Intravenous Lipotecan (TLC388 HCl for Injection)

Lipotecan

Min-Hsiung Kao

The purpose of this study is to find a safe and tolerable dose of Lipotecan® when administered to patients with advanced solid tumors.

Lipotecan® is a drug product of TLC388 HCl, which is a potent camptothecin analog with cytotoxic activities against a variety of human tumor cell lines in vitro and anti-tumor activities in several xenograft models with human tumor cell lines. Structurally, TLC388 HCl is related to other camptothecins, but it has been chemically modified to improve stability and potency, and to minimize toxicities.

Phase I Study of Intravenous Lipotecan® (TLC388 HCl for Injection) in Patients With Advanced Solid Tumors

A Phase 1 Open-Label, Sequential Dose Escalation Study Investigating the Safety, Tolerability, and Pharmacokinetics of Intravenous Lipotecan® (TLC388 HCl for Injection) When Administered to Patients With Advanced Solid Tumors

MTD is the highest dose of drug that did not cause an unacceptable side effect (= Dose Limiting Toxicity (DLT)). A 3+3 study design was used to determine MTD. The MTD was the highest dose level at which 0 of 3 or 1 of 6 patients experience a DLT, with the next higher dose having at least 2 of 3 or 2 of 6 patients experiencing a DLT.

Number of participants with AEs that occurred during treatment and follow-up period (30 days after last treatment). Drug-related AEs and SAEs were followed until resolved or stabilized. AEs were classified by the investigator according to severity graded using CTCAE version 3.0 and relationship to study drug. The severity scale is: Grade 1= Mild, Grade 2= Moderate, Grade 3= Severe, Grade 4= Life-threatening or disabling, Grade 5= Death related to AE

Drug product Lipotecan consists of TLC388 diastereomers (S,S-TLC388 and S,R-TLC388 in 2:1 ratio). Three metabolites as TLC-U1, TLC-U2 and topotecan were identified in rats, dogs and human.

Patients were evaluated by tumor assessment using RECIST guidelines. Possible evaluations include: Complete Response (CR): disappearance of all target lesions. Partial Response (PR): at least a 30% decrease in the size of target lesions. Progressive Disease (PD): at least a 20% increase in the size of target lesions. Stable Disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.

Taiwan Liposome Company

Lipotecan was administered intravenously on day 1, 8 and 15 of a 28-day cycle.

Overall Population

Age, Categorical

Age, Continuous

Sex: Female, Male

United States

Taiwan

Region of Enrollment

Shu Chi Hsu

Lipotecan was administered intravenously on day 1, 8 and 15 of a 28-day cycle according to the dose assigned.

All Participants

Patients received at least one dose of Lipotecan.

Maximum Tolerated Dose (MTD) of Lipotecan

Complete Response (CR)

Partitial Response (PR)

Stable Disease (SD)

Progression Disease (PD)

No assessment

Anti-tumor Activity

Patients received at least one dose of Lipotecan

Number of Participants With Adverse Events

Patients complete cycle 1 and 2 treatments without major protocol deviation.

Maximum Observed Dose-normalized Plasma Concentration (Cmax) of S,R-TLC388

Maximum Observed Dose-normalized Plasma Concentration (Cmax) of S,S-TLC388

Maximum Observed Dose-normalized Plasma Concentration (Cmax) of Topotecan

Maximum Observed Dose-normalized Plasma Concentration (Cmax) of TLC-U1

Maximum Observed Dose-normalized Plasma Concentration (Cmax) of TLC-U2

Time to Reach Maximum Observed Plasma Concentration (Tmax) of S,R-TLC388

Time to Reach Maximum Observed Plasma Concentration (Tmax) of S,S-TLC388

Time to Reach Maximum Observed Plasma Concentration (Tmax) of Topotecan

Time to Reach Maximum Observed Plasma Concentration (Tmax) of TLC-U1

Time to Reach Maximum Observed Plasma Concentration (Tmax) of TLC-U2

Dose-normalized Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-t)] of S,R-TLC388

Dose-normalized Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-t)] of S,S-TLC388

Dose-normalized Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-t)] of Topotecan

Dose-normalized Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-t)] of TLC-U1

Dose-normalized Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-t)] of TLC-U2

Plasma Decay Half-Life (t1/2) of S,R-TLC388

Plasma Decay Half-Life (t1/2) of S,S-TLC388

Plasma Decay Half-Life (t1/2) of Topotecan

Plasma Decay Half-Life (t1/2) of TLC-U1

Plasma Decay Half-Life (t1/2) of TLC-U2

Participants received 1.5 mg/m\^2/dose, given as a 30 minute IV infusion on Days 1, 8 and 15 of a 28 day cycle. Each 28 day (4 week) period will constitute one cycle of treatment. Dose escalation of Lipotecan® will be based upon the safety and tolerability data from the first treatment cycle in each patient and determined by Safety Review Committee (SRC) for this study.

