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

NCT00747474 | Completed Phase 1 Results DMC

• 1 other identifier: TLC388-101
• Study Type: interventional
• Target: 54
• Locations: 2 countries
• Sites: 4

Brief Summary

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

Conditions

Advanced Solid Tumors

Outcome Measures

Primary Outcomes (22)

• Maximum Tolerated Dose (MTD) of Lipotecan

  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.

  First treatment to toxicity up to 42 days

• Number of Participants With Adverse Events

  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

  an average of 6 months

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

  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.

  0, 15m, 29m, 33m, 40m, 50m, 1 h, 1h 30m, 2h, 4h, 8h post-dose

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

  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.

  0, 15m, 29m, 33m, 40m, 50m, 1 h, 1h 30m, 2h, 4h, 8h post-dose

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

  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.

  0, 15m, 29m, 33m, 40m, 50m, 1 h, 1h 30m, 2h, 4h, 8h post-dose

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

  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.

  0, 15m, 29m, 33m, 40m, 50m, 1 h, 1h 30m, 2h, 4h, 8h post-dose

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

  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.

  0, 15m, 29m, 33m, 40m, 50m, 1h, 1h30m, 2h, 4h, 8h

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

  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.

  0, 15m, 29m, 33m, 40m, 50m, 1 h, 1h 30m, 2h, 4h, 8h

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

  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.

  0, 15m, 29m, 33m, 40m, 50m, 1 h, 1h 30m, 2h, 4h, 8h post-dose

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

  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.

  0, 15m, 29m, 33m, 40m, 50m, 1 h, 1h 30m, 2h, 4h, 8h post-dose

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

  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.

  0, 15m, 29m, 33m, 40m, 50m, 1 h, 1h 30m, 2h, 4h, 8h post-dose

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

  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.

  0, 15m, 29m, 33m, 40m, 50m, 1 h, 1h 30m, 2h, 4h, 8h post-dose

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

  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.

  0, 15m, 29m, 33m, 40m, 50m, 1 h, 1h 30m, 2h, 4h, 8h post-dose

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

  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.

  0, 15m, 29m, 33m, 40m, 50m, 1 h, 1h 30m, 2h, 4h, 8h post-dose

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

  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.

  0, 15m, 29m, 33m, 40m, 50m, 1 h, 1h 30m, 2h, 4h, 8h post-dose

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

  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.

  0, 15m, 29m, 33m, 40m, 50m, 1 h, 1h 30m, 2h, 4h, 8h post-dose

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

  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.

  0, 15m, 29m, 33m, 40m, 50m, 1 h, 1h 30m, 2h, 4h, 8h post-dose

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

  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.

  0, 15m, 29m, 33m, 40m, 50m, 1 h, 1h 30m, 2h, 4h, 8h post-dose

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

  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.

  0, 15m, 29m, 33m, 40m, 50m, 1 h, 1h 30m, 2h, 4h, 8h post-dose

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

  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.

  0, 15m, 29m, 33m, 40m, 50m, 1 h, 1h 30m, 2h, 4h, 8h post-dose

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

  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.

  0, 15m, 29m, 33m, 40m, 50m, 1 h, 1h 30m, 2h, 4h, 8h post-dose

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

  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.

  0, 15m, 29m, 33m, 40m, 50m, 1 h, 1h 30m, 2h, 4h, 8h post-dose

Secondary Outcomes (1)

• Anti-tumor Activity

  From start of treatment assessed every 2 cycles up to 2.5 years

Study Arms (1)

Lipotecan

EXPERIMENTAL

Intravenous Lipotecan (TLC388 HCl for Injection)

Drug: Lipotecan

Interventions

Lipotecan DRUG

Lipotecan IV day 1, 8, 15

Also known as: Lipotecan (TLC388)

Lipotecan

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Adult patients defined by age ≥18 years.
• Pathologically confirmed advanced solid tumors for which standard therapy proven to provide clinical benefit does not exist or is no longer effective
• Evaluable disease, either measurable on imaging or with informative tumor marker(s), by RECIST (Response Evaluation Criteria in Solid Tumors) criteria.

You may not qualify if:

• Pregnancy or lactation. Women of childbearing potential must have a negative pregnancy test within 7 days prior to enrolment. Male and female patients of childbearing potential must agree to use appropriate birth control (barrier methods with spermicides, oral or parenteral contraceptives and/or intrauterine devices) during the entire duration of the study, or the patient must be surgically sterile (with documentation in the patient's medical records).
• Previous malignancy, except for non-basal-cell carcinoma of skin or carcinoma-in-situ of the uterine cervix, unless the tumor was treated with curative intent more than 2 years prior to study entry.
• Receipt of more than 3 prior regimens of chemotherapy.
• Chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to baseline. Receipt of radiotherapy to \>25 % of bone marrow. Major surgery within 4 weeks prior to baseline.
• Concomitant treatment with, or anticipated use of, pharmaceutical or herbal agents which are potent inhibitors or inducers of cytochrome P450 enzymes unless approved by the Sponsor.
• Uncontrolled intercurrent illness that would jeopardize patient safety, interfere with the objectives of the protocol, or limit patient compliance with study requirements, as determined by the Investigator.

Sponsors & Collaborators

• Taiwan Liposome Company: lead

Study Sites (4)

Medical College of Georgia

Augusta, Georgia, 30912, United States

Location

Bidmc, Dfci, Mgh

Boston, Massachusetts, 02215, United States

Location

Montefiore Medical Center

The Bronx, New York, 10461, United States

Location

National Taiwan University Hospital

Taipei, Taiwan

Location

MeSH Terms

Interventions

TLC 388

Results Point of Contact

• Title: Shu Chi Hsu
• Organization: Taiwan Liposome Company, Ltd.

shuchi@tlcbio.com

650-872-8816

Study Officials

• Min-Hsiung Kao

  Taiwan Liposome Company, Ltd.

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: GT60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 3, 2008
• First Posted: September 5, 2008
• Study Start: September 1, 2008
• Primary Completion: August 1, 2011
• Study Completion: December 1, 2011
• Last Updated: November 18, 2019
• Results First Posted: February 9, 2012

Record last verified: 2019-10

Locations

TW (1); US (3)