Depocyt® With Sorafenib in Neoplastic Meningitis

A Single Arm Pilot Study of Intrathecally Administered DepoCyt® With Systemic Sorafenib in the Treatment of Neoplastic Meningitis From Solid Tumors

The purpose of this study is to determine the tolerability and side effects of oral sorafenib in combination with intrathecal DepoCyt.

Study Overview

• Status: Terminated
• Conditions: Neoplastic Meningitis
• Intervention / Treatment: Drug: DepoCyt; Drug: Sorafenib

Detailed Description

After an Ommaya reservoir has been placed in the patient's head, the patient will receive DepoCyt through that reservoir every 2 weeks for 5 doses, then every 4 weeks for an additional 5 doses (a total of 10 DepoCyt treatments). Patients will also receive oral sorafenib at 400 mg twice a day throughout the treatment course until disease progression or death. Patients will receive brain magnetic resonance imaging (MRIs) with contrast (and whole spine, if necessary) and spinal fluid studies will be obtained every 8 weeks through the Ommaya reservoir until disease progression, death, or unacceptable toxicity. In addition, patients will have spinal fluid obtained to test for sorafenib levels at each study visit after the start of sorafenib as well as prior to sorafenib treatment for controls.

• Study Type: Interventional
• Enrollment (Actual): 2
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Florida
    • Tampa, Florida, United States, 33612
      • H. Lee Moffitt Cancer Center and Research Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients must have neoplastic meningitis (NM) from solid tumor malignancy (excluding metastatic melanoma, leukemia, lymphoma, or primary malignant glioma) diagnosed by: Positive cerebrospinal fluid (CSF) cytology - or - Definitive neurologic signs/symptoms of NM with positive magnetic resonance imaging (MRI) findings or supportive CSF profile.
• Adequate bone marrow, liver, and renal function as assessed by the following: Hemoglobin ≥ 9.0 g/dl, Absolute neutrophil count (ANC) ≥ 1,500/mm³, Platelet count ≥ 100,000/mm³, Total bilirubin ≤ 1.5 times upper limit of normal (ULN), alanine transaminase (ALT) and aspartate transaminase (AST) ≤ 2.5 times the ULN ( ≤ 5 x ULN for patients with liver involvement), Creatinine ≤ 1.5 times ULN, international normalized ratio (INR) < 1.5 or a prothrombin time/partial thromboplastin time (PT/PTT) within normal limits. Patients receiving anti-coagulation treatment with an agent such as warfarin or heparin may be allowed to participate. For patients on warfarin, the international normalized ratio (INR) should be measured prior to initiation of sorafenib and monitored at least weekly, or as defined by the local standard of care, until INR is stable
• Must have a Karnofsky performance score ≥ 60% (i.e. the patient must be able to care for himself/herself with occasional help from others)
• Must be healthy enough to receive ventricular access device (VAD) placement.
• Patients with a ventriculoperitoneal (VP) shunt that have an on/off device in their shunt systems are eligible for the study provided they are able to tolerate shunt closure for ≥ 4 hours without developing clinical signs of increased intracranial pressure.
• Women of childbearing potential (WOCBP) must have a negative serum pregnancy test performed within 7 days prior to the start of treatment
• WOCBP and men must agree to use adequate contraception (barrier method of birth control) prior to study entry and for the duration of study participation. Men should use adequate birth control for at least 3 months after the last administration of sorafenib.
• Ability to understand and the willingness to sign a written informed consent. A signed informed consent must be obtained prior to any study specific procedures.

Exclusion Criteria:

• Neoplastic meningitis (NM) from metastatic melanoma, leukemia, lymphoma, or primary malignant glioma
• Uncontrolled systemic disease from their primary cancer
• Must not have had prior intrathecal chemotherapy, sorafenib, or brain or spine radiation for the treatment of neoplastic meningitis.
• Concomitant therapy with high-dose systemic methotrexate, cytarabine, thiotepa, or an agent known to have penetration into the central nervous system (CNS)
• Patients with clinical evidence of obstructive hydrocephalus or compartmentalization of CSF flow as documented by radioisotope Indium (Technetium-DTPA when Indium unavailable) flow study are not eligible for this trial. If patients have evidence of cerebrospinal fluid (CSF) flow blockage that is subsequently proven to be relieved after focal radiation therapy (XRT), they can enroll immediately after repeat flow study shows block to be relieved.
• Use of any investigational drug within 28 days prior to study entry.
• Patients with a life expectancy of ≤ 2 months
• Cardiac disease: Congestive heart failure > class II New York Heart Association (NYHA). Must not have unstable angina or new onset angina (began within the last 3 months)or myocardial infarction within past 6 months.
• Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy.
• Uncontrolled hypertension defined as systolic blood pressure > 150 mmHg or diastolic pressure > 90 mmHg, despite optimal medical management.
• Known human immunodeficiency virus (HIV) infection or chronic Hepatitis B or C.
• Active clinically serious infection > Common Terminology Criteria for Adverse Events (CTCAE) Grade 2.
• Thrombolic or embolic events such as a cerebrovascular accident including transient ischemic attacks within past 6 months.
• Pulmonary hemorrhage/bleeding event ≥ CTCAE Grade 2 within 4 weeks of first dose of study drug.
• Any other hemorrhage/bleeding event ≥ CTCAE Grade 3 within 4 weeks of first dose of study drug.
• Serious non-healing wound, ulcer, or bone fracture.
• Evidence or history of bleeding diathesis or coagulopathy
• Major surgery, open biopsy or significant traumatic injury within 4 weeks of first study drug.
• Use of St. John's Wort or rifampin.
• Known or suspected allergy to sorafenib or any agent given in the course of this trial.
• Any condition that impairs patient's ability to swallow whole pills.
• Any malabsorption problem.
• Patients who are pregnant or breast-feeding.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

