroendocrine Carcinomas Patients

Title of Study:

An Open-Label, Single-Arm, Two-Stage, Multicenter, Phase II Study to Evaluate the Efficacy and Safety of TLC388 as Second-line Treatment in Subjects with Poorly Differentiated Neuroendocrine Carcinomas

Investigational product:

Lipotecan®\*

\*Lipotecan® is the trade name of TLC388 HCl, a Topoisomerase I inhibitor)

Phase of development:

Phase II

Number of subjects:

Plan to enroll 44 subjects

Objectives:

Primary objectives:

To determine the objective response rate

Secondary objectives:

To evaluate Disease control rate, Progression free survival, Overall survival, Safety profile and Biomarkers

This is a phase II, open-label, single-arm, two-stage, multicenter study to evaluate the efficacy and safety of Lipotecan® monotherapy in subjects with poorly differentiated neuroendocrine carcinomas. Only those subjects who have failed to first line chemotherapy (Etoposide plus platinum) due to treatment intolerance or radiographic progressive disease (PD), as per RECIST v1.1, are eligible to participate in the study. The scheduled assessments should be performed as identified on a calendar schedule, and should not be affected by delays in therapy, drug holidays or any other events that might be lead to imbalance in a treatment arm in the timing of disease assessment. Efficacy results are based on radiographic assessments reviewed by the investigator.

Eligible subjects will receive 40 mg/m2 of Lipotecan®, given as a 30 (+3) minute intravenous infusion, on Days 1, 8 and 15 of a 28-day cycle until PD, unacceptable toxicity or consent withdrawal occurs.

Eligibility Criteria:
Inclusion Criteria:

1. Pathologically confirmed poorly differentiated neuroendocrine carcinomas.
2. Patients who had first-line treatment failure (First line therapy must be etoposide plus platinum) due to treatment intolerance or radiographic progressive disease (as per RECIST v1.1).
3. At least one measurable lesion in a non-irradiated area.
4. Aged \> 20 years old.
5. ECOG Performance Status ≤ 2.
6. Life expectancy greater than 12 weeks.
7. Adequate bone marrow function :

   * absolutely neutrophil count ≥ 1500 /mm3 or WBC ≥ 4000/mm3
   * Hemoglobin \> 9 g/dl
   * platelet count ≥ 100,000 /mm3
8. Adequate liver function :

   * ALT \& AST ≤ 2.5 x ULN if without liver metastasis or ≤ 5 x ULN if with hepatic metastasis Alkaline phosphatase ≤ 2.5 x ULN if without liver and bone metastasis; or ≤ 5 x ULN if with hepatic metastasis or bone metastasis
   * Total Bilirubin \< 2 x ULN
9. Adequate renal function: creatinine \< 1.5 x ULN.
10. Subjects who are willing and able to comply with all of the study procedures, and able to sign the informed consent.

Exclusion Criteria:

1. Major surgery within two weeks prior to entering the study.
2. Patients with CNS metastasis, including clinical suspicion.
3. Patients who are under active or uncontrolled infections.
4. Patients with concomitant illness that might be aggravated by chemotherapy.
5. Patients who are pregnant or with breast feeding.
6. Other concomitant or previously malignancy within 5 yrs except for in situ cervix cancer or squamous cell carcinoma of the skin treated by surgery only.
7. Fertile men and women unless using a reliable and appropriate contraceptive method
8. A history of or the presence of one or more cardiac diseases, such as congestive heart failure (New York Heart Association Class III or IV), myocardial infarction or unstable angina and related surgeries, within 3 months prior to the initiation of the treatment dose.
9. Patients with a known history of human immunodeficiency virus infection.
10. The presence of active or uncontrolled systemic infection (bacterial, viral, other) except for chronic hepatitis B and hepatitis C.
11. Use of any investigational agent within 4 weeks of baseline.
12. Uncontrolled and unstable concurrent medical or psychiatric illness that will jeopardize the safety of the subject, interfere with the objectives of the protocol, or affect the subject compliance with study requirements, as determined by the investigator.
13. Known hypersensitivity or adverse drug reactions to Lipotecan® or its components.