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

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

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

Study Overview

• Status: Completed
• Conditions: Neuroendocrine Carcinomas
• Intervention / Treatment: Drug: TLC 388

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 23
• Phase: Phase 2

Contacts and Locations

Study Locations

• Taiwan
  • Kaohsiung, Taiwan
    • Kaohsiung Medical University Chung-Ho Memorial Hospital
  • Kaohsiung, Taiwan
    • Chung Gung Memorial Hospital(Kaohsiung City)
  • Linkou, Taiwan
    • Chang Gung Memorial Hospital (Lin-Kou),
  • Taichung, Taiwan, 407
    • Taichung Veterans General Hospital
  • Tainan, Taiwan
    • National Cheng-Kung University Hospital
  • Taipei, Taiwan, 100
    • National Taiwan University Hospital
  • Taipei, Taiwan
    • Taipei Veterans General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Assigned Interventions; TLC 388	Drug: TLC 388; 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.; Other Names: Lipotecan®,

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: National Health Research Institutes, Taiwan
• Collaborators: National Taiwan University Hospital; Chang Gung Memorial Hospital; Kaohsiung Medical University Chung-Ho Memorial Hospital; Taipei Veterans General Hospital, Taiwan; National Cheng-Kung University Hospital; Taichung Veterans General Hospital
• Investigators: Study Chair: Yee Chao, MD., PhD, Taipei Veterans General Hospital, Taiwan; Study Director: Hui-Jen Tsai, MD., PhD, National Health Research of Institutes; Study Director: Ming-Huang Chen, MD., PhD, Taipei Veterans General Hospital, Taiwan; Principal Investigator: Cheng-Chung Wu, MS, Taichung Veterans General Hospital; Principal Investigator: Chiun Hsu, MD., PhD, National Taiwan University Hospital; Principal Investigator: Chia-Jui Yen, MD., PhD, National Cheng-Kung University Hospital; Principal Investigator: Yen-Yang Chen, MD, Chang Gung Memorial Hospital; Principal Investigator: Ta-Chih Liu, MD., PhD, Kaohsiung Medical University Chung-Ho Memorial Hospital

Publications and helpful links

General Publications

• Chen MH, Chou WC, Hsiao CF, Jiang SS, Tsai HJ, Liu YC, Hsu C, Shan YS, Hung YP, Hsich CH, Chiu CH, Liu TC, Cho SF, Liu TW, Chao Y. An Open-Label, Single-Arm, Two-Stage, Multicenter, Phase II Study to Evaluate the Efficacy of TLC388 and Genomic Analysis for Poorly Differentiated Neuroendocrine Carcinomas. Oncologist. 2020 May;25(5):e782-e788. doi: 10.1634/theoncologist.2019-0490. Epub 2019 Dec 18.

Study record dates

Study Major Dates

• Study Start (Actual): July 4, 2015
• Primary Completion (Actual): April 18, 2018
• Study Completion (Actual): December 1, 2018

Study Registration Dates

• First Submitted: May 4, 2015
• First Submitted That Met QC Criteria: May 26, 2015
• First Posted (Estimate): May 29, 2015

Study Record Updates

• Last Update Posted (Actual): April 3, 2019
• Last Update Submitted That Met QC Criteria: April 1, 2019
• Last Verified: December 1, 2018

More Information

Terms related to this study

• Keywords: PDNC(Poorly Differentiated Neuroendocrine Carcinomas); TLC-388 (Lipotecan®)
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Carcinoma; Carcinoma, Neuroendocrine
• Other Study ID Numbers: T1Z14

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes