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Dose Escalation of Carmustine in Surgically Implanted Polymers in Patients With Recurrent Malignant Glioma: A New Approaches to Brain Tumor Therapy CNS Consortium Trial

Alessandro Olivi, Stuart A. Grossman, Stephen Tatter, Fred Barker, Kevin Judy, Jeffrey Olsen, Jeffrey Bruce, Dana Hilt, Joy Fisher, Steve Piantadosi

From the New Approaches to Brain Tumor Therapy CNS Consortium and Guilford Pharmaceuticals, Baltimore, MD.

Address reprint requests to Alessandro Olivi, MD, c/o The NABTT CNS Consortium, 1650 Orleans St, Room G93, The Sydney Kimmel Cancer Center at Johns Hopkins, Baltimore, MD 21231; email: jfisher{at}jhmi.edu.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Purpose: This New Approaches to Brain Tumor Therapy CNS Consortium study sought to determine the maximum-tolerated dose (MTD) of carmustine (BCNU) that can be implanted in biodegradable polymers following resection of recurrent high-grade gliomas and the systemic BCNU exposure with increasing doses of interstitial BCNU.

Patients and Methods: Forty-four adults underwent tumor debulking and polymer placement. Six patients per dose level were studied using polymers with 6.5%, 10%, 14.5%, 20%, and 28% BCNU by weight. Toxicities were assessed 1 month after implantation by a safety monitoring committee to determine whether subsequent escalations should occur. Nine additional patients were studied at the MTD to confirm safety. BCNU blood levels were obtained before and after polymer implantation.

Results: No dose-limiting toxicities were identified at the 6.5%, 10%, or 14.5% dose levels, although difficulties with wound healing, seizures, and brain edema were noted. At the 20% dose, these effects seemed more prominent, and six additional patients were treated at this dose and tolerated treatment well. Three of four patients receiving the 28% polymers developed severe brain edema and seizures, and accrual to this cohort was stopped. Nine additional patients received 20% polymer, confirming this as the MTD. Maximum BCNU plasma concentrations with the 20% loaded polymers were 27 ng/mL. Overall median survival was 251 days.

Conclusion: The MTD of BCNU delivered in polymer to the surgical cavity is 20%. This polymer provides five times more BCNU than standard commercially available BCNU polymers and results in minimal systemic BCNU exposure. Additional studies are needed to establish the efficacy of high-dose BCNU polymers.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
APPROXIMATELY 17,500 new cases of primary CNS malignancy are diagnosed each year in the United States, and primary CNS tumors account for approximately 12,000 deaths per year. In adults malignant gliomas account for the majority of primary brain tumors.^1,2

The prognosis for patients with high-grade astrocytomas remains poor. The median survival for patients with glioblastoma multiforme is less than 1 year, and median survival for patients with anaplastic astrocytoma (AA) is less than 2 years.³ Despite significant efforts, the therapeutic approaches to these patients and their overall survival have changed little during the last three decades. Surgery and radiation therapy remain the mainstays of therapy. Adjuvant chemotherapy provides little additional benefit.^3–5 Although these malignancies are not pathologically confined to their site of origin,⁶ most of these tumors first recur locally.⁷ As a result, novel local treatment approaches have been of significant interest to the scientific community. Some have concentrated on the local delivery of radiation therapy, including radioactive seed implants,⁸ novel implanted devices,⁹ and focused external beam radiation.^10,11 Others have infused novel gene therapy vectors,¹² immunotoxins,¹³ or chemotherapy directly into the brain tumor.^14,15

