Pharmacokinetic Study of Liposomal Vincristine in Patients With Malignant Melanoma & Hepatic Dysfunction

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to see how vincristine, when placed in an oil droplet called a liposome (VSLI), is absorbed, distributed (moved around) and excreted from the the body (pharmacokinetics). This study will also assess the safety of VSLI and to see if VSLI will slow the growth or shrink tumors in patients with metastatic melanoma that has resulted in liver impairment, and who have relapsed after previous therapies.

Detailed Description
-----------------
OBJECTIVES: Primary: To assess the pharmacokinetics of VSLI administered intravenously to patients with malignant melanoma and hepatic dysfunction secondary to metastases. Secondary: To assess the safety and antitumor activity of VSLI in this population.

Official Title
-----------------
An Evaluation of the Pharmacokinetic Profile of VSLI (Vincristine Sulfate Liposome Injection, 0.16 mg/mL) in Patients With Malignant Melanoma and Hepatic Dysfunction Secondary to Metastases

Conditions
-----------------
Malignant Melanoma

Intervention / Treatment
-----------------
* Drug: Vincristine Sulfate Liposomes Injection


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients must have histologically confirmed, surgically nonresectable Stage III or IV metastatic cutaneous, mucosal, or choroidal melanoma, and not be eligible for a treatment protocol of a higher priority. Patients must have secondary tumor involvement of the liver confirmed by CT scan and a bilirubin level of 1.6-3.0 mg/dL (National Cancer Institute, Common Terminology Criteria for Adverse Events Grade 2) (MD Anderson Cancer Center normal range is 0-1.0 mg/dL). Patients must have bidimensionally measurable disease. Patients with nonchoroidal melanoma must have received prior chemotherapy for metastatic disease with cytotoxic or biological drugs. Patients with choroidal melanoma may or may not have received prior chemotherapy for metastatic disease with cytotoxic or biological drugs. Patients must have a Performance Status of 0, 1, 2, or 3 (Zubrod Scale). Patients must have recovered from the adverse effects of prior chemotherapy (including cytotoxic agents and biological response modifiers), and/or irradiation therapy. Patients must have an absolute neutrophil count ≥1.0 x 10*9/L and a platelet count of ≥100 x 10*9/L. Patients must have adequate renal function demonstrated by a creatinine level of ≤2.0 mg/dL. Patients must have a life expectancy of >8 weeks. Patients must provide a signed informed consent document indicating that they are aware of the investigational nature of this study in keeping with the policies of the hospital. Exclusion Criteria: Patients treated with radiotherapy, chemotherapy, immunotherapy, vaccine treatment and/or alternative anticancer treatments (including investigational drugs) within 3 weeks prior to study enrollment. Patients treated with hepatic chemo-embolization within 4 weeks prior to study enrollment. Patients with severe hepatic impairment demonstrated by plasma ammonia levels >105 mMol/L or serum albumin <2.0 g/dL or serum bilirubin >3.0 mg/dL. Patients with serious intercurrent illness. Patients who have had major surgery within 4 weeks of enrollment. Patients with advanced symptomatic central nervous system (CNS) involvement by melanoma and those on phenytoin or requiring steroids for brain metastases, spinal cord compression, or meningeal carcinomatosis.Patients with asymptomatic and stable metastatic CNS disease can be enrolled. Patients receiving treatment with phenytoin and/or corticosteroids within 1 week of enrollment. Patients must remain off of these medications for the duration of the treatment phase of the study. Patients with a history of neurological disorders unrelated to chemotherapy (including familial neurological diseases and acquired demyelinating disorders). Patients with Grade 3 or greater sensory, motor or autonomic neuropathy at screening from any cause. Patients receiving treatment with drugs known to inhibit or induce hepatic drug metabolism by cytochrome P450-3A4 isoenzymes and/or P-glycoprotein within 1 week of study enrollment. Patients must remain off of these drugs until the collection of the Cycle 4 pretreatment PK sample. Patients with past or current history of liver parenchymal or hepatobiliary disease unrelated to cancer (including but not limited to conditions such as liver cirrhosis, acute/chronic hepatitis, ascending cholangitis, etc). Patients who are pregnant or lactating. Females of childbearing potential must have a negative urine or blood pregnancy test at screening. Both men and women must be practicing an adequate method of birth control for the duration of the study. Acceptable methods of birth control include use of an intrauterine device (IUD), oral contraceptive pills, implanted, transdermal, or injected contraceptives, barrier methods with spermicide, and abstinence. Patients who are unable to return for follow up re-evaluation and assessment of response to VSLI.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: VSLI<br>Single armed study; all subjects received VSLI | Drug: Vincristine Sulfate Liposomes Injection<br>* Marqibo (VSLI) 1.0 mg/m2 delivered by intravenous infusion over 1 hour every 2 weeks.<br>* Other names: Marqibo;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| T 1/2 | The PK profiles of total plasma VCR following a single intravenous infusion at a target dose of 1.0 mg/m2 for approximately 1 hour every 2 weeks (one cycle) to three male and four female subjects with malignant melanoma and hepatic dysfunction secondary to metastases were measured. | cycle 1 day 1 | 
| Clearance | The pharmacokinetic profile of VCR on Day 1 of Cycle 1 Cl is mL/h/m2 | Day 1 of Cycle 1 | 
| Volume of Distribution | The PK profiles of total plasma VCR following a single intravenous infusion at a target dose of 1.0 mg/m2 for approximately 1 hour | cycle 1 day 1 |