Dose-escalation Study of Intravenous Liposomal Vinorelbine Tartrate Injection in Patients With Advanced Malignancy

Study Overview
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Brief Summary
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This is a phase I/IIa, Open label, Dose-escalation Study Investigating the Safety, Tolerability, and Pharmacokinetics of Intravenous Liposomal Vinorelbine Tartrate Injection in Patients with Advanced Malignancy.

Detailed Description
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Protocol No: TLC178A1001 Name of Finished Product: LipoVNB (Liposomal Vinorelbine Tartrate) Title of Study: Phase I/IIa, Open label, Dose-escalation Study Investigating the Safety, Tolerability, and Pharmacokinetics of Intravenous Liposomal Vinorelbine Tartrate Injection in Patients with Advanced Malignancy. Study duration: Every patient will have a treatment period of 4-week cycles until completion of 6 cycles, progression of disease or intolerance, withdrawal of consent or Investigator's judgment, whichever occurs first.

Official Title
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A Phase I/IIa, Open Label, Dose-escalation Study Investigating the Safety, Tolerability, and Pharmacokinetics of Intravenous Liposomal Vinorelbine Tartrate Injection in Patients With Advanced Malignancy

Conditions
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Cancer

Intervention / Treatment
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* Drug: TLC178


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Male or female, ≥18 years of age (≥20 years of age in Taiwan) Patients with histologically/cytologically confirmed solid tumor, or lymphoma including PTCL or CTCL. Malignancies for which there is no standard therapy, or previously treated locally advanced, refractory/relapsed or metastatic disease for which local curative surgery, curable radiotherapy, or satisfactory systemic anticancer therapy is no longer available Having at least one measurable tumor ECOG Performance Status of ≤2 Women of childbearing potential must have a negative pregnancy test. Exclusion Criteria Patient with untreated or inadequate controlled brain metastases. Prior systemic standard or investigational anticancer therapy, including target therapy, chemotherapy, immunotherapy within 28 days prior to the first dose of study drug. The above mentioned conditions which the Investigator considers there is no more drug effect, such as ≥5 half-lives are permitted Prior radiotherapy within 4 weeks before screening Prior autologous stem cell transplantation within 3 months of screening and allogeneic stem cell transplantation within 6 months of screening More than 5 lines of previous cytotoxic therapies. For patients of CTCL who failed romidepsin, more than 4 lines of previous therapies Major surgery within 4 weeks prior to first administration of study drug History of myocardial infarction, unstable angina or severe congestive heart failure (New York Heart Classification Class IV) or major stroke within 3 months prior to screening period Medical history of uncontrolled but clinically significant abnormal cardiac conduction abnormalities at electrocardiogram (ECG) at screening, any history or evidence of long QT syndrome or QTcF interval >450 msec for males and >470 msec for females (according to Fridericia's correction) at screening Known HIV infection; active hepatitis B or C without concurrent treatment Coexistence of any active and uncontrolled infection Poor vital organ function defined Uncontrolled and unstable concurrent medical condition including psychiatric disorders and alcohol/substance dependence/abuse that will jeopardize the safety of the patient, interfere with the objectives of the study, or affect the patient compliance with study requirements, as determined by the Investigator Known allergy or hypersensitivity to the study drug or its components Use of strong inhibitors or inducers of cytochrome P450 enzymes CYP3A4 Pregnant or breast feeding women.

Ages Eligible for Study
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Minimum Age: 18 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: TLC178<br>Liposomal Vinorelbine | Drug: TLC178<br>* TLC178<br>* Other names: Liposomal Vinorelbine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose (MTD) determination | To determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) ofintravenous LipoVNB given every 4 weeks (Q4W) in patients with advanced malignancies. | 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics (PK) parameters of AUC (0-inf) calculated by plasma concentration of vinorelbine[ | Area under the plasma concentration time curve from zero (predose) extrapolated to infinity | from day 1 to day 29 | 
| Pharmacokinetics (PK) parameters of AUC (0-inf) calculated by plasma concentration of majormetabolite, 4-O-deacetylvinorelbine | Area under the plasma concentration time curve from zero (predose) extrapolated to infinity | from day 1 to day 29 | 
| Pharmacokinetics (PK) parameters of AUC(0 - last) calculated by plasma concentration ofvinorelbine | Area under the plasma concentration time curve from zero (predose) to the time of the lastquantifiable concentration | from day 1 to day 29 | 
| Pharmacokinetics (PK) parameters of AUC(0 - last) calculated by plasma concentration of majormetabolite, 4-O-deacetylvinorelbine | Area under the plasma concentration time curve from zero (predose) to the time of the lastquantifiable concentration | from day 1 to day 29 | 
| Pharmacokinetics (PK) parameters of Cmax calculated by plasma concentration of vinorelbine | Maximum plasma concentration observed | from day 1 to day 29 | 
| Pharmacokinetics (PK) parameters of tmax calculated by plasma concentration of vinorelbine | Time of Cmax | from day 1 to day 29 | 
| Pharmacokinetics (PK) parameters of tmax calculated by plasma concentration of major metabolite,4-O-deacetylvinorelbine | Time of Cmax | from day 1 to day 29 | 
| Pharmacokinetics (PK) parameters of t1/2 calculated by plasma concentration of vinorelbine | Apparent terminal half life | from day 1 to day 29 | 
| Pharmacokinetics (PK) parameters of t1/2 calculated by plasma concentration of 4-O-deacetylvinorelbine | Apparent terminal half life | from day 1 to day 29 | 
| Pharmacokinetics (PK) parameters of MRT(0-inf) calculated by plasma concentration of vinorelbine | Mean residence time extrapolated to infinity | from day 1 to day 29 | 
| Pharmacokinetics (PK) parameters of MRT(0-inf) calculated by plasma concentration of 4-O-deacetylvinorelbine | Mean residence time extrapolated to infinity | from day 1 to day 29 | 
| Dose exposure relationship in patients with advanced malignancies treated with single and multipledoses of LipoVNB | single and multiple dose effect | up to 6 months | 
| Number of participants with treatment-related adverse events as assessed by CTCAE v4.03 | treatment related AE | up to 6 months | 
| Incidence of Treatment-Emergent Adverse Events | TEAE percentage | up to 6 months | 
| LipoVNB antitumor activity assessed by response rate | antitumor response rate | up to 6 months | 
| LipoVNB antitumor activity assessed by duration of response | antitumor efficacy | up to 6 months | 
| Progression free survival (PFS) of patients with advanced malignancies treated with LipoVNB | PFS | up to 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Advanced Malignancy, lymphoma, TLC178