Clinical experience with biodegradable polymers that deliver BCNU (1,3-bis[2-chloroethyl]-1-nitrosourea), also known as carmustine, into the surgical bed of resected high-grade astrocytomas began in 1987. This was preceded by several preclinical studies that provided considerable data demonstrating that the polymers were safe and that they delivered high concentrations of BCNU locally.^16,17 An abbreviated phase I study was conducted in 21 patients, and a dose of 3.85% BCNU by weight (7.7 mg BCNU per polymer) was chosen for clinical development.¹⁸ A randomized phase III trial demonstrated the efficacy of these carmustine-impregnated polymers.¹⁹ This study served as the basis for the United States Food and Drug Administration approval of 3.8% loaded BCNU polymers (a biodegradable wafer, composed of a copolymer matrix impregnated with carmustine; commercially available as Gliadel [Guilford Pharmaceuticals, Baltimore, MD]) in patients with recurrent high-grade astrocytomas. Subsequent studies in newly diagnosed patients indicate that these polymers are safe²⁰ and that they also provide a significant, albeit modest, benefit in patients with newly diagnosed glioblastomas.²¹ Additional studies are also underway to test the efficacy of this form of treatment in patients with brain metastases.

Experimental studies indicate that increasing the concentration of BCNU in the polymers improves survival in rodents with brain tumors.²² In addition, a toxicity study in rodents demonstrated that concentrations ranging from 4% to 20% are well tolerated.²² A primate toxicity study confirmed that polymers with BCNU concentrations as high as 20% were well tolerated when implanted into the monkey brain.²² Furthermore, recent experimental pharmacokinetic studies have shown that 20% BCNU-loaded polymers provide significant penetration of BCNU into the brain.²³ These findings indicate that higher doses of BCNU in the biodegradable polymer wafers may be more efficacious without additional adverse effects in humans.

In light of these observations, this phase I, multicenter, open-label trial of escalating doses of BCNU in the polymer wafer was conducted in patients with recurrent malignant glioma.

	PATIENTS AND METHODS

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This study was conducted by the New Approaches to Brain Tumor Therapy (NABTT) CNS Consortium, which is funded by the National Cancer Institute (Bethesda, MD). Participating institutions included Johns Hopkins Hospital (Baltimore, MD), Massachusetts General Hospital (Boston, MA), Wake Forest University (Winston Salem, NC), Henry Ford Hospital (Detroit, MI), the Moffitt Cancer Center (Tampa, FL), Brown University (Providence, RI), Columbia University (New York, NY), Emory University (Atlanta, GA), Northwestern University (Chicago, IL), the University of Pennsylvania (Philadelphia, PA), and Washington University at St. Louis (St. Louis, MO). The clinical research protocol was approved by the Cancer Therapy Evaluation Program at the National Cancer Institute and by the institutional review boards of each participating institution. Informed consent was obtained from each patient who joined this research study. All patients eligible for this study were registered through the NABTT CNS Consortium Central Operations Office (Baltimore, MD).

Patient Population
Patients were eligible for this study if they were older than 18 years of age and able to give informed consent. In addition, they were required to have a previous diagnosis of malignant glioma, radiologic evidence of progressive disease, a unilateral supratentorial tumor measuring at least 1 cm in diameter where debulking would likely be beneficial to the patient regardless of the planned adjuvant therapy, a Karnofsky performance score (KPS) of 60, more than 3 months since completion of external beam radiation, more than 4 weeks since their last chemotherapy (> 6 weeks for nitrosoureas), diagnosis of recurrent glioma at the time of surgery (by frozen section or squash preparation), a negative pregnancy test, and a willingness to use appropriate birth control measures.

Patients were ineligible if they had not received prior external beam radiation, if there was more than one focus of tumor, if tumor crossed the midline, if there was concomitant life-threatening disease that might result in death within 56 days, or if the patient had a known hypersensitivity to nitrosoureas. In addition, patients with a history of prior focal brain irradiation (gamma knife, stereotactic radiosurgery, seed implants, and so on), prior local chemotherapy or gene therapy, or seizures resistant to medical therapy requiring hospitalization were also ineligible for this trial.

BCNU Wafer Preparation
The BCNU wafers were prepared by Guilford Pharmaceuticals and delivered to participating NABTT institutions. Copolymers of poly-carboxyphenoxypropane and sebacic acid were prepared in 20:80 ratio as previously described.¹⁷ Briefly, polymer and different quantities of carmustine were codissolved in methylene chloride and spray-dried into microspheres that were compressed into disks of 1.5 cm diameter and 1.0 mm thickness and sterilized by 2.2 x 10 Gy gamma radiation. The wafers prepared for this study contained 6.5%, 10% 14.5%, 20%, and 28% weight concentration. The corresponding BCNU doses for 200-mg wafers, the maximum total BCNU doses, and the number of patients enrolled per dose group are summarized in Table 1.

Six patients from participating NABTT sites were enrolled onto each dose group. When each group was fully enrolled, the study was temporarily closed for further accrual until short-term toxicity data were available. Once the last patient in each treatment group had completed the 28-day evaluation period, the safety of that dose was evaluated by the independent Safety Monitoring Committee. This committee was chaired by Michael Walker (National Institutes of Health, Bethesda, MD) and included Edward Laws (University of Virginia, Charlottesville, VA), Philip Gutin (Memorial Sloan-Kettering Cancer Center, New York, NY), and Frank Dorsey (PARAEXEL, Alexandria, VA).

Dose-limiting toxicities were defined as decline in KPS of 40 points from baseline that was sustained for 2 weeks; two or more episodes of status epilepticus; abnormal wound healing requiring a surgical procedure other than simple sutures; evidence of systemic toxicity (WBC 1,999/mm³, granulocytes 999/mm³, platelets 49,999/mm³, hemoglobin 7.9 g/dL, ALT and AST or alkaline phosphatase > 5.0 times the normal limit, bilirubin > 1.5 times upper the limit or two-fold increase, renal function > 3.0 times the normal limit or two-fold increase from baseline); death that was considered by the investigator as probably or definitely related to the BCNU-containing polymer; or any serious adverse event, which in the opinion of the Safety Monitoring Committee was thought to pose unacceptable risk.

The safety profile of each cohort of patients was reviewed 4 weeks after toxicity information was complete for that group of patients. The Safety Monitoring Committee reviewed these toxicities to determine whether the dose was "safe" and the next higher dose could be studied, an additional six patients should be added at the same dose, the dose was too toxic and dose reduction was required, or the maximum-tolerated dose (MTD) had been reached. If no patient or only one patient in the six-patient cohort had dose-limiting toxicities, dose escalation was permitted. If two patients had dose-limiting toxicity, the cohort would be expanded by another six patients. If more than two patients experienced dose-limiting toxicity, this dose level was considered to have unacceptable toxicity and 10 additional patients would be studied at the dose below it to obtain additional safety data.

Magnetic resonance imaging scans were obtained at baseline and on day 56. Patients were not allowed to receive additional chemotherapy, immunotherapy, or other investigational medications for 56 days after implantation of the polymers.

Pharmacokinetic Study Design
After wafer implantation, 3-mL blood samples were taken at 10 predetermined intervals and subsequently analyzed for carmustine levels. The sampling times were presurgery; 3, 6, 9, 12, 24, 36, 48, and 72 hours after implantation of the wafers; and day of discharge. All samples were collected in Vacutainers and stored in a freezer at -20°C until they were shipped to Guilford Pharmaceuticals for analysis. A high-performance liquid chromatographic–mass spectrometric method was used to quantify BCNU levels in human whole blood. A liquid-liquid extraction of BCNU from citrate buffer stabilized with or without acetonitrile blood was performed with dichloromethane-pentane (50:50, %vol/vol). A SCIEX API III triple quadrupole mass spectrometer (Applied Biosystems, Foster City, CA) was used with a 1090 series II high-performance liquid chromatograph (Hewlett Packard, Agilent Technologies, Palo Alto, CA). A Hypersil 3µC18 (100 mm x 4.6 mm; Phenomenex, Torrance, CA) was used to separate BCNU from the internal standard (lomustine [CCNU]). The following ion transitions were monitored: BCNU (185.1 to 79.4 m/z) and CCNU (205.2 to 80.1 m/z). The analytic range of the assay was from 1 to 50 ng/mL.

Statistical Methods
The primary objective of this study was to select an optimal dose of BCNU wafer on the basis of safety (MTD). The primary safety variables associated with this study were the indices of unacceptable toxicity listed above. All of the doses were selected in advance of the study, as were escalation and de-escalation rules. The cohort sizes were chosen without a statistical rationale but were intended to increase the clinical reliability of the findings.

	RESULTS

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