Intrathecal Mafosfamide
Intrathecal Mafosfamide
This research study is an investigational treatment with the experimental drug Mafosfamide.
 This treatment is only for children with cancer that has spread to the meninges (tissues that
 cover the spinal column and brain) and has continued to grow despite treatment with standard
 therapy.

 Mafosfamide is a drug reported to have antitumor effects in animals and that has been given
 safely into the cerebrospinal fluid (the fluid within and surrounding the brain) in a small
 number of children and adults. Since there is limited experience in adults and children in
 giving mafosfamide in this way, the main purpose of this study is to determine the
 appropriate safe dose of mafosfamide when given intrathecally, that is directly into the
 cerebrospinal fluid.

 The purposes for this study are to (a) determine what dose of mafosfamide can be safely given
 into the cerebrospinal fluid through an Ommaya reservoir (surgically implanted catheters used
 to sample cerebrospinal fluid and to instill medication into the cerebrospinal fluid) and
 lumbar puncture (spinal tap) or lumbar reservoir; (b) look for side effects of drug
 treatment; (c) to study the pharmacology (how the human body handles the drug) when given
 directly into the spinal fluid; and (d) see if this drug is beneficial to the patient.
Mafosfamide is given directly into the cerebrospinal fluid twice a week for six successive
 weeks. If after six weeks the disease has not shown any evidence of progression (tumor
 growth) patients will continue to receive intrathecal (I.T.) mafosfamide once a week for one
 month, followed by twice monthly (every other week) for four months, followed by once a
 month. Patients may continue to receive mafosfamide as long as unacceptable side effects do
 not occur and there is no growth of the tumor.

 Patients will have a weekly physical exam and blood tests. The cerebrospinal fluid will be
 tested each time they receive drug for the presence of cancer cells. If the patient has an
 Ommaya reservoir (a surgically implanted catheter that is used to sample cerebrospinal fluid
 from the fluid chambers in the head and to install medication into the cerebrospinal fluid)
 then the doctor may recommend that they receive one dose of mafosfamide through the Ommaya
 reservoir and the next dose via lumbar puncture (spinal tap) or lumbar reservoir. A lumbar
 reservoir is a catheter that is surgically implanted into the lower back. This catheter is
 used to sample cerebrospinal fluid and to install medication into the cerebrospinal fluid.

 All patients must be observed for a minimum of eight hours after the first dose of
 intrathecal mafosfamide. If the first dose is well tolerated (there are no major side
 effects), further doses of mafosfamide will be administered with close observation for at
 least two hours after administration during the first six weeks of drug administration.
 Administration of the mafosfamide and sampling of the cerebrospinal fluid from the Ommaya
 reservoir, lumbar reservoir, or spinal tap takes about 30 minutes. In addition, after
 mafosfamide has been given by lumbar puncture, patients must remain lying down on their
 stomach for one hour.

 In patients who have Ommaya reservoirs or lumbar catheters, samples of spinal fluid will be
 taken from the reservoirs following the first two doses of mafosfamide. For each series of
 tests, a total of eight spinal fluid samples will be taken with a needle from the Ommaya
 reservoir over a period of 24 hours after the dose. A spinal tap will be also be performed
 two hours after the dose on these two days. If you have a lumbar reservoir, eight spinal
 fluid samples will be taken with a needle from the Ommaya reservoir, over a period of 24
 hours after the dose. These samples of cerebrospinal fluid will be used to measure the amount
 of mafosfamide found in the cerebrospinal fluid at the time they are drawn. This will help us
 understand how the body handles mafosfamide.

 For patients with leukemia, a bone marrow aspiration (taking some bone marrow out of the
 pelvis bone) is necessary before receiving intrathecal mafosfamide. This is to make sure that
 there is no cancer in the bone marrow.
-  Over 3 years of age with meningeal malignancies that are progressive or refractory to
 conventional therapy. Patients with meningeal malignancies secondary to an underlying
 solid tumor are eligible at initial diagnosis if there is no conventional therapy.

 -  Patients with leukemia, lymphoma, or other solid tumor who also have overt meningeal
 involvement by their tumor.

 -  Must have a life expectancy of at least 8 weeks and an ECOG performance status of 2 or
 better.

 -  Must sign an informed consent indicating that they are aware of the investigational
 nature of this study.

 -  Patients must have recovered from the acute toxic effects of all prior intrathecal
 chemotherapy, immunotherapy, or radiotherapy, prior to entering this study and must be
 without significant systemic illness (e.g. infection). Patients must not have received
 any CNS therapy within 1 week prior to starting treatment on this study or
 craniospinal irradiation within 8 weeks prior to starting treatment on this study.
 Patients must not have received intrathecal chemotherapy within 1 week (2 weeks if
 prior DTC101).

 -  Must not have clinically significant abnormalities with regard to liver function,
 renal function or metabolic parameters (electrolytes, calcium and phosphorus).

 -  Durable Power of Attorney (DPA): A DPA must be offered to all patients ≥ 18 years of
 age.

 Exclusion Criteria:

 -  Receiving other therapy (either intrathecal or systemic) designed specifically to
 treat their meningeal malignancy are not eligible for this study. However, patients
 receiving concomitant chemotherapy to control systemic or bulk CNS disease will be
 eligible, provided the systemic chemotherapy is not a phase I agent, an agent which
 significantly penetrates the CNS (e.g., high dose methotrexate, (> 1 gm/m2), thiotepa,
 high dose cytarabine, (> 2 gm/m2 per day), 5-fluorouracil, intravenous
 6-mercaptopurine or topotecan), or an agent known to have serious unpredictable CNS
 side effects.

 -  Clinical evidence of obstructive hydrocephalus or compartmentalization of the CSF flow
 as documented by a radioisotope Indium111 or Technitium99-DTPA flow study are not
 eligible for this protocol. If a CSF flow block or compartmentalization is
 demonstrated, focal radiotherapy to the site of block to restore flow and a repeat CSF
 flow study showing clearing of the blockage is required for the patient to be eligible
 for the study.

 -  Patients who have leukemia or lymphoma and a concomitant bone marrow relapse.

 -  Women of childbearing age must not be pregnant or lactating.

 -  Patients must not have received any other systemic investigational agent within 14
 days prior to, or during, study treatment. The 14 day period should be extended if the
 patient received any investigational agent which is known to have delayed toxicities
 after 14 days. Patients must not have received any other intrathecal investigational
 within 7 days prior to, or during, study treatment. The 7 day period should be
 extended if the patient received any investigational agent which is known to have
 delayed toxicities after 7 days or a prolonged half-life.