EXPERIMENTAL: Intrathecal DepoCyt and Oral Sorafenib; This is a single arm pilot study. Investigators planned to enroll approximately 10 patients to receive concurrent intrathecal DepoCyt and oral Sorafenib. DepoCyt: through a reservoir every 2 weeks for 5 doses, then every 4 weeks for an additional 5 doses (a total of 10 DepoCyt treatments). Oral Sorafenib: at 400 mg twice a day throughout the treatment course until disease progression or death.

Drug: DepoCyt; Patients were to receive DepoCyt through a reservoir every 2 weeks for 5 doses, then every 4 weeks for an additional 5 doses.; Other Names: Liposomal Cytarabine; cytarabine liposome injection; Drug: Sorafenib; Patients received oral sorafenib at 400 mg twice a day; Other Names: BAY 43-9006; Nexavar; oral multi-kinase inhibitor

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Adverse Events (AEs)	Safety and tolerability of sorafenib with DepoCyt. Toxicities were to be reported using tables and descriptive statistics by type and grade. All patients were to be followed up until death.	6 Months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Progression Free Survival (PFS) at 6 Months	Kaplan-Meier analysis of PFS was to be performed and the PFS at 6 months in the study patients were be empirically described. All patients were to be followed up until death.	6 Months
Number of Participants With Overall Survival (OS)	Several secondary endpoints were to be analyzed in a descriptive fashion. All patients were to be followed up until death.	6 Months
Sorafenib Levels in Cerebrospinal Fluid (CSF)	CSF sorafenib level was to be measured over time, and the means and standard errors of the sorafenib level were to be plotted at specific sampling time points. CSF sorafenib levels may also have been correlated with patients' PFS, OS, or cytology using descriptive statistical methods (e.g., KM analysis stratified by high vs. low CSF sorafenib levels). The log transformation of lab values were to be employed on the continuous variables whenever necessary.	6 Months
CSF and Serum Vascular Endothelial Growth Factor (VEGF) Levels	CSF and serum VEGF levels were to be measured over time, and the means and standard errors of the respective VEGF levels were to be plotted at specific sampling time points. The respective VEGF levels may also have been correlated with patients' PFS, OS, or cytology using descriptive statistical methods similarly as mentioned above. The log transformation of lab values were to be employed on the continuous variables whenever necessary.	6 Months

Collaborators and Investigators

• Sponsor: H. Lee Moffitt Cancer Center and Research Institute
• Collaborators: Bayer

Publications and helpful links

Helpful Links

• Moffitt Cancer Center Clinical Trials website

Study record dates

Study Major Dates

• Study Start: August 1, 2009
• Primary Completion (ACTUAL): February 1, 2011
• Study Completion (ACTUAL): February 1, 2011

Study Registration Dates

• First Submitted: August 24, 2009
• First Submitted That Met QC Criteria: August 24, 2009
• First Posted (ESTIMATE): August 25, 2009

Study Record Updates

• Last Update Posted (ESTIMATE): September 9, 2013
• Last Update Submitted That Met QC Criteria: September 4, 2013
• Last Verified: January 1, 2012

More Information

Terms related to this study

• Keywords: Breast Cancer; Brain and Nervous System; Neurologic Oncology; Neoplastic Meningitis from solid tumors
• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Neoplasms; Neoplasms by Site; Central Nervous System Neoplasms; Nervous System Neoplasms; Meningeal Neoplasms; Meningitis; Meningeal Carcinomatosis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protein Kinase Inhibitors; Sorafenib; Cytarabine
• Other Study ID Numbers: MCC-15783; Bayer IST000266 (OTHER: Bayer)