Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Nervous System Diseases

Symptoms and General Pathology

Breast Neoplasms

Meningeal Carcinomatosis

Meningitis

Neuroinflammatory Diseases

Meningeal Neoplasms

Central Nervous System Neoplasms

Nervous System Neoplasms

Anti-Infective Agents

Antineoplastic Agents

All Drugs and Chemicals

Cytarabine

Sorafenib

Antimetabolites

Antiviral Agents

Immunosuppressive Agents

Immunologic Factors

Protein Kinase Inhibitors

Enzyme Inhibitors

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.

Patients were to receive DepoCyt through a reservoir every 2 weeks for 5 doses, then every 4 weeks for an additional 5 doses.

DepoCyt

Patients received oral sorafenib at 400 mg twice a day

Edward Pan, M.D.

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

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.

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

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.

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.

Several secondary endpoints were to be analyzed in a descriptive fashion. All patients were to be followed up until death.

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.

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.

Bayer

H. Lee Moffitt Cancer Center and Research Institute

First On Study (9/10/09) to last Off Study (5/18/10)

Intrathecal DepoCyt and Oral Sorafenib

Age, Categorical

Sex: Female, Male

United States

Region of Enrollment

The study closed early due to low accrual of 2 of 10 expected patients. Neither patient completed 8 weeks of treatment as outlined in the protocol. Both patients expired before reaching the 6 month Progression Free Survival endpoint.

Number of Participants With Adverse Events (AEs)

Number of Participants With Progression Free Survival (PFS) at 6 Months

Number of Participants With Overall Survival (OS)

Sorafenib Levels in Cerebrospinal Fluid (CSF)

CSF and Serum Vascular Endothelial Growth Factor (VEGF) Levels

Overall Study

Brain Diseases

Central Nervous System Diseases

Brain Neoplasms

Antibodies

Antibodies, Monoclonal

Bevacizumab

Immunoglobulins

Antineoplastic Agents, Immunological

Angiogenesis Inhibitors

Growth Inhibitors

Bevacizumab 10 mg/kg by vein over about 1 hour, every 2 weeks.

10 mg/kg by vein over about 1 hour, every 2 weeks.

Ivo D. Tremont, MD

The goal of this clinical research study is to learn if and how Avastin (bevacizumab) may affect cancer that has spread to the meninges of the brain or the spinal cord. The safety of this drug will also be studied.

Objectives:

1. Primary:

1. Determine preliminary response data of intravenous bevacizumab in patients with NM

a. As measured by clearance of malignant cells from the Cerebrospinal fluid (CSF) at 2, 4, 6, 12, 18, and 24 weeks, then every 8 weeks up to 54 weeks, and

b. Time to neurological progression (TTNP)

2. Secondary:

1. Evaluate the safety of intravenous bevacizumab in patients with NM
2. Further describe the efficacy of this intervention as measured by

   1. improvement of MR imaging evidence of disease
   2. overall survival
   3. maintenance of quality of life
3. Determine effects of systemically administered bevacizumab on CSF, serum, and urine Vascular endothelial growth factor (VEGF)levels levels
4. Correlate changes in CSF VEGF with response measurements.
5. Correlate primary tumor tissue VEGF expression with CSF VEGF levels
6. Correlate urine VEGF levels with serum and CSF VEGF levels
7. Evaluate serum and CSF VEGF index

The Study Drug:

Bevacizumab is designed to prevent or slow down the growth of cancer cells by blocking the growth of blood vessels.

Study Drug Administration:

If you are found to be eligible to take part in this study, every 2 weeks, you will receive bevacizumab by vein over about 1 hour.

Study Visits:

At Weeks 2 and 4:

* Samples of CSF from your spinal cord will be collected to check for the presence of cancer cells.
* Blood (about 3 tablespoons) will be drawn for routine tests and to check your blood's ability to clot normally.
* If you already have an Ommaya reservoir tap in place, samples of CSF from your brain will be collected to look for the presence of cancer cells.
* You will be asked about any drugs you may be taking and if you have experienced any side effects.
* You will have a neurological exam.

