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


Phase 1
18 Years
N/A
Not Enrolling
Both
Neoplastic Meningitis, Solid Tumor, Lymphoma, Leukemia, Brain Tumor

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Trial Information

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


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.


Inclusion Criteria:



1. Age >/=18 years.

2. Histologic confirmation of primary malignancy at original diagnosis. All primary
tumor types may be enrolled into the study (solid tumor, lymphoma, leukemia, or brain
malignancy).

3. Neoplastic meningitis/leptomeningeal metastasis refractory to conventional
intrathecal therapy and defined as presence of tumor cells on cytology after
cytospin, OR neuroimaging evidence of leptomeningeal tumor by MRI accompanied by
clinical evidence of leptomeningeal tumor.

4. Patient is not eligible for higher priority clinical trial.

5. If patient had surgical resection prior to enrollment, at least 2 weeks should have
elapsed prior to enrollment into the study and patient must have completely recovered
from the side effects of such therapy.

6. For those patients taking steroid medications, the dose of steroid should be stable
for at least 7 days prior to obtaining the Gd-MRI of the brain and spine, if
medically feasible.

7. Karnofsky Performance Status (KPS) of >/= 60.

8. Laboratory Parameters: 1) Absolute Neutrophil Count (ANC) >/=1.5 x 10^9/L; 2)
Hemoglobin (Hgb) >/=9 g/dl; 3) Platelets >/= 100 x 10^9/L; 4) AST and ALT Upper Limit of Normal (ULN); 5) Serum bilirubin /= 50 ml/min

9. Life expectancy of at least 8 weeks based on the judgment of the clinical
investigator.

10. Written informed consent obtained.

Exclusion Criteria:

1. Concurrent intrathecal or intraventricular therapy for leptomeningeal disease or
other malignancy.

2. Concurrent oral or intravenous cytotoxic therapy for leptomeningeal disease or other
malignancy. Patients who are receiving non-cytotoxic concurrent drug for their
malignancy may be allowed on the study, provided that the non-cytotoxic drug was
started for at least 4 weeks prior to entry into the study and that no apparent
toxicity from the non-cytotoxic drug is evident.

3. Clinical evidence of obstructive hydrocephalus or compartmentalization of CSF flow.

4. Patient has previously received anthracycline therapy up to the following cumulative
doses: doxorubicin >/= 550 mg/m^2 (>/= 450 mg/m^2 if patient has had prior chest
radiotherapy), epirubicin >/= 1000 mg/m^2 (>/= 800 mg/m^2 if prior chest radiation),
idarubicin >/= 150 mg/m^2 (>/= 130 mg/m^2 if prior chest radiotherapy) and
daunorubicin >/= 550 mg/m^2 (>/= 400 mg/m^2 if prior chest radiotherapy).

5. Patients on anticonvulsant medications or other types of medications which are known
liver-enzyme inducers.

6. Patients who are pregnant or breast feeding, or adults (male or female) of
reproductive potential not employing an effective method of birth control (such as
oral, implantable, or injectable contraceptives ) (Women of childbearing potential
must have a negative serum pregnancy test within 72 hours prior to administration of
RTA 744 Injection)

7. Total urinary protein in 24 hours urine collection > 500 mg

8. Any of the following concurrent severe and/or uncontrolled medical conditions which
could compromise participation in the study: 1) Uncontrolled diabetes (patients
diagnosed with Type 1 or Type 2 diabetes who are currently under treatment by a
physician for this condition and are not able to control blood sugars with management
for glucose levels above 250 mg/dL). 2) Active or uncontrolled infection. 3) Acute or
chronic liver disease (i.e., hepatitis, cirrhosis). 4) Confirmed diagnosis of HIV
infection

9. Impaired cardiac function, other significant prior cardiac disease or arrhythmia of
any type, including any of the following: 1) LVEF < 45% as determined by MUGA scan or
echocardiogram. 2) Complete left bundle branch block. 3) Obligate use of a cardiac
pacemaker. 4) ST depression of > 1mm in >/= 2 leads and/or T wave inversions in >/= 2
contiguous leads. 5) Congenital long QT syndrome.

10. 9. (continued) 6) History or presence of ventricular or atrial tachyarrhythmias. 7)
Clinically significant resting bradycardia (< 50 beats per minute). 8) QTc > 480 msec
on screening ECG. 9) Uncontrolled high blood pressure(>140/90), history of labile
hypertension, or history of poor compliance with an antihypertensive regimen. 10)
Unstable angina pectoris. 11) Symptomatic congestive heart failure.

11. Myocardial infarction history of CHF or arrhythmias

12. Patients who are taking therapeutic doses of anticoagulant therapy (prophylactic
dosing is allowed.)

13. Patients who have received the following types of prior or concurrent therapy, or who
have not recovered from the toxic effects of such therapy: 1) investigational drugs
less than 4 weeks prior to entry on this study. 2) intrathecal chemotherapy within 2
weeks prior to entry into this study. 3) systemic cytotoxic chemotherapy within 4
weeks prior (6 weeks for nitrosourea or mitomycin-C or 2 weeks for vincristine) to
entry on this study. 4) radiation therapy within 2 weeks prior to entry on this
study. 5) any medication known to cause QT interval prolongation.

14. Patients who have had any surgery, including resection of a brain tumor within 2
weeks prior to entry on this study

15. Patients unwilling to or unable to comply with the protocol

16. Patients who have a contraindication to MRI imaging (cardiac pacemaker, other
ferromagnetic metal implants, claustrophobia not amenable to conscious sedation, and
obesity greater than 300 lbs).

Type of Study:

Interventional

Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

To study the highest tolerable dose of RTA 744 that can be given to patients with cancer that has spread to the meninges of the brain or the spine.

Outcome Time Frame:

3 Years

Safety Issue:

Yes

Principal Investigator

Morris D. Groves, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

M.D. Anderson Cancer Center

Authority:

United States: Food and Drug Administration

Study ID:

2006-0506

NCT ID:

NCT00512460

Start Date:

September 2006

Completion Date:

March 2010

Related Keywords:

  • Neoplastic Meningitis
  • Solid Tumor
  • Lymphoma
  • Leukemia
  • Brain Tumor
  • Neoplastic Meningitis
  • Leptomeningeal Disease
  • Solid Tumor
  • Lymphoma
  • Leukemia
  • Brain Tumor
  • RTA 744
  • Brain Neoplasms
  • Leukemia
  • Lymphoma
  • Meningitis
  • Meningeal Carcinomatosis

Name

Location

U.T.M.D. Anderson Cancer CenterHouston, Texas  77030