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Journal of Clinical Oncology, Vol 23, No 7 (March 1), 2005: pp. 1555-1563 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.06.053 Intrathecal Mafosfamide: A Preclinical Pharmacology and Phase I TrialFrom the Texas Children's Cancer Center/Department of Pediatrics, Baylor College of Medicine, Houston, TX; Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD; Mayo Clinic, Rochester, MN; St. Jude Children's Research Hospital, Memphis, TN; Children's Hospital and Medical Center, Seattle, WA; Children's Hospital National Medical Center, Washington, DC; M.D. Anderson Cancer Center, Houston, TX; current address (R.H.): Department of Pediatrics, University of New Mexico, Albuquerque, NM; current address (P.C.A.): Children's Hospital Philadelphia, Philadelphia, PA; current address (K.J.): Mayo Clinic, Jacksonville, FL. Address reprint requests to Susan M. Blaney, MD, Texas Children's Cancer Center, 6621 Fannin St, CC 1410 00, Houston, TX 77030-2399; e-mail: sblaney{at}txccc.org
PURPOSE: Preclinical studies of mafosfamide, a preactivated cyclophosphamide analog, were performed to define a tolerable and potentially active target concentration for intrathecal (IT) administration. A phase I and pharmacokinetic study of IT mafosfamide was performed to determine a dose for subsequent phase II trials. PATIENTS AND METHODS: In vitro cytotoxicity studies were performed in MCF-7, Molt-4, and rhabdomyosarcoma cell lines. Feasibility and pharmacokinetic studies were performed in nonhuman primates. These preclinical studies were followed by a phase I trial in patients with neoplastic meningitis. There were five dose levels ranging from 1 mg to 6.5 mg. Serial CSF samples were obtained for pharmacokinetic studies in a subset of patients with Ommaya reservoirs. RESULTS: The cytotoxic target exposure for mafosfamide was 10 µmol/L. Preclinical studies demonstrated that this concentration could be easily achieved in ventricular CSF after intraventricular dosing. In the phase I clinical trial, headache was the dose-limiting toxicity. Headache was ameliorated at 5 mg by prolonging the infusion rate to 20 minutes, but dose-limiting headache occurred at 6.5 mg dose with prolonged infusion. Ventricular CSF mafosfamide concentrations at 5 mg exceeded target cytotoxic concentrations after an intraventricular dose, but lumbar CSF concentrations 2 hours after the dose were less than 10 µmol/L. Therefore, a strategy to alternate dosing between the intralumbar and intraventricular routes was tested. Seven of 30 registrants who were assessable for response had a partial response, and six had stable disease. CONCLUSION: The recommended phase II dose for IT mafosfamide, administered without concomitant analgesia, is 5 mg over 20 minutes.
The meninges, which are protected by the blood-CSF barrier from the cytotoxic effects of systemic anticancer chemotherapy, are a site of recurrence for many cancers.1 One approach to circumvent the limited access of systemic agents to the CSF is direct intrathecal (IT) administration of anticancer drugs.2 IT methotrexate and cytarabine are effective for the treatment and prevention of meningeal leukemia and lymphoma, but these agents have limited effectiveness in patients with solid tumors that spread to the meninges,3 and meningeal leukemia/lymphoma can become refractory to IT methotrexate and cytarabine. Therefore, the development of new IT agents with a broader range of mechanisms of action is essential. Cyclophosphamide is the most widely used alkylating agent and has a broad spectrum of antitumor activity. However, it is a prodrug, which requires oxidation by hepatic cytochrome P450 (CYP) enzymes (primarily CYP2B6)4 to the active alkylating species, 4-hydroxycyclophosphamide, to express an antitumor effect. This active metabolite is unstable and subsequently undergoes spontaneous decomposition to biologically active alkylating species such as phosphoramide mustard. Because of the requirement for hepatic activation, cyclophosphamide cannot be used for regional chemotherapy. However, mafosfamide, a chemically stable 4-thioethane sulfonic acid salt of 4-hydroxycyclophosphamide (Fig 1), is a preactivated cyclophosphamide derivative that does not require hepatic activation and, therefore, may potentially be useful for regional chemotherapy.
Mafosfamide exhibits in vitro cytotoxic activity comparable to or exceeding that of 4-hydroperoxy-cyclophosphamide,5 another preactivated cyclophosphamide derivative that has been used to purge tumor cells from stem-cell collections before reinfusion. Additionally, mafosfamide has shown significant preclinical in vivo activity against a number of transplantable murine tumors, including P388 and L1210 leukemia, B16 melanoma, and cyclophosphamide-resistant P388 leukemia.5,6 In vivo activity has also been demonstrated against a variety of solid tumors including Lewis lung carcinoma and colon 38 tumor.5,6 Systemic administration of mafosfamide via the intravenous route was studied clinically in phase I trials in Europe. However, this route of administration was limited by severe local pain at the injection site.7,8 The approach to the development of new IT agents differs from that of new systemic agents because of the potential for severe local neurotoxicity from intrathecally instilled drugs. Before human trials, we determine a target concentration of the drug based on in vitro cytotoxicity studies with human tumor cell lines. These cytotoxic concentrations are likely to be more relevant to CSF than plasma because CSF protein concentrations are low and protein drug binding is less in CSF than in plasma. The drug is then administered intrathecally in a nonhuman primate model that has proven to be highly predictive of the CSF pharmacology of drugs in humans,9 in order to determine whether the target cytotoxic concentration of the drug can be achieved in the CSF with a dose that is tolerable. If the target concentration can be achieved with a safe dose in nonhuman primates, then human trials are initiated with a starting dose based on the animal studies. In this report, we present the results of the preclinical studies that served as the basis for a phase I trial of IT mafosfamide, and the results of the phase I clinical trial that was performed in patients with neoplastic meningitis.
Drug: Supply, Formulation, Use, and Administration Mafosfamide (4-sulfoethylthio-cyclophosphamide L-lysine), synthesized by ASTA Medica, (Frankfurt, Germany) was initially supplied by the Investigational Drug Branch, National Cancer Institute (Bethesda, MD). During the trial, the Investigational New Drug application was transferred to Dr Susan Blaney, who supplied the drug to the participating sites for the remainder of the trial. Mafosfamide was supplied in 50-mg vials of the freeze-dried residue of an aqueous solution adjusted to pH 4.2. The contents of the vial were completely dissolved in 5 mL of pyrogen-free saline. For cytotoxicity studies, the drug was dissolved in dimethyl sulfoxide at a concentration of 0.01M and diluted in media to the desired concentrations. For the nonhuman primate studies, 1 mL of drug solution was injected into the Ommaya reservoir, after which the reservoir was pumped four to six times to ensure adequate mixing throughout the ventricular system. For the clinical studies, the reconstituted solution of drug was further diluted with preservative-free saline such that the final solution was in no less than 10 mL saline for all doses  5 mg or 5 mL for all doses less than 5 mg. Drug administration was isovolumetric (ie, an amount of CSF equivalent to the volume of drug to be administered was removed before drug injection). Drug was initially administered at a rate of 2 mL/min. This rate was subsequently decreased to 1 mL/min because of local pain that was associated with more rapid injection rates. If drug was administered via an Ommaya reservoir, the reservoir was flushed slowly for 1 to 2 minutes with 2 mL of CSF or normal saline after drug administration. If drug was administered via lumbar puncture, patients were placed prone, in a flat or Trendelenburg position, for 1 hour after the injection. All patients were hospitalized overnight after their first dose of IT mafosfamide. Patients were required to stay in the outpatient clinic for a minimum 2-hour observation period after subsequent doses.
In Vitro Cytotoxicity Study
Nonhuman Primate Study
Phase I Trial and Pharmacokinetic Study
Patient eligibility.
Patients Dose and schedule of administration. During induction, patients received IT mafosfamide twice weekly (every 3 to 4 days) for 4 weeks (eight doses). Patients who achieved a complete response (CR) then received four doses of weekly IT mafosfamide (consolidation), followed by twice-monthly maintenance therapy for 4 months, and monthly therapy thereafter for up to 8 additional months (continuation therapy). Patients with a partial response (PR) or stable disease (SD) after the initial 4 weeks of induction received 2 additional weeks of twice-weekly induction therapy before proceeding with consolidation and maintenance. Patients with disease progression at the end of induction or at any time during consolidation or maintenance were taken off-study. The starting dose was 1 mg (approximately 15% of the human-equivalent dose that was nontoxic in the nonhuman primates) with subsequent escalations to 2, 3.5, 5, and 6.5 mg. CSF (1 mL) and blood (2 mL) for pharmacokinetic analysis were obtained from patients with indwelling Ommaya reservoirs immediately before and at 15 minutes, 30 minutes, and 1, 2, 3, 5, and 8 hours after drug administration. A sample of lumbar CSF was also obtained at 2 hours following intraventricular drug administration in patients with Ommaya reservoirs. A minimum of three patients were entered at each dose level. The dose level was expanded to include up to six patients if one patient experienced dose-limiting (grade 3 or greater) toxicity. When dose-limiting toxicity was observed in two patients of a cohort of three to six patients receiving the same dose of drug, the maximum tolerated dose was exceeded, and an additional three to six patients were added at the dose level immediately below the dose level at which the unacceptable level of toxicity was observed. The dose was not escalated to a higher dose level until at least three patients treated at the previous dose level had received a minimum of at least 4 weeks of induction chemotherapy without dose-limiting toxicity. During the course of the study, the protocol was amended to administer the mafosfamide at a constant rate over 20 minutes via an infusion pump, and then to alternate the site of mafosfamide administration between the intralumbar and intraventricular routes. These modifications were made in an attempt to lessen or eliminate toxicities temporally associated with drug administration and to attempt to circumvent the problems of uneven distribution throughout the neuraxis. Pretreatment and follow-up studies. A complete history, a physical examination including a detailed neurological examination, and laboratory studies were obtained before treatment and then weekly throughout the course of the study. Pretreatment laboratory evaluations included CBCs, electrolyte, calcium, phosphorus, blood urea nitrogen, creatinine, and liver function tests. CSF studies included a cell count, differential, protein, and glucose. Studies were performed from both ventricular and lumbar CSF in patients with Ommaya reservoirs. Cytospins of CSF were performed and reviewed for the presence of blasts in leukemia/lymphoma patients, and CSF cytology studies were performed in solid tumor patients. Bone marrow aspirates were required to be negative in patients with leukemia/lymphoma within the 2 weeks preceding protocol entry. Bone marrow aspirates were also examined as clinically indicated in patients with solid tumors. A pretreatment head MRI or CT scan was also obtained. A radionuclide CSF flow study (111I-DTPA or 99Tc-DTPA) was required for all solid tumor patients and for leukemia/lymphoma patients if CSF analysis, myelogram, computed tomography (CT), or magnetic resonance imaging (MRI) studies suggested evidence of CSF blockage. During therapy, CSF evaluations were performed with each dose of IT mafosfamide and 24 hours after the initial dose. Patients with ventricular access devices had lumbar and ventricular CSF evaluated following the fourth week of therapy, before continuation therapy, and every 3 months during maintenance therapy. Radiographic evaluations in solid tumor patients with evidence of leptomeningeal metastases on CT or MRI scans were performed after 4 weeks of induction therapy, before the start of continuation, and every 3 months during continuation therapy. Criteria for assessment of toxicity and response. Toxicities were evaluated according to the National Cancer Institute Common Toxicity Criteria, version 1. Patients were removed from study if they experienced any grade 3 or greater significant neurotoxicity or other organ toxicity that was judged to be drug-related. A CR was defined as the complete clearing of all malignant cells from lumbar CSF (and ventricular CSF in patients with Ommaya reservoirs). In addition, in patients with evidence of disease on CT or MRI scan, complete clearing of radiographic disease for a minimum of 4 weeks was required. A PR was defined as a 50% decrease in the absolute number of malignant cells on cytospin from lumbar (and ventricular CSF in patients with Ommaya reservoirs). In addition, if baseline radiographic studies were positive, a greater than 50% improvement on CT or MRI was required. Progressive disease (PD) was defined as at least a 50% increase in the number of malignant cells in the ventricular or lumbar CSF, or an increase of greater than 25% in the size of measurable lesions on CT or MRI scans, or the recurrence of malignant cells in the CSF or new lesions on CT or MRI in a patient who had previously attained a response. SD was defined as failing to fulfill the criteria for a CR, a PR, or PD. Mafosfamide sample analysis. Blood and CSF were processed and analyzed for 4-hydroxycyclophosphamide using previously described methods.12 In brief, CSF samples were placed in polypropelene tubes and immediately frozen in a mixture of methanol and dry ice and then stored at –70°C until analysis. Blood samples were derivatized immediately with m-aminophenol in acid, and centrifuged. The supernatant was aspirated and frozen at –70°C until the time of the assay. CSF was derivatized immediately after thawing. The acidification releases acrolein from both mafosfamide and 4-hydroxycyclophosphamide (Fig 1), and the acrolein reacts with the m-aminophenol to produce fluorescent 7-hydroxyquinolone. Methyl vinyl ketone was added to the acidic m-aminophenol reaction mixture. Methyl vinyl ketone generates fluorescent 7-hydroxyquinoline, which was the internal high-pressure liquid chromatography (HPLC) standard. This derivatization procedure detects acrolein or any compound that releases acrolein. The fluorescent products were measure by HPLC utilizing a fluorometric detector. Excitation occurred at 330 nm, and a 418-nm emission filter was used. The analytic column was a µBondapack phenyl column (Waters Associates, Milford, MA). Elution was isocratic with a mobile phase of 10% acetonitrile in 0.15M formic acid at a flow rate of 2 mL/min. Retention times for 7-hydroxyquinolone and 4-methyl-7-hydroxyquinoline were 16 and 19 minutes, respectively. The limit of sensitivity for the assay was 0.2 µmol/L. Standard curves were linear (r2 > 0.99) over the range of 0.2 µmol/L to 10 µmol/L.
Pharmacokinetic data analysis.
Plasma concentration versus time data following intraventricular mafosfamide administration were fitted to both mono (n = 1) and biexponential (n = 2) equations,
 i, the rate constants.13 Akaike's information criterion14 was used to determine which equation best fit the data. The half-life for each phase of elimination was calculated by dividing 0.693 by the rate constant (i) for that phase. Model-independent methods were used to calculate other pharmacokinetic parameters. The area under the drug concentration versus time curve (AUC) was derived by the linear trapezoidal method15 and extrapolated to infinity by adding the quotient of the final concentration divided by the terminal rate constant (n). CSF clearance was determined by dividing the dose by the AUC in CSF.
In Vitro Cytotoxicity Study The target mafosfamide concentration was defined as the concentration that produced a 90% inhibition of clonogenic survival (IC90) after a 1-hour exposure in vitro. The IC90 of mafosfamide was 1.9, 9.0, and 9.8 µmol/L for the rhabdomyosarcoma, MCF-7, and Molt-4 cell lines, respectively (Fig 2), based on the clonogenic assays.
Nonhuman Primate Study The mean peak (5 minutes postinjection) mafosfamide concentration in the ventricular CSF following intraventricular administration of a 0.655-mg mafosfamide dose was 119 µmol/L (range, 100 to 145 µmol/L). Mafosfamide was rapidly eliminated from ventricular CSF with a mean clearance of 0.17 ± 0.06 mL/min. This is five-fold more rapid than the CSF bulk flow rate (0.03 mL/min) in the model. The half-life of mafosfamide in ventricular CSF was 1.8 hours (range, 0.6 to 3.4 hours), and the mean AUC was 84 µmol/L · h (range, 73 to 93 µmol/L · h). These drug exposures in ventricular CSF exceed the IC90s from the in vitro cytotoxicity studies. The concentration of mafosfamide in blood was 0.3 µmol/L (near lower limits of assay sensitivity) at 30, 60, and 90 minutes and was undetectable at other sampling times. A mild but transient CSF pleocytosis was observed following intralumbar mafosfamide administration. The maximum CSF WBC count ranged from 20 to 120 cells/µL. Counts of this magnitude are typically seen in this nonhuman primate model after IT drug administration. CBCs and serum chemistries were not affected by intraventricular or intralumbar mafosfamide. No acute or chronic neurologic or systemic toxicities were observed in any of the animals in either the single-dose (n = 3) or chronic-dosing (n = 3) studies. Two of the three animals experienced transient, spontaneously resolving cyanosis after intraventricular mafosfamide, which was felt to be secondary to the anesthetic used for lumbar catheter placement.
Phase I Trial and Pharmacokinetic Study
Maximum Tolerated Dose and Dose-Limiting Toxicities Mafosfamide was generally well tolerated by this heterogeneous group of patients with neoplastic meningitis (Table 2). There were no reported drug-related adverse events at the 1-mg dose level. However, as the mafosfamide dose was increased, headaches, which were often associated with flushing or neck pain and typically occurred during or immediately following the completion of drug administration, were observed with increasing frequency. At the 2-mg and 3.5-mg dose levels, one patient in each cohort of three experienced a grade 2 headache. At the 5-mg dose level, two of the first three patients experienced a grade 2 headache, which was accompanied by facial pain and swelling in one patient. The second patient received only one dose of study drug because of this adverse event, and the cohort was expanded. Two of the additional patients in the expanded 5-mg cohort subsequently experienced a grade 2 headache.
Clinically, it seemed that the patients experiencing headaches at the 5-mg level received mafosfamide at a rate faster than the recommended 2 mL/min (5 mg over 5 minutes); suggesting that this acute toxicity was related to the rate of drug administration. The protocol was therefore amended to accrue additional patients at the 5-mg dose level with a reduced rate of drug administration (0.5 mL/min or 5 mg over 20 minutes via an infusion pump). There was only one grade 2 headache in the three patients who received a 5-mg dose at the reduced dose rate. Therefore, the mafosfamide dose for the subsequent cohort was increased to 6.5 mg (infused over 20 minutes). One of three patients at the 6.5-mg dose level experienced a grade 3 headache, grade 2 emesis, and facial flushing. This patient also experienced grade 2 headache following a dose reduction to 5 mg. Although these toxicities were transient, it was considered impractical to prolong the infusion time for this intrathecally administered agent. There were no apparent differences in the observed toxicities between patients who received drug via a single site of administration (Ommaya reservoir or lumbar puncture) versus those who received the drug alternating between the intraventricular and intralumbar routes of administration.
Antitumor Activity
Pharmacokinetics Ventricular CSF samples for pharmacokinetic studies were obtained in a subset of patients with indwelling Ommaya reservoirs after an intraventricular dose. Mafosfamide was rapidly eliminated from the CSF with an average half-life of 70 ± 34 minutes. The CSF pharmacokinetic parameters for mafosfamide following an intraventricular dose administered over 5 minutes are presented in Table 4. A representative concentration versus time curve for patients enrolled at the 5-mg over 5 minutes dose level are shown in Figure 3. The average lumbar CSF concentration (n = 8), approximately 2 hours after an intraventricular dose at the 5-mg dose level, was 5.3 ± 2.5 µmol/L. There was no quantifiable mafosfamide in plasma following IT administration at the dose levels evaluated in this study.
There are substantial differences in the approach to the preclinical and clinical development of new agents for intrathecal administration when compared with the approach for the development of new agents for systemic administration.16 In this report, we describe the results of preclinical studies that served as the basis for the development of a phase I clinical trial of IT mafosfamide, a chemically stable thioethane sulfonic acid salt of cyclophosphamide that breaks down spontaneously in aqueous solution to the active metabolite of cyclophosphamide, 4-hydroxycyclophosphamide. Mafosfamide was selected as a potential candidate agent for intrathecal dosing because its mechanism of action (alkylating agent) differs from that of most available IT agents, which are primarily antimetabolites. We initially performed in vitro cytotoxicity studies with a panel of human tumor cell lines. The goal of these studies was to identify a cytotoxic concentration or a minimum drug exposure (AUC) that could be used as a target CSF concentration or AUC following IT mafosfamide administration. We then evaluated the safety, feasibility, and pharmacokinetics of IT mafosfamide in a nonhuman primate model that is highly predictive of the CSF pharmacology of drugs in humans.17-19 The goal of these preclinical CSF pharmacokinetic studies was to determine whether the cytotoxic target exposure or drug concentration, as defined by the in vitro studies, could be attained following administration of a nontoxic dose of mafosfamide. In addition, chronic dosing studies were performed to ensure that there was no evidence of cumulative systemic or neurologic toxicity following IT drug administration. These preclinical pharmacokinetic studies of IT mafosfamide demonstrated that ventricular mafosfamide exposure, after administration of a dose that was well tolerated by the animals, was 10-fold higher than the IC90 of the least sensitive cell line. In addition, there was no evidence of cumulative systemic or neurologic toxicity with chronic intralumbar mafosfamide administration. This approach to developing new IT agents has also been successfully applied to the development of diaziquone, topotecan, 6-mercaptopurine, gemcitabine, and DTC-101 for IT administration.17-23 In this phase I clinical trial of IT mafosfamide, the initial dosage escalations between 1 mg and 5 mg were uneventful. However, at the 5-mg dose level, several patients experienced intense but transient headaches during or immediately after drug administration. These headaches, which seemed to be in part related to the dose rate of mafosfamide administration, appeared to be ameliorated by a reduction in the dose rate of IT mafosfamide administration (ie, the mafosfamide was given over a longer period using an infusion pump to ensure a constant dose rate of drug administration). This strategy lessened the toxicity at the 5-mg dose level, but severe headache occurred at the next higher dose level (6.5 mg) despite the protracted dose rate of administration. The pharmacokinetic data from a subset of patients who received drug at the 5-mg level revealed that lumbar mafosfamide CSF concentrations measured approximately 2 hours after an intraventricular dose were approximately 10% of the simultaneous ventricular mafosfamide concentrations. The lumbar CSF concentrations approached, but did not consistently exceed, the in vitro cytotoxic target concentration of 10 µmol/L. Further prolonging the duration of mafosfamide infusion in order to escalate the dose above the 5-mg dose level was felt to be an impractical solution to achieve higher lumbar CSF concentrations. Therefore, a schedule alternating the site of mafosfamide administration between the intralumbar and intraventricular routes was employed. We hypothesized that we could circumvent the problems of uneven distribution throughout the neuraxis and achieve exposures exceeding the in vitro cytotoxic target exposure both in the lumbar and ventricular CSF using this dosing strategy, which was successfully employed for patients at the 3.5-mg and 5-mg dose levels administered over 20 minutes. Anecdotal experience from patients treated with IT mafosfamide in Austria suggested that IT mafosfamide could be safely given at doses of 20 mg if administered in conjunction with an analgesic to prevent headaches.24 Although this rescue strategy with narcotic analgesics may permit further IT mafosfamide dose escalation, it may not be practical for long-term treatment in a preventive setting. Although there were no CRs observed in this phase I trial, there was objective antitumor activity as evidenced by PRs in 24% of patients who were assessable for response. Unfortunately, the initial trial design did not allow patients with less than a CR after induction therapy to continue to receive protocol therapy. Therefore, the duration of benefit derived from mafosfamide in patients with PRs or SD is unknown. Anecdotally, there were two patients who each received mafosfamide for approximately 1 year—one with an ependymoma and one with leukemia. In summary, the recommended phase II dose of IT mafosfamide without concomitant analgesia is 5 mg administered at a constant infusion rate over 20 minutes. Studies to determine the maximum tolerated dose of IT mafosfamide administered with concomitant analgesia are in progress.
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Research Funding: Susan M. Blaney, ASTA Medica. For a detailed description of these categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section of Information for Contributors found in the front of every issue.
Supported by grant MO1RR00188, General Clinical Research Center, National Center for Research Resources, National Institutes of Health, Bethesda, MD, and Asta Medica, Frankfurt, Germany. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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4. Roy P, Yu LJ, Crespi CL, et al: Development of a substrate-activity based approach to identify the major human liver P-450 catalysts of cyclophosphamide and ifosfamide activation based on cDNA-expressed activities and liver microsomal P-450 profiles. Drug Metab Dispos 27:655-666, 1999 5. Alberts D, Einsphar J, Struck R, et al: Comparative in vitro cytotoxicity of cyclophosphamide, its major active metabolites and the new oxazaphosphorine ASTA Z 7557 (INN mafosfamide). Inv New Drugs 2:1411-1418, 1984 6. Atassi G, Hilgard P, Pohl J: Antineoplastic activity of ASTA Z 7557 (NSC-34582, INN mafosfamide) on transplantable murine tumors. Inv New Drugs 2:169-173, 1984 7. Bruntsch U, Groos F, HIller T, et al: Phase I study of mafosfamide-cyclohexlyamine (ASTA-Z-7557, NSC 345842) and limited phase I data on mafosfamide-lysine. Cancer Chemother Pharm 16:182-183, 1986[CrossRef][Medline] 8. Abele R, Aapro M, Haefliger J, et al: Phase I study of cyclohexylamine and lysine salt of mafosfamide. Cancer Chemother Pharm 16:182-183, 1986 9. McCully C, Balis F, Bacher J, et al: A Rhesus monkey model for continuous infusion of drugs into cerebrospinal fluid. Lab Animal Sci 40:520-525, 1990 10. Park C, Bergsagel D, McCullough E: Mouse myeloma tumor stem cells: A primary cell culture assay. J Natl Cancer Inst 46:411-422, 1971 11. Guide for the Care and Use of Laboratory Animals. DHEW Publication (NIH) 85-23, Revised 1988 12. Alacron J: Fluorometric determination of acrolein and related compounds with m-aminophenol. Anal Chem 30:1704-1708, 1968[CrossRef] 13. Knott G: MLAB: A mathematical modeling tool. Comput Programs Biomed 10:271-280, 1979[CrossRef][Medline] 14. Yamaoka K, Nakagawa T, Uno T: Application of Akaike's information criterion (AIC) in the evaluation of linear pharmacokinetic equations. J Pharmacokinet Biopharm 6:165-175, 1978[CrossRef][Medline] 15. Gibaldi M, Perrier D: Estimation of areas in Pharmacokinetics (2nd ed). New York, NY, Marcel Dekker Inc, 1982, pp 445-449 16. Blaney S, Poplack D: New cytotoxic drugs for intrathecal administration. J Neuro-Oncol 38:219-223, 1998[CrossRef][Medline]
17. Blaney SM, Heideman R, Berg S, et al: Phase I clinical trial of intrathecal topotecan in patients with neoplastic meningitis. J Clin Oncol 21:143-147, 2003 18. Berg S, Balis F, Zimm S, et al: Phase I/II trial and pharmacokinetics of intrathecal diaziquone in refractory meningeal malignancies. J Clin Oncol 10:143-148, 1992[Abstract]
19. Adamson P, Balis F, Arndt C, et al: Intrathecal 6-mercaptopurine: Preclinical pharmacology, phase I/II trial, and pharmacokinetic study. Cancer Res 51:6079-6083, 1991 20. Blaney S, Cole D, Balis F, et al: Plasma and CSF pharmacokinetic study of topotecan in nonhuman primates. Cancer Res 53:725-727, 1992 21. Blaney SM, Cole DE, Godwin K, et al: Intrathecal administration of topotecan in nonhuman primates. Cancer Chemother Pharmacol 36:121-124, 1995[Medline]
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23. Egorin MJ, Zuhowski EG, McCully CM, et al: Pharmacokinetics of intrathecal gemcitabine in nonhuman primates. Clin Cancer Res 8:2437-2442, 2002 24. Slavc I, Schuller E, Czech T, et al: Intrathecal mafosfamide therapy for pediatric brain tumors with meningeal dissemination. J Neurooncol 38:213-218, 1998[CrossRef][Medline] Submitted June 7, 2004; accepted December 2, 2004. This article has been cited by other articles:
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