Cohort 1 (1.5 mg/m^2)

Participants received 3 mg/m\^2/dose, given as a 30 minute IV infusion on Days 1, 8 and 15 of a 28 day cycle. Each 28 day (4 week) period will constitute one cycle of treatment. Dose escalation of Lipotecan® will be based upon the safety and tolerability data from the first treatment cycle in each patient and determined by Safety Review Committee (SRC) for this study.

Cohort 2 (3 mg/m^2)

Participants received 6 mg/m\^2/dose, given as a 30 minute IV infusion on Days 1, 8 and 15 of a 28 day cycle. Each 28 day (4 week) period will constitute one cycle of treatment. Dose escalation of Lipotecan® will be based upon the safety and tolerability data from the first treatment cycle in each patient and determined by Safety Review Committee (SRC) for this study.

Cohort 3 (6 mg/m^2)

Participants received 9 mg/m\^2/dose, given as a 30 minute IV infusion on Days 1, 8 and 15 of a 28 day cycle. Each 28 day (4 week) period will constitute one cycle of treatment. Dose escalation of Lipotecan® will be based upon the safety and tolerability data from the first treatment cycle in each patient and determined by Safety Review Committee (SRC) for this study.

Cohort 4 (9 mg/m^2)

Participants received 13.5 mg/m\^2/dose, given as a 30 minute IV infusion on Days 1, 8 and 15 of a 28 day cycle. Each 28 day (4 week) period will constitute one cycle of treatment. Dose escalation of Lipotecan® will be based upon the safety and tolerability data from the first treatment cycle in each patient and determined by Safety Review Committee (SRC) for this study.

Cohort 5 (13.5 mg/m^2)

Participants received 20 mg/m\^2/dose, given as a 30 minute IV infusion on Days 1, 8 and 15 of a 28 day cycle. Each 28 day (4 week) period will constitute one cycle of treatment. Dose escalation of Lipotecan® will be based upon the safety and tolerability data from the first treatment cycle in each patient and determined by Safety Review Committee (SRC) for this study.

Cohort 6 (20 mg/m^2)

Participants received 30 mg/m\^2/dose, given as a 30 minute IV infusion on Days 1, 8 and 15 of a 28 day cycle. Each 28 day (4 week) period will constitute one cycle of treatment. Dose escalation of Lipotecan® will be based upon the safety and tolerability data from the first treatment cycle in each patient and determined by Safety Review Committee (SRC) for this study.

Cohort 7 (30 mg/m^2)

Participants received 40 mg/m\^2/dose, given as a 30 minute IV infusion on Days 1, 8 and 15 of a 28 day cycle. Each 28 day (4 week) period will constitute one cycle of treatment. Dose escalation of Lipotecan® will be based upon the safety and tolerability data from the first treatment cycle in each patient and determined by Safety Review Committee (SRC) for this study.

Cohort 8 (40 mg/m^2)

Participants received 35 mg/m\^2/dose, given as a 30 minute IV infusion on Days 1, 8 and 15 of a 28 day cycle. Each 28 day (4 week) period will constitute one cycle of treatment. Dose escalation of Lipotecan® will be based upon the safety and tolerability data from the first treatment cycle in each patient and determined by Safety Review Committee (SRC) for this study.

Cohort 9 (35 mg/m^2)

Cohort 10 (40 mg/m^2)

Participants received 50 mg/m\^2/dose, given as a 30 minute IV infusion on Days 1, 8 and 15 of a 28 day cycle. Each 28 day (4 week) period will constitute one cycle of treatment. Dose escalation of Lipotecan® will be based upon the safety and tolerability data from the first treatment cycle in each patient and determined by Safety Review Committee (SRC) for this study.

Cohort 11 (50 mg/m^2)

Participants received 60 mg/m\^2/dose, given as a 30 minute IV infusion on Days 1, 8 and 15 of a 28 day cycle. Each 28 day (4 week) period will constitute one cycle of treatment. Dose escalation of Lipotecan® will be based upon the safety and tolerability data from the first treatment cycle in each patient and determined by Safety Review Committee (SRC) for this study.

Spots Global Cancer Trial Database for Phase I Study of Intravenous Lipotecan® (TLC388 HCl for Injection) in Patients With Advanced Solid Tumors

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Study Description

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