At Weeks 6, 12, 18, and 24, and then every 8 weeks:

* Samples of CSF from your spinal cord will be collected to check for the presence of cancer cells.
* Blood (about 3 tablespoons) will be drawn for routine tests and to check your blood's ability to clot normally.
* If you already have an Ommaya reservoir tap in place, samples of CSF from your brain will be collected to look for the presence of cancer cells.
* You will have a physical exam (Weeks .
* Your performance status will be recorded.
* You will be asked about any drugs you may be taking and if you have experienced any side effects.
* You will have a neurological exam.
* You will complete the questionnaire about your quality of life.
* You will have an MRI scan to check the status of the disease.
* Urine will be collected to test kidney function and for routine tests. If indicated urine will be collected over a 24 hour period.

Every 2 weeks, your blood pressure will be measured.

Length of Study:

You will be on study for up to 54 weeks (about 1 year). You will be taken off study early if the disease gets worse or you experience intolerable side effects.

End-of-Study Visit:

If you go off study early, the following tests and procedures will be performed:

* You will have a physical exam.
* Your performance status will be recorded.
* You will have a neurological exam.
* Samples of CSF from your spinal cord will be collected to look for the presence of cancer cells.
* Blood (about 3 tablespoons) will be drawn for routine tests and to check your blood's ability to clot normally. You will complete the questionnaire about your quality of life.
* If you already have an Ommaya reservoir tap in place, samples of CSF from your brain will be collected to look for the presence of cancer cells.

Follow-up Visits:

If you do not go off study early, within 4 weeks after the last dose of study drug, every 4 weeks for 3 months, and then every 3 months from then on, you will have follow-up visits. The following tests and procedures will be performed:

* You will have a physical exam.
* Your performance status will be recorded.
* You will have a neurological exam.
* Samples of CSF from your spinal will be collected to look for the presence of cancer cells.
* Blood (about 3 tablespoons) will be drawn for routine tests and to check your blood's ability to clot normally.

You will have an MRI scan to check the status of the disease.

-If you already have an Ommaya reservoir tap in place, samples of CSF from your brain will be collected to look for the presence of cancer cells.

This is an investigational study. Bevacizumab is FDA approved and commercially available for the treatment of colon, breast, and lung cancer. Its use for the treatment of cancer that has spread to the meninges of the brain or the spinal cord is investigational.

Up to 25 patients will take part in this study. All will be enrolled at MD Anderson.

A Pilot Study of Bevacizumab for Neoplastic Meningitis

A Pilot Study of Systemically Administered Bevacizumab in Patients With Neoplastic Meningitis (NM)

Neoplastic meningitis is considered an unmeasurable metastatic site by Response Evaluation Criteria in Solid Tumors (RECIST), and as such no standardized methodologies are routinely used; therefore response assessed from cerebrospinal fluid (CSF) obtained via lumbar puncture (and from ventricular reservoir if present) and analyzed for malignant cells along with reference recording of magnetic resonance imaging (MRI) of areas of enhancement over time; however, MRI alone in LMD/NM is considered non-evaluable by RECIST criteria. Those participants with only MRI criteria for enrollment, but who later develop CSF positivity after enrollment were declared "progressors" based on the CSF criteria.

CSF response for participants with Neoplastic Meningitis (NM) or leptomeningeal disease (LMD) defined as conversion from positive to negative cytology or cytometry as measured routinely by total clearance of malignant cells from the CSF where assessments performed from 2 weeks up to week 54 of treatment. Clearance of malignant cells determined by standard clinical testing using cytospin analysis in clinical laboratory. Percentage reflects number of participants of total treated with no response, e.g. participants with continued positive CSF cytology or flow cytometry.

Time to Progression defined as time to disease progression measured from date of enrollment, confirmation of disease progression via laboratory testing; Time to neurological progression (TTNP) reflects worsening clinical signs/symptoms or development of new clinical signs/symptoms which investigator feels can be attributed to leptomeningeal disease progression and are severe enough to warrant a change in therapy.

Genentech, Inc.

M.D. Anderson Cancer Center

Of the twenty participants, five were not treated and therefore are not included in the adverse event reporting.

Age, Continuous

John F de Groot, Professor, Neuro-Oncology

Of the 20 registered, 5 were screening failures therefore are not included in the analysis.

