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


Phase 1
3 Years
21 Years
Not Enrolling
Both
Neoplastic Meningitis

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Trial Information

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


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.


Inclusion Criteria:



1. Age: Patients must be greater than or equal to 3 years and less than or equal to 21
years of age at study registration.

2. Diagnosis: Patients must have neoplastic meningitis secondary to an underlying
leukemia/lymphoma or a solid tumor (including primary CNS tumors or carcinomas of
unknown primary site) for which there is no conventional therapy. Patients with CNS
leukemia/lymphoma must be refractory to conventional therapy, including XRT (i.e.,
2nd or greater relapse). Neoplastic meningitis is defined as follows:
(a)Leukemia/Lymphoma: CSF cell count over 5/┬ÁL AND evidence of blast cells on
cytospin preparation or by cytology or (b) Solid tumor: Presence of tumor cells on
cytospin preparation or cytology OR the unequivocal presence of meningeal disease on
MRI scans.

3. Patients who have leukemia/lymphoma: Patients with CNS leukemia or lymphoma must have
a negative bone marrow aspirate assessed within two weeks prior to registration.

4. Performance Status (Appendix III of full protocol): Karnofsky Performance Scale (KPS
for greater than 16 yrs of age) or Lansky Performance Score (LPS for less than or
equal to 16 years of age) greater than or equal to 60 assessed within two weeks prior
to registration. Patients who are unable to walk because of paralysis, but who are in
a wheelchair, will be considered ambulatory for the purposes of the performance
score.

5. Recovery from Prior Therapy: Patients must have recovered from the acute neurotoxic
effects of all prior chemotherapy, biological therapy, immunotherapy, or radiotherapy
prior to entering this study and must be without uncontrolled significant systemic
illness

5.1 Chemo:

1. Patients must have received their last dose of systemically administered therapy
specifically for the treatment of their leptomeningeal disease (must be
discussed with study chair) at least three (3) weeks prior to study
registration.

2. Patients must have received their last dose of intrathecal therapy at least one
(1) week (2 weeks if intrathecal DepoCyt) prior to study registration.

5.2 XRT: Patients must have had their last fraction of craniospinal irradiation
greater than or equal to 8 weeks prior to study registration.

6. The following laboratory values must be assessed within two (2) weeks prior to
registration. Laboratory tests should be repeated within 48 hours of beginning
therapy, if there has been a significant clinical change.

6.1 Electrolytes:

1. Sodium: greater than or equal to 125 and less than or equal to 150 mmol/L

2. Calcium: greater than or equal to 7 mg/dL

3. Magnesium: greater than or equal to 0.7 mmol/L

7. Intraventricular access device: Patients must have or be willing to have an
intraventricular access device such as an Ommaya reservoir.

8. Female patients of childbearing potential must have a negative serum or urine
pregnancy test prior to registration. Patient must not be breast-feeding.

9. Patients of childbearing or child fathering potential must be willing to use a
medically acceptable form of birth control, which includes abstinence, while being
treated on this study.

10. Signed informed consent according to institutional guidelines must be obtained.

Exclusion Criteria:

1. CSF Flow: Patients with clinical evidence of obstructive hydrocephalus are not
eligible for this protocol. Patients with compartmentalization of CSF flow, as
documented by radioisotope Indium111 or Technetium99-DTPA flow study are not eligible
for this protocol. Requirement for CSF flow studies are:

1.1 Solid or CNS tumor patients: Nuclear medicine CSF flow studies are required
within 7 days prior to registration in all patients with underlying solid or CNS
tumors. Informed consent must be obtained prior to the CSF flow study.

1.2 Leukemia or lymphoma patients: Nuclear medicine CSF flow studies are only
required if CSF analysis or an MRI suggests that there may be a blockage to CSF flow.
The study must be obtained within 7 days prior to registration. Informed consent must
be obtained prior to the CSF flow study.

2. Underlying illness: Patients with any significant medical illnesses that, in the
investigator's opinion, cannot be adequately controlled with appropriate therapy or
would compromise a patient's ability to tolerate this therapy.

3. Concomitant Therapy Patients receiving other therapy (either intrathecal or systemic)
designed to treat their leptomeningeal disease are not eligible for this study. Note:
Patients receiving concomitant chemotherapy to control systemic disease or bulk CNS
disease will be eligible, 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. Please discuss plans for systemic therapy with the Study
Chair prior to study entry.

4. Patients with a ventriculoperitoneal (VP) or ventriculoatrial (VA) shunt are not
eligible unless they are completely shunt-independent, e.g., shunts that have an
on/off valve that is always in the "off" position.

5. Patients must be free of uncontrolled infection, except HIV patients with
AIDS-related lymphomatous meningitis.

6. Patients currently receiving or who have received an investigational agent within
the14 days prior to study registration. The 14 day period should be extended if the
investigational agent is known to have delayed toxicity.

7. Patients with impending spinal cord compression or other CNS involvement requiring
emergent local XRT (e.g., acute visual loss secondary to optic nerve involvement).

8. Patients receiving concomitant radiation therapy to the CNS. Note: Patients may
receive radiation therapy to extra-CNS sites, e.g. painful bone metastases not in the
craniospinal axis.

Type of Study:

Interventional

Study Design:

Allocation: Non-Randomized, Endpoint Classification: Pharmacokinetics Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Supportive Care

Outcome Measure:

To estimate the MTD of intrathecal topotecan administered daily for 5 consecutive days.

Outcome Time Frame:

14 days

Safety Issue:

No

Principal Investigator

Susan Blaney, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Baylor College of Medicine

Authority:

United States: Food and Drug Administration

Study ID:

H-17990

NCT ID:

NCT00674674

Start Date:

October 2005

Completion Date:

December 2010

Related Keywords:

  • Neoplastic Meningitis
  • topotecan
  • pharmacokinetics
  • neoplastic
  • meningitis
  • Meningitis
  • Meningeal Carcinomatosis

Name

Location

Texas Children's Hospital Houston, Texas