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

Study Overview
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Brief Summary
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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

Detailed Description
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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.

Official Title
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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

Conditions
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Neuroendocrine Carcinomas

Intervention / Treatment
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* Drug: TLC 388


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pathologically confirmed poorly differentiated neuroendocrine carcinomas. 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). At least one measurable lesion in a non-irradiated area. Aged > 20 years old. ECOG Performance Status ≤ 2. Life expectancy greater than 12 weeks. Adequate bone marrow function : absolutely neutrophil count ≥ 1500 /mm3 or WBC ≥ 4000/mm3 Hemoglobin > 9 g/dl platelet count ≥ 100,000 /mm3 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 Adequate renal function: creatinine < 1.5 x ULN. Subjects who are willing and able to comply with all of the study procedures, and able to sign the informed consent. Exclusion Criteria: Major surgery within two weeks prior to entering the study. Patients with CNS metastasis, including clinical suspicion. Patients who are under active or uncontrolled infections. Patients with concomitant illness that might be aggravated by chemotherapy. Patients who are pregnant or with breast feeding. 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. Fertile men and women unless using a reliable and appropriate contraceptive method 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. Patients with a known history of human immunodeficiency virus infection. The presence of active or uncontrolled systemic infection (bacterial, viral, other) except for chronic hepatitis B and hepatitis C. Use of any investigational agent within 4 weeks of baseline. 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. Known hypersensitivity or adverse drug reactions to Lipotecan® or its components.

Ages Eligible for Study
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Minimum Age: 20 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Assigned Interventions<br>TLC 388 | Drug: TLC 388<br>* 40 mg/m2 of TLC 388, 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.<br>* Other names: Lipotecan®,;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| the objective response rate | Analysis for the objective response rate will be conducted on both the per protocol(PP) and evaluable data sets. | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease control rate | The Disease control rate (DCR) is the percentage of subjects who have a best-response rating of CR or PR or SD (DCR= CR+PR+SD) (according to RECIST v1.1) when assessed after every 8 weeks of study drug (up to 6 cycles) and maintained for at least 28 days. | 5 years | 
| Progression free survival | Progression-free survival will be calculated as the duration between the first date of randomization and the date of disease recurrence or progression according to RECIST v1.1 (failed), taking the status of tumor at the treatment has been completed as the reference, or death (failed), or the date of withdrawal (last contact date, censored), or the scheduled data analysis date (censored). | 5 years | 
| Overall survival | Overall survival will be calculated from the date of randomization to either the date of death from all causes, or to the date of withdrawal (last contact date, censored), or to the scheduled data analysis date (censored). | 5 years | 
| Number of Participants with Adverse Events as a Measure of Safety and Tolerability | Physical examinations, lab abnormality and other toxicities graded by the NCI Common Toxicity Criteria will be examined to evaluate safety profiles of the study treatments. Particular attention will be paid to Grade 3 or 4 toxicities. | 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PDNC(Poorly Differentiated Neuroendocrine Carcinomas), TLC-388 (Lipotecan®)