Cerebrospinal Fluid (CSF) Response Rate: Percentage of Participants Positive for Tumor Cells

TTNP

Median Time to Progression (TTP) and Median Time to Neurological Progression (TTNP)

No Change/Stable Disease (SD)

Progressive Disease (PD)

Complete Remission (CR)

Participant Response: Cerebrospinal Fluid (CSF) Examination

Blood and Lymph Conditions

Immune System Diseases

Rare Diseases

Recurrence

Lymphoma

Leukemia

Lymphosarcoma

4.8 mg/m\^2 by vein Over 2 Hours On Days 1-3.

RTA 744

Morris D. Groves, MD

1. The primary objectives of this study are:

   1. To determine the tolerability of RTA 744 Injection in patients with leptomeningeal disease (LMD) secondary to any type of primary tumor.
   2. In a selected group of 6-10 patients who will receive RTA 744 at or near the maximum tolerated dose (MTD), to characterize the multiple-dose pharmacokinetics of RTA 744 in plasma and CSF.
2. The secondary objectives of this study are:

   1. To document any potential antitumor activity of RTA 744 in this patient population.
   2. To correlate pharmacokinetic information with clinical (efficacy and safety) responses, as a possible help in selecting appropriate doses for later studies.

RTA 744 is designed to enter the spinal fluid and kill cancer cells both in the spinal fluid and in the rest of body.

Before you can start receiving the study drug, you will have "screening tests." These tests will help the doctor decide if you are eligible to take part in this study. Your complete medical history will be recorded. You will be asked about any drugs you have taken and are taking. You will have a physical exam, including measurement of vital signs (blood pressure, heart rate, temperature, and breathing rate). You will have a neurological exam. Blood (about 2 tablespoons) will be drawn for routine tests. This routine blood draw will include a pregnancy test for women who are able to have children. To be eligible to take part in this study, the pregnancy test must be negative. Urine will be collected over a 24-hour period to test kidney function and for routine tests. You will have a magnetic resonance imaging (MRI) scan of the brain and spine.

You will have a chest x-ray. You will be asked questions about your ability to perform daily activities (performance status evaluation). You will have an electrocardiogram (ECG -- a test that measures the electrical activity of the heart). You will have either a multiple gated acquisition scan (MUGA) or an echocardiogram to check your heart's health. Samples (1 1/2 teaspoons) of cerebrospinal fluid from your spine and brain will be collected to look for the presence of cancer cells. The spinal sample will be collected through a lumbar puncture (spinal tap). The other sample will be taken from your brain through an Ommaya Reservoir tap. Radioactive dye will be injected into the CSF to make sure the CSF flows freely throughout the spinal canal. This is called an Indium-111 DPTA or Technetium 99m-DPTA Flow Study.

If you are found to be eligible to take part in this study, you should receive the same dose of RTA 744 throughout the study. The amount of study drug you receive will be determined by when you begin the study. Every 21 days on study is considered 1 study "cycle." If you have intolerable side effects, the drug dosing for the next cycle may be delayed for up to 21 days to allow any symptoms or side effects to resolve. You may be given a lower dose level.

The first participant on this study will receive the dose that has been found to be well-tolerated in an ongoing study involving participants with primary brain tumors. After this participant has completed 1 study cycle, the next participant will be given a higher dose of RTA 744. Each new participant will receive a higher dose level until a patient has an intolerable side effect. When this happens, at least 2 more participants will be given the dose level that causes the intolerable side effect. If there are no further intolerable side effects to RTA 744, the next group of 3 participants will be given the next higher dose of RTA 744. Each time, the dose of RTA 744 will not be increased until the effects of the previous dose level have been studied. Doses will increase with each group of patients until the highest tolerable dose is found.

On Day 1 Cycle 1, before you receive the first dose of RTA 744, you will have a physical exam, neurological exam, and a performance status evaluation. If the screening neurological exam was performed less than 1 week before Day 1, the neurological exam will not need to be repeated. You will also be asked about any drugs, treatments, or herbal medicines you are taking. You will be asked how you are feeling and if whether you are experiencing any symptoms or side effects. Blood (less than 2 tablespoons) and urine will be collected for routine tests, unless blood and urine were collected for screening within the past 72 hours.

After completion of these tests, you will receive RTA 744 through a needle in your vein over a 2-hour period on Days 1-3. You must remain in the clinic for 2 hours after the drug is given to make sure you are not having any side effects.

During Cycle 1, you will be asked to return to the clinic once a week for 3 weeks. At these visits, blood (less than 2 tablespoons) will be drawn for routine tests. You will be asked how you are feeling and whether you are having any side effects.

On Day 21, you will have a neurologic exam.

Before receiving the study drug on Day 1 of Cycles 2-18, you will have a physical exam, neurological exam, and a performance status evaluation. You will also be asked about any drugs, treatments, or herbal medicines you are taking. Blood (less than 2 tablespoons) and urine will be collected for routine tests. You will have an ECG. Before Cycles 4, 6, 8, 10, 12, 14,16, and 18, you will have a MUGA scan or an echocardiogram. Once you have completed the tests, you will receive the study drug in the same manner as Cycle 1.

During Days 1-3, you will be asked how you are feeling and to report any symptoms or side effects you may have noticed during or after receiving RTA 744.

On Day 15, blood (about 3 teaspoons) will be drawn for routine tests. This blood draw may be performed by an outside laboratory. If no clinic visit is scheduled on Day 15, you will be contacted by telephone to find out if you have experienced any side effects. This phone call should last less than 5 minutes.

On Day 21, blood (less than 2 tablespoons) will be drawn for routine tests.

One time (per cycle) between Day 15 and Day 21 of Cycles 2, 4, 6, 8, 10, 12, 14, 16, and 18, a sample (about 2 teaspoon each time) of CSF will be collected from your spine through a spinal tap, and from your brain through an Ommaya Reservoir tap. This will be done in order to look for cancer cells. You will also have an MRI of the brain and spine.

An ECG will be performed during the last week of all cycles. A MUGA scan or an echocardiogram will be performed during the last week of Cycles 4, 6, 8, 10, 12, 14, 16, and 18.

You will have an MRI within 1 week of the end of the last cycle.

You may remain on study for up to 18 cycles (13 months). You will be taken off study if the disease gets worse or intolerable side effects occur.

Once you are off study, you will have an end-of-study visit. At this visit, your complete medical history will be recorded. You will be asked about any drugs you have taken and are taking. You will have a physical exam, including measurement of vital signs. You will have a neurological exam. Blood (about 2 tablespoons) will be drawn for routine tests. Urine will be collected over a 24-hour period to test kidney function and for routine tests. You will have an MRI of the brain and spine.

You will have a chest x-ray. You will have a performance status evaluation. You will have ECG and MUGA scans or echocardiogram. Samples (1 1/2 teaspoons each) of cerebrospinal fluid from your spine and brain will be collected to look for the presence of cancer cells. The spinal sample will be collected through a spinal tap. The other sample will be taken from your brain through an Ommaya Reservoir tap. Radioactive dye will also be injected into the CSF to make sure the CSF flows freely throughout the spinal canal.

THIS IS AN INVESTIGATIONAL STUDY. RTA 744 is not FDA approved or commercially available. It has been authorized for use in research only.

Up to 18 patients will take part in this study. All will be enrolled at M. D. Anderson.

RTA 744 Injection in Patients With Leptomeningeal Disease

A Phase I Safety and Pharmacokinetic Study of Intravenous RTA 744 Injection in Patients With Recurrent, Progressive or Refractory Neoplastic Meningitis

Reata Pharmaceuticals, Inc.

Gemcitabine

Intrathecal gemcitabine will be given on a weekly schedule for the first cohort of patients at the 5 mg dose level and then a twice-weekly (i.e., every 3 to 4 days) schedule. Drug administration will be by the intraventricular (Ommaya reservoir injection) route.

Patients will be hospitalized overnight following their first dose of gemcitabine. If the first dose is well tolerated, subsequent induction doses may be administered in the outpatient setting with close observation for a minimum of 2 hours after administration.

Dose Levels and Dose Escalation:

Dose Level 1a: 5 mg

Dose Level 1b: 5 mg

Dose Level 2: 10 mg

Dose Level 3: 20 mg

Dose Level 4: 30 mg

Dose Level 5: 40 mg

Dose Level 6: 50 mg

Schedule

Induction: At Dose Level 1athe first cohort of patients will receive intrathecal gemcitabine on a weekly basis for a total of 6 weeks. If that is tolerated, the subsequent cohort will receive intrathecal gemcitabine on a twice-weekly basis (Dose Level 1b) for a total of 6 weeks. Subsequent cohorts (Dose Levels 2 - 6) will receive intrathecal gemcitabine on a twice weekly basis for a total of 6 weeks (12 doses).

In the absence of disease progression or DLT, patients may proceed to consolidation.

Consolidation: Intrathecal gemcitabine will be administered weekly for a total of 6 doses. The first dose of consolidation will be given 1 week after the last induction dose. In the absence of disease progression or DLT, patients may proceed to maintenance.

Maintenance: Intrathecal gemcitabine will be given twice monthly for 4 months and monthly thereafter. In the absence of progressive disease or dose-limiting toxicity, the total duration of therapy will be 1 year.

Susan Blaney, MD

Subject's are being asked to take part in this study because he or she has a type of cancer that has spread to the meninges (tissues that cover the brain and spinal cord).

There is no known effective treatment for this specific disease or the subject has received all of the treatments that are known to work for his or her specific disease without success. Currently, there is no other effective treatment for this type of cancer.

The purposes of this study are:

* to determine the highest dose of gemcitabine, an anti-cancer drug, that can safely be given directly into the spinal fluid of children and adults whose cancer no longer responds to standard treatment;
* to find out what effects (good and bad) gemcitabine has when given directly into the cerebrospinal fluid (called intrathecal administration) in children and adults with neoplastic meningitis (cancer that has spread to the lining of the brain and spinal cord);
* to determine if gemcitabine is beneficial to the patient;
* to understand how gemcitabine is handled by the body after intrathecal administration.

WHAT IS INVOLVED IN THE STUDY? Before participating in this study, there will be a screening process.

Administration:

Gemcitabine will be received directly into the cerebrospinal fluid (fluid that circulates around the brain and spinal cord) through an Ommaya reservoir (or other similar type of reservoir). An Ommaya reservoir is a surgically implanted catheter that is used to inject medication or to withdraw cerebrospinal fluid from the fluid chambers in the head.

All patients will be hospitalized overnight following their first dose of gemcitabine. If the first dose is well tolerated, further doses of gemcitabine will be administered in the outpatient clinic with close observation for a minimum of 2 hours after administration.

Weeks 1-6 Cohort 1a (first three patients):

Gemcitabine will be given once a week for 6 weeks. Patients may continue therapy if the disease has not worsened.

Weeks 1-6 (all other patients enrolled on this study):

Gemcitabine will be given twice a week for 6 weeks. Patients may continue therapy if the disease has not worsened.

Weeks 7-12:

Gemcitabine will be given once a week for 6 weeks.

Weeks 13-29 (approximately):

Gemcitabine will be given twice monthly for 4 months.

Weeks 30-52 (approximately):

Gemcitabine will be given monthly for the duration of the study.

For safety reasons, the first patients treated in the study will receive a low dose of gemcitabine. If that dose does not cause severe side effects, the next group will receive a higher dose of gemcitabine than given to the earlier group, or may receive a lower dose if side effects occur. In addition, the first three patients treated on this study will receive the gemcitabine once weekly. If this is tolerated, subsequent patients will receive the medication twice weekly.

Following the first dose of gemcitabine investigators would like to draw special blood and spinal fluid samples to help learn how much of the drug is in the blood and spinal fluid. These studies are called pharmacokinetics. A total of 10 samples will be collected. The blood samples may be collected from an intravenous catheter or a central venous catheter. The spinal fluid samples may be collected either via Ommaya reservoir or lumbar reservoir.

In addition to intrathecal gemcitabine, the patient may receive other chemotherapy, not given directly into the fluid surrounding the brain and spine, as recommended by his or her doctor for the treatment or prevention of cancer outside the lining of the brain and spinal cord.

The maximum length of treatment with gemcitabine is one year. However, at the end of the study, monthly check-ups are required to monitor the disease and to make sure that any side effects from the study drug have stopped.

Intrathecal Gemcitabine to Treat Neoplastic Meningitis, IT Gemcitabine

Intrathecal Gemcitabine Therapy for Neoplastic Meningitis: A Phase I and Pharmacokinetic Study

The MTD of IT gemcitabine will be that dose at which less than 20% of patients experience DLT as defined earlier. Escalations are planned in groups of three patients, with an additional three patients to be added at the first indication of DLT.

University of Pittsburgh

National Cancer Institute (NCI)

Children's Hospital of Pittsburg

Seattle Children's Hospital

Mayo Clinic

Brown University

Baylor College of Medicine

Professor of Pediatrics-Hem-Oncology

Lymphoma, B-Cell

Neoplasms by Histologic Type

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Lymphoma, Non-Hodgkin

B-cell Lymphoma

50 mg intrathecal every 14 days for 8 doses, then every 28 days for six doses

cytarabine liposome injection

David Rizzieri, MD

The purpose of this study is to determine the response rate of lymphomatous meningitis or leukemic meningitis to DepoCyt. The safety of DepoCyt, the number of people who respond well to the study drug, and the response of symptoms to the study drug will also be determined.

DepoCyt is a sustained-release formulation of the chemotherapy drug, cytarabine (Ara-C), which is used for the treatment of patients with lymphomatous or leukemic meningitis, a complication of lymphoma/leukemia that is characterized by the spread of cancer to the central nervous system.

DepoCyt is introduced into the spinal fluid, through a needle inserted into the spinal canal or through a reservoir placed under the scalp by a neurosurgeon. DepoCyt will be given every two weeks i.e. week 1 and week 3 initially. After the second dose, a lumbar puncture will be done to check the spinal fluid for cancer cells. If there has been a good response, DepoCyt will be given every 14 days for 6 doses i.e., weeks 5, 7, 9, 11, 13, 15 and then every 28 days for six doses i.e., weeks 19, 23, 27, 31, 35, and 39. Blood tests and lumbar punctures will be done throughout the study.

DepoCyt for Active Lymphomatous or Leukemic Meningitis

Phase II Study of Intrathecal Therapy With DepoCyt for Active Lymphomatous or Leukemic Meningitis

To evaluate response rate using intrathecal DepoCytTM in two cohorts of patients, one with active lymphomatous meningitis and another with active leukemic meningitis.

Enzon Pharmaceuticals, Inc.

Duke University

Subjects with Lymphomatous or Leukemic Meningitis.

All Subjects

Lymphomatous

Leukemic

Total

Adverse events for both arms, lymphomatous and leukemic, were combined due to low accrual and early study termination.

Dr. David Rizzieri

Primary outcome measure was not assessed due to early study termination.

Response Rate

Time to Neurologic Progression

Topotecan

Topoisomerase I Inhibitors

Induction (4 weeks): Patients will receive IT topotecan for 5 consecutive days during weeks 1 and 3.

The Induction period is the first 4 weeks of therapy.

Consolidation (6 weeks): Patients will receive IT topotecan for 5 consecutive days during weeks 1 and 4. The Consolidation period is 6 weeks in duration. Consolidation begins immediately after completion of the 4th week of Induction.

Maintenance (4 weeks for 11 courses): Patients will receive IT topotecan for 5 consecutive days during week 1. Each course of Maintenance is 4 weeks in duration. Maintenance begins immediately after completion of the 6th week of Consolidation.

1. To find the optimal dose of topotecan that can safely be given directly into the spinal fluid (called intrathecal administration) of children whose cancer has spread to the lining of the brain and/or spinal cord.
2. To find out what effects (good and bad) topotecan has when given directly into the cerebrospinal fluid in children with neoplastic meningitis (cancer that has spread to the lining of the brain and spinal cord).

   * Cerebrospinal fluid is the fluid that circulates around the brain and spinal cord.
3. To determine if intrathecal topotecan is beneficial to patients.
4. To better understand how topotecan is handled by the body after intrathecal administration.
5. To evaluate the cerebrospinal fluid for signs (markers) of tumor spread.

This is a multi-center, non-randomized pharmacokinetically-guided optimal dosing study of intraventricular topotecan in children with neoplastic meningitis. Topotecan will be administered daily for five consecutive days utilizing the schema shown in the Schema below. Concomitant chemotherapy to control systemic disease or bulk CNS disease is allowable provided that the systemic chemotherapy is not an investigational agent or one of the following: high-dose methotrexate (\> 1g/m2), high-dose cytarabine (\> 1g/m2), 5-fluorouracil, capecitabine, thiotepa, a nitrosourea, or topotecan. The starting dose for this trial was derived from pharmacokinetic simulations that utilized data from a prior phase I study of intrathecal topotecan. The simulations were performed to estimate the length of time that ventricular CSF concentrations of topotecan lactone would remain above an optimal "target level" of 1 ng/mL. One of the primary objectives of this study is to estimate the dose of intrathecal topotecan that will result in CSF lactone concentrations exceeding 1 ng/mL for at least eight hours after an intrathecal injection. Dose escalations for patient cohorts will be conducted following the traditional phase 1 design in order to determine the maximum tolerated dose (MTD). The MTD will be called pharmacokinetically optimal if that dose achieves the targeted PK parameter in at least 23 of 25 patients treated at that dose level.

Phase 1 Intrathecal Topotecan for Neoplastic Meningitis

A Phase I Pharmacokinetic Optimal Dosing Study of Intrathecal Topotecan for Children With Neoplastic Meningitis

GlaxoSmithKline

Professor of Pediatrics

Temozolomide

Antineoplastic Agents, Alkylating

Alkylating Agents

DepoCyt Starting 50 mg Intrathecal Day 1 every 14 days for 12 weeks (6 treatments), then every 28 days for 40 weeks (10 treatments). Temozolomide 100 mg/m\^2 by mouth daily for 7 days every 14 days.

Starting dose of 50 mg Intrathecal on Day 1 every 14 days for a total of 12 weeks (6 treatments). After the first 12 weeks, 50 mg Intrathecal on Day 1 every 28 days for 40 weeks (10 treatments).

100 mg/m\^2 (capsules) by mouth daily for 7 consecutive days every 14 days.

Objectives:

- To determine the safety, tolerability and maximum tolerated dose (MTD) of oral temozolomide using a 7 days on and 7 days off regimen combined with intrathecal liposomal cytarabine (DepoCyt) in patients with neoplastic meningitis from solid tumors and systemic lymphoma.

Liposomal cytarabine is a slow-release formulation of cytarabine or Ara-C. It is designed to slowly release cytarabine to increase exposure of cancer cells to the drug in the treatment of leptomeningeal disease. Temozolomide is a chemotherapy drug that is designed to attach to the DNA of rapidly dividing cells (cancer cells). The cells recognize this and self-destruct.

Tests called an Indium-111 or Technetium 99m-DPTA CSF flow study, where radioactive dye is injected into the CSF, will be done to make sure the CSF flows freely throughout the spinal canal. These are done as part of the screening evaluation. If the flow study is okay, you will be eligible to take part in this study. But if there is a block of the CSF pathway, the area may be treated (usually with radiation) and then you can be re-evaluated and may still be enrolled in the study if a repeat flow study shows that the block has been cleared.

If you have a ventriculoperitoneal (VP) or ventriculoatrial (VA) shunt in place, you will have a shunt closure test in which your shunt system will be closed and you will be monitored for 4 hours for the development of clinical signs of increased intracranial pressure. The shunt closure test is performed to allow for a long enough time for the shunt to be closed after liposomal cytarabine is injected. Researchers want to make sure that the drug will stay in the CSF system long enough to perform its function, without being siphoned off through the shunt.

An Ommaya Reservoir (a small round plastic pouch with a tube that goes into the brain and CSF) will be placed under the scalp by a neurosurgeon before starting therapy if you do not already have one in place. The reservoir will be used to deliver the liposomal cytarabine and to collect samples of CSF when they are needed.

Liposomal cytarabine will be given through the Ommaya Reservoir once every 14 days on Day 1 for a total of 12 weeks (6 treatments). This is called Induction Treatment. After the first 12 weeks, liposomal cytarabine will be given on Day 1 every 28 days for 40 weeks (10 treatments). This is called Maintenance Treatment. If you are not already taking daily dexamethasone, you will begin to take dexamethasone by mouth twice a day on the day before the depocyt starts each course and continuing 5 days after the administration of liposomal cytarabine.

Temozolomide will be taken by mouth once a day for 7 days (Days 1 - 7) every 14 days starting from the second treatment of liposomal cytarabine Day 14. You will take it continuously throughout Induction and Maintenance treatment with liposomal cytarabine. Your doctor may prescribe an anti-nausea medication to be taken 1 hour before taking temozolomide. Your doctor will choose the most appropriate anti-nausea medication for you at that time. You should swallow the temozolomide capsules (usually between 1 and 5) whole and quickly one after the other. You should not chew the temozolomide capsules. If vomiting occurs during the course of treatment, no re-dosing will be done before the next scheduled dose. You should take temozolomide at bedtime and fast (not eat or drink anything except water) for at least 1 hour before each dose and for 1 hour after each dose.

Three (3) participants at a time will be enrolled in the Phase I portion of this study. The first group of participants will receive a certain dose of temozolomide. If this dose is tolerated, then an additional 3 will be treated at this dose. If no more than 1 participant has a severe side effect, then that will be the dose for the Phase II portion of this study.

During the Phase II portion, if a participant has shown the ability to tolerate the first dose level, the next dose may be increased, which will be decided by the treating physician at the next treatment timepoint.

During the study, blood samples (about 1 tablespoon each) for routine tests will be repeated every week during Induction and then every 2 weeks during the Maintenance period. The Gd-MRI of the brain and spine will be repeated at Week 6 and 12 and then every 8 weeks. Within 72 hours of each liposomal cytarabine dosing, vital signs and a physical and neurological exam will be done. CSF will be removed from the Ommaya Reservoir every 2 weeks and through lumbar puncture every 6 weeks during Induction and from the Ommaya Reservoir every 4 weeks and through lumbar puncture every 8 weeks during the Maintenance period to look for cancer cells in the fluid.

Treatment will continue unless the disease gets worse or unacceptable side effects occur. Treatment will be given on an outpatient basis. At the end of the study, vital signs, a complete physical and neurological exam, and routine blood tests (about 1 tablespoon) will be performed. CSF samples for cytology, protein, glucose, and cell count will be taken. The Gd-MRI scan will be repeated. You will be asked to complete a questionnaire about how you are feeling.

After completion of the study, you will have a physical and neurological exam and vital signs and CSF samples collected every 28 days for 3 months and then every 3 months for up to 1 year. If there are any signs of your tumor getting worse or returning, you will have a Gd-MRI.

This is an investigational study. Temozolomide is approved by the FDA for the treatment of some brain tumors and is commercially available. Liposomal cytarabine is authorized for research use only in the treatment of brain tumors. The use of these two drugs together is experimental. About 180 patients will take part in this study. About 18 will be enrolled at UT MD Anderson Cancer Center.

DepoCyt Plus Temozolomide in Patients With Neoplastic Meningitis

Phase I Study of Temozolomide and Intrathecal DepoCyt in Patients With Neoplastic Meningitis

The MTD is the dose at which 0/3 or 1/6 participants experience Dose Limiting Toxicity (DLT) with the next higher dose having at least 2/3 or 2/6 participants encountering DLT. MTD based on the assessment of DLT during the first 28 days of treatment on the regimen.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Depocyt® With Sorafenib in Neoplastic Meningitis	NCT00964743	Neoplastic Meni...	DepoCyt Sorafenib	18 Years -	H. Lee Moffitt Cancer Center and Research Institute
Depocyt® With Sorafenib in Neoplastic Meningitis	NCT00964743	Neoplastic Meni...	DepoCyt Sorafenib	18 Years -	H. Lee Moffitt Cancer Center and Research Institute
A Pilot Study of Bevacizumab for Neoplastic Meningitis	NCT00924820	Neoplastic Meni...	Bevacizumab	18 Years -	M.D. Anderson Cancer Center
RTA 744 Injection in Patients With Leptomeningeal Disease	NCT00512460	Neoplastic Meni... Solid Tumor Lymphoma Leukemia Brain Tumor	RTA 744	18 Years -	M.D. Anderson Cancer Center
Intrathecal Gemcitabine to Treat Neoplastic Meningitis, IT Gemcitabine	NCT00074607	Meningitis Neoplasms	Gemcitabine	3 Years -	Baylor College of Medicine
DepoCyt for Active Lymphomatous or Leukemic Meningitis	NCT00523939	Neoplastic Meni... Lymphoma, B Cel...	cytarabine lipo...	18 Years -	Duke University
Phase 1 Intrathecal Topotecan for Neoplastic Meningitis	NCT00674674	Neoplastic Meni...	Topotecan Topotecan Topotecan	3 Years - 21 Years	Baylor College of Medicine
DepoCyt Plus Temozolomide in Patients With Neoplastic Meningitis	NCT00515788	Neoplastic Meni...	DepoCyt Temozolomide	18 Years -	M.D. Anderson Cancer Center

Spots Global Cancer Trial Database for neoplastic meningitis