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Phase I Trial of Intrathecal Liposomal Cytarabine in Children With Neoplastic Meningitis

From the Texas Children's Cancer Center/Baylor College of Medicine, Houston; University of Texas Southwestern Medical School, Dallas TX; Children's Hospital and Medical Center, Seattle, WA; Children's Hospital Los Angeles, Los Angeles; Stanford University Medical Center, Stanford, CA

Address reprint requests to Lisa Bomgaars, MD, Texas Children's Cancer Center, 6621 Fannin, MC 3-3320, Houston, TX 77030; e-mail: lbomgaars{at}txccc.org

	ABSTRACT

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PURPOSE: We performed a phase I trial of intrathecal (IT) liposomal cytarabine (DepoCyt; Enzon Pharmaceuticals, Piscataway, NJ and SkyePharma Inc, San Diego, CA) to determine the maximum-tolerated dose, the dose-limiting toxicities, and the plasma and CSF pharmacokinetics of IT lipsomal cytarabine in children 3 years of age with advanced meningeal malignancies.

PATIENTS AND METHODS: Eighteen assessable patients received IT liposomal cytarabine through either an indwelling ventricular access device or via lumbar puncture. Liposomal cytarabine was given once every 2 weeks during induction, once every 4 weeks during consolidation, and once every 8 weeks during the maintenance phase of treatment. The initial dose was 25 mg, with subsequent escalations to 35 and 50 mg. CSF pharmacokinetic samples were obtained in a subset of patients.

RESULTS: Arachnoiditis, characterized by fever, headache, nausea, vomiting, and back pain was noted in the first two patients at the 25 mg dose level. Therefore, subsequent patients were treated with dexamethasone, beginning the day of liposomal cytarabine administration and continuing for 5 days. Headache (grade 3) was dose limiting in two of eight patients enrolled at the 50 mg dose level. Eight of the 14 patients assessable for response demonstrated evidence of benefit manifest as prolonged disease stabilization or response.

CONCLUSION: The maximum-tolerated dose and recommended phase II dose of liposomal cytarabine in patients between the ages of 3 and 21 years is 35 mg, administered with dexamethasone (0.15 mg/kg/dose, twice a day for 5 days). A phase II trial of IT liposomal cytarabine in children with CNS leukemia in second or higher relapse is in development.

	INTRODUCTION

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The meninges are a unique site of recurrence for certain malignancies, which is in large part a result of the limited penetration of systemically administered anticancer drugs across the blood-brain barrier. Direct intrathecal instillation of anticancer drugs is one approach that has successfully been used by oncologists, particularly in the treatment and prevention of leptomeningeal leukemias and lymphomas, to circumvent the pharmacologic sanctuary resulting from the blood-brain barrier. However, there are still only three anticancer agents, methotrexate, cytarabine, and hydrocortisone, that are routinely administered intrathecally. Cytarabine and methotrexate are both cell–cycle-specific agents that exert their cytotoxic effect during the S phase of the cell cycle. Therefore, these agents are most effective when cytotoxic concentrations are maintained for a relatively prolonged period of time. For most agents, however, maintaining prolonged cytotoxic concentrations requires either frequent lumbar punctures, which are painful and inconvenient, or neurosurgical placement of an indwelling ventricular Ommaya reservoir.

Liposomal cytarabine is a slow-release formulation of cytarabine that is manufactured by encapsulating the aqueous drug solution in spherical multivesicular particles known as DepoFoam (SkyePharma Inc, San Diego, CA). DepoFoam particles, which consist of 96% water and 4% biodegradable lipid, have bilayer lipid membranes that enclose multiple noncentric aqueous chambers.¹ Cytarabine is released gradually from the DepoFoam into the CSF, thereby prolonging exposure to the drug. The pharmacokinetic advantage of this novel cytarabine formulation was demonstrated in adult phase I studies where the terminal half-life of liposomal cytarabine was approximately 40 times longer than that of standard cytarabine.^2,3 Liposomal cytarabine is currently approved by the Food and Drug Administration for the treatment of adults with lymphomatous meningitis.

In this report, we present the results of a phase I trial of intrathecal (IT) liposomal cytarabine in children with neoplastic meningitis. The primary objectives of this trial were to perform a limited dose escalation of IT liposomal cytarabine to define a safe dose for use in future clinical studies and to evaluate the CSF pharmacokinetics in children.

	PATIENTS AND METHODS

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Eligibility Criteria
Patients 3 years and 21 years of age with a histologically proven diagnosis of leukemia, lymphoma, or other solid tumor with overt meningeal involvement refractory to conventional therapy were eligible for this trial. Patients with leukemia or lymphoma had a CSF cell count 5/mm³ and evidence of blast cells on cytologic examination. Patients with solid tumors had a CSF cytology positive for malignant cells or had evidence of meningeal disease on computed tomography (CT) or magnetic resonance imaging (MRI) scans. Other eligibility criteria included: (1) an Eastern Cooperative Oncology Group performance status of 0, 1, or 2; (2) life expectancy of at least 8 weeks; (3) total serum bilirubin less than 2.0 mg/dL and ALT less than 5 times the upper limit of normal; (4) serum creatinine less than 1.5 mg/dL; and (5) a platelet count > 40,000/mm³ within 48 hours before treatment. Exclusion criteria included: (1) severe, uncontrolled infection; (2) pregnancy or lactation; (3) administration of systemic CNS-directed therapy within 3 weeks (6 weeks if prior nitrosourea), intrathecal chemotherapy within 1 week or craniospinal irradiation within 8 weeks of starting the study; (4) evidence of obstructive hydrocephalus or compartmentalization of CSF flow; (5) evidence of bone marrow disease at the time of enrollment; or (6) prior treatment with liposomal cytarabine or another investigational agent within 14 days before enrollment.

Patients could not receive other therapy targeted specifically at their leptomeningeal disease, but could receive concomitant chemotherapy to control systemic disease or bulk CNS disease provided that the systemic chemotherapy was not an investigational agent or an agent with significant penetration into the CNS (eg, high-dose methotrexate 1 gm/m², high-dose cytarabine 1 gm/m², intravenous (IV) 6-mercaptopurine, thiotepa, flurouracil, or topotecan).

Informed consent was obtained in accordance with federal and individual institutional guidelines before entry on this study.

Patient history, physical examination, and laboratory studies (complete blood count, electrolytes, blood urea nitrogen, creatinine, liver function tests, and calcium and phosphorus) were obtained before treatment. A baseline head MRI, with and without contrast, was obtained within 2 weeks before liposomal cytarabine treatment. Imaging of the spine was required for patients with neoplastic meningitis resulting from a solid tumor. A CSF flow study (¹¹¹I-DTPA or ⁹⁹Tc-DTPA) was required for all solid tumor patients and for leukemia/lymphoma patients if laboratory or imaging studies suggested evidence of a CSF blockage. 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. Leukemia/lymphoma patients were required to have a negative bone marrow aspirate within 2 weeks of study. Likewise, pretreatment bone marrow aspirates were required as clinically indicated in children with solid tumors.

Drug Administration and Study Design
Liposomal cytarabine (DepoCyt) was supplied by SkyePharma (San Diego, CA; formerly DepoTech) in single-use 5 mL vials containing 50 mg (10 mg/mL). The appropriate dose of the drug was withdrawn into a syringe after the vial was brought to room temperature and gently agitated to resuspend the liposomal cytarabine particles. If necessary, the appropriate dose of the drug was further diluted with preservative and pyrogen-free saline to a final volume of 5 mL. The drug was administered intrathecally via lumbar puncture or through an intraventricular reservoir. Drug administration through the intraventricular reservoir was isovolumetric (ie, an amount of CSF equivalent to the volume of drug to be administered was removed before drug administration). Reservoirs were flushed slowly for 1 to 2 minutes after drug administration with approximately 2 mL of CSF or normal saline and then pumped six times. Patients who received intralumbar drug were kept in a recumbent position for 1 hour following drug administration to increase drug distribution throughout the neuroaxis.⁴

The starting liposomal cytarabine dose was 25 mg, which was 50% of the dose recommended for adults with neoplastic meningitis. Subsequent dose escalations were to 35 mg and 50 mg. No intrapatient dose escalation was permitted. During induction patients received liposomal cytarabine once every 2 weeks for a total of two to three doses, depending on their initial response to therapy. Patients with a partial response (PR) or stable disease (SD) after two doses of induction therapy could received a third dose 2 weeks after the second dose. Patients with a complete response (CR) proceeded directly to consolidation. Consolidation consisted of two doses of liposomal cytarabine administered once every 4 weeks beginning 4 weeks after the last induction dose. Maintenance therapy with liposomal cytarabine was administered once every 8 weeks for a total of six doses, beginning 4 weeks after the last consolidation dose.

During therapy, CSF studies were obtained before each dose of liposomal cytarabine. Patients with ventricular access devices had lumbar and ventricular CSF evaluations before consolidation and maintenance and every 3 months during maintenance therapy. Other laboratory studies, including CBCs and assessments of renal and hepatic function, were obtained every 2 weeks during induction and before each dose of liposomal cytarabine during consolidation and maintenance. Neuroimaging studies for evaluation of disease status were required for patients with positive findings at baseline at week 4 of induction, week 14 of consolidation, weeks 30 and 46 of maintenance, and as clinically indicated.

At least three patients were treated at each dose level. In the event of drug-related non-neurologic adverse events, the cohort of patients at a dose level was expanded to six patients if one of three patients experienced a grade 4 toxicity, or if two of three patients experienced grade 3 toxicity. In patients experiencing neurologic drug-related adverse events, the maximum tolerated dose was exceeded if one patient of a cohort of three experienced grade 4 toxicity, or if two patients of a cohort of up to six experienced grade 3 toxicity. Non-neurologic drug-related adverse events were dose-limiting if grade 4 toxicity was observed in two patients of a cohort of up to six, or if grade 3 toxicity was observed in four patients in a cohort of up to six. The dose was not escalated to a higher dose level until at least three patients in a cohort had successfully completed induction therapy. Arachnoiditis was not considered a dose-limiting toxicity (DLT) in patients not receiving concomitant dexamethasone therapy.

Toxicities were evaluated using version 1 of the National Cancer Insitute common toxicity criteria.⁵ Patients were considered assessable for toxicity if they received at least one dose of liposomal cytarabine.

Evaluation of Response
CR was defined as the complete clearing of all malignant cells for a minimum of 4 weeks from lumbar CSF (and ventricular CSF in patients with Ommaya reservoirs). In addition, if there was evidence of disease on CT or MRI scan, complete clearing of radiographic disease for at least 4 weeks was required. A PR was defined as a greater than 50% decrease in the absolute number of malignant cells from lumbar CSF (and ventricular CSF in patients with Ommaya reservoirs) for at least 4 weeks. If baseline radiographic studies were positive, a 50% decrease in the sum of the products of the bi-dimensional masses for a minimum of 4 weeks was also required. Progressive disease (PD) was defined an increase of 50% in the absolute number of malignant cells in the CSF, an increase of 25% in the size of measurable lesions on imaging studies, or the recurrence of malignant cells in the CSF or new lesions on CT/MRI in a patient who has previously attained a response. Stable disease was defined as failure to fulfill the criteria for either a CR, PR, or PD.

Pharmacokinetic Studies
Pharmacokinetic samples for assessment of cytarabine concentrations were obtained in a subset of patients enrolled in the study. Ventricular CSF samples were only obtained from patients with a ventricular access device using standard sterile technique. The reservoir was pumped six times following drug administration and before each pharmacokinetic sample to allow for proper distribution and clearing of medication from the reservoir. Ventricular CSF samples (1 mL) were obtained on days 1 and 15 before liposomal cytarabine administration and at 0.5, 2, 6, and 24 hours after dosing. A single ventricular CSF sample was also obtained on days 4 and 8, and on one occasion between days 24 through 28 before drug dosing. Lumbar CSF samples (1 mL) were obtained on day 8 immediately before liposomal cytarabine administration on day 15 and once between days 24 and 28.

Following collection, CSF samples were immediately transferred to polypropylene tubes containing 40 µmol/L tetrahydrouridine (THU) to prevent in vitro catabolism of cytarabine to uracil arabinoside by cytidine deaminase. The samples were immediately centrifuged at 13,000 g for 5 minutes to separate the DepoFoam particles from the supernatant, which was transferred to a separate tube containing THU. Samples were subsequently stored at –20°C until analysis.

Blood samples (4 mL) for assessment of cytarabine concentrations were obtained immediately before the dose and at 2 hours after the dose on days 1 and 15. Blood samples were collected directly into heparinized tubes containing THU and centrifuged at 2,600 g for 10 minutes. Plasma was transferred to a polypropylene tube and stored at –20°C until analysis.

Blood and CSF samples were analyzed for cytarabine using a previously described LC/MS/MS assay.⁵ The lower limit of quantification for cytarabine was 15 ng/mL.

Pharmacokinetic Data Analysis
Noncompartmental cytarabine pharmacokinetic parameters for CSF were estimated. The area under the concentration versus time curve (AUC) was calculated using the linear trapezoidal rule, and the residual area from the last quantifiable concentration to infinity was calculated using the approximation AUC_t-x = C_tlast/k_el, where k_el is the apparent terminal elimination rate constant determined by log-linear regression of the terminal log-linear segment of the CSF concentration-time curve. The apparent terminal elimination half-life was calculated by 0.693/k_el. The minimum concentration was obtained directly from the experimental data without interpolation. Plasma pharmacokinetic results are descriptive.

	RESULTS

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Patients
A total of 19 patients were enrolled on this trial, all of whom were eligible. One patient was not assessable for toxicity or response because the parents declined liposomal cytarabine administration after enrollment. Four patients were not assessable for response and did not contribute to the dose escalation phase of the protocol for the following reasons: noncompliance with the dosing schedule (n = 1), concurrent craniospinal radiation (n = 1), failure to obtain a baseline radiographic evaluation within the 2 weeks before initiation of liposomal cytarabine treatment (n = 1), and death as a result of a bone marrow relapse (n = 1).

Three patients were treated at the 25 mg dose level, seven at the 35 mg dose level, and eight at the 50 mg level. A total of 78 doses (median, three doses; range, two to 10 doses) were administered. Three patients received 10 total doses of liposomal cytarabine, the maximum allowed per protocol. Patient characteristics for the 18 patients assessable for toxicity are listed in Table 1.

View this table: [in this window] [in a new window]   Table 2. Common Adverse Events ( grade 2) Attributed to Liposomal Cytarabine

Three of eight patients treated at the 50-mg dose level discontinued liposomal cytarabine as a result of toxicity (n = 2) or disease-related factors (n = 1). One patient experienced headache and decreased vision in the left eye following the third induction dose of liposomal cytarabine. The headache resolved with an increase in the decadron dose. The visual changes were attributed to an optic neuropathy related to the patient's underlying acute myeloid leukemia and the patient was removed from study to receive radiation therapy. The other two patients at the 50-mg dose level experienced grade 3 headaches associated with nausea and vomiting. Nuclear medicine CSF flow studies in these two patients did not reveal evidence of obstructed CSF flow. Thus, the symptoms were attributed to liposomal cytarabine and resolved with supportive therapy, which included an increase in the decadron dose, analgesics, and cessation of IT therapy. One of these two patients also had associated visual changes and blinking episodes of unknown etiology. However, a MRI performed during at the time of symptoms showed progression of the patient's baseline leukoencephalopathy. Three of the 10 patients with leukemia enrolled on study had white matter changes noted at baseline; however, this was the only patient who had radiographic progression of leukoenceophalopathy during therapy.

Antitumor Activity
Fourteen patients were assessable for response. All of the assessable leukemia patients (n = 7) had objective responses; four patients had a CR and three patients had a PR. The four patients with CRs achieved complete clearing of malignant cells following one (n = 3) or three (n = 1) doses of the study drug. Liposomal cytarabine was discontinued in the two patients with PRs, one of whom had complete clearing of malignant cells at the time of study exit, as a result of DLT. The third patient with a PR was removed from study due to drug supply issues, with complete clearing of malignant cells from the CSF following three doses of liposomal cytarabine. Of the seven assessable patients with leukemia, six received concomitant systemic chemotherapy during the induction period. All six received vincristine in combination with a variety of other agents including: asparaginase, methotrexate, 6-mercaptopurine, 6-thioguanine, ifosfamide, etoposide, cytarabine, cytoxan, adriamycin, and daunomycin. Three patients received L-asparaginase as part of their therapy; however, this did not appear to impact response as only two of four patients with CR and one of three patients with PR received this agent. The single patient who did not receive any concomitant systemic therapy had a complete response. Among the seven patients with solid tumors, two patients with medulloblastoma had SD. The remaining five patients had PD following two or three doses of the drug. One of seven patients received concominant oral etoposide during induction, and had SD. Responses were noted at all dose levels (Table 3).

	DISCUSSION

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In this study, we demonstrated the feasibility of administering liposomal cytarabine to children with refractory neoplastic meningitis. Headache (grade 3) with associated nausea and emesis was the DLT at the 50-mg dose level. Mild headache and back or neck pain were the most common adverse events associated with liposomal cytarabine administration. Although arachnoiditis was observed in the first two patients enrolled at the 25-mg dose level, it was prevented in subsequent doses and patients with concomitant administration of dexamethasone. These toxicities in this pediatric trial are quite similar to the observed toxicity profile for liposomal cytarabine in adult phase I/II studies.^3,6-9 However, children tolerated an overall lower dose of liposomal cytarabine than adults. The recommended dose for further study in the pediatric population is 35 mg versus 50 mg in adults.

This trial confirms the observations in adults that prolonged exposure to cytarabine above levels that are known to be cytotoxic in vitro can be achieved after either intralumbar or intraventricular dosing.² The children evaluated in this study appear to have a more rapid elimination of liposomal cytarabine compared with adults treated at similar dose levels,³as evidenced by their overall decreased total drug exposure and shorter terminal half-life. Nonetheless, the duration of CSF exposure to cytarabine concentrations that exceed cytotoxic levels for children who were enrolled on this trial was at least 8 days compared with only 3 hours for the standard formulation of cytarabine.¹⁰

Responses were seen in patients with leukemia at all dose levels. Six of the seven assessable leukemia patients received concomitant systemic chemotherapy in addition to the 5-day decadron pulse administered with the liposomal cytarabine. Although the systemic therapy was restricted to agents without significant CNS penetration, it is possible either the concurrent systemic therapy or required decadron pulse could be confounding factors in the evaluation of response on this study. The prolonged drug exposure may also result in a quality-of-life benefit to the use of liposomal cytarabine rather than free cytatabine, since liposomal cytarabine can be administered less frequently.

In conclusion, this study has demonstrated the safety and feasibility of administering IT liposomal cytarabine in children with neoplastic meningitis. The recommended dose of liposomal cytarabine, administered with concomitant dexamethasone, in children older than 3 years of age is 35 mg. Promising evidence of antitumor activity for liposomal cytarabine plus concomitant, systemically administered dexamethasone, particularly in patients with refractory CNS leukemia, was observed. The Children's Oncology Group is currently planning a phase II trial of liposomal cytarabine, administered with concomitant dexamethasone, to further assess the response and toxicity profile of this agent in children with refractory CNS leukemia.

	Authors' Disclosures of Potential Conflicts of Interest

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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. Honoraria: Susan Blaney, Enzon. Research Funding: Susan Blaney, DepoTech Corp, SkyePharma. 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 form and the ‘Disclosures of Potential Conflicts of Interest’ section of Information for Contributors found in the front of every issue.

	NOTES

 
Supported by DepoTech Corporation/Skye Pharma Inc, San Diego, CA.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
1. Murry DJ, Blaney SM: Clinical pharmacology of encapsulated sustained-release cytarabine. Ann Pharmacother 34:1173-1178, 2000[Abstract]

2. Chamberlain MC, Kormanik P, Howell SB, et al: Pharmacokinetics of intralumbar DTC-101 for the treatment of leptomeningeal metastases. Arch Neurol 52:912-917, 1995[Abstract/Free Full Text]

3. Kim S, Chatelut E, Kim JC, et al: Extended CSF cytarabine exposure following intrathecal administration of DTC 101. J Clin Oncol 11:2186-2193, 1993[Abstract/Free Full Text]

4. Blaney S, Poplack D, Godwin K, et al: Effect of body position on ventricular CSF methotrexate concentration following intralumbar administration. J Clin Oncol 13:177-179, 1995[Abstract/Free Full Text]

5. National Cancer Institute: Guidelines for Reporting of Adverse Drug Reactions. Bethesda, MD, Divisions of Cancer Treatment, National Cancer Institute, 1988

6. Chamberlain MC, Khatibi S, Kim JC, et al: Treatment of leptomeningeal metastasis with intraventricular administration of depot cytarabine (DTC 101). A phase I study. Arch Neurol 50:261-264, 1993[Abstract/Free Full Text]

7. Glantz MJ, Jaeckle KA, Chamberlain MC, et al: A randomized controlled trial comparing intrathecal sustained-release cytarabine (DepoCyt) to intrathecal methotrexate in patients with neoplastic meningitis from solid tumors. Clin Cancer Res 5:3394-3402, 1999[Abstract/Free Full Text]

8. Glantz MJ, LaFollette S, Jaeckle KA, et al: Randomized trial of a slow-release versus a standard formulation of cytarabine for the intrathecal treatment of lymphomatous meningitis. J Clin Oncol 17:3110-3116, 1999[Abstract/Free Full Text]

9. Jaeckle KA, Batchelor T, O'Day SJ, et al: An open label trial of sustained-release cytarabine (DepoCyt) for the intrathecal treatment of solid tumor neoplastic meningitis. J Neurooncol 57:231-239, 2002[CrossRef][Medline]

10. Zimm S, Collins JM, Miser J, et al: Cytosine arabinoside cerebrospinal fluid kinetics. Clin Pharmacol Ther 35:826-830, 1984[Medline]

Submitted January 8, 2004; accepted July 3, 2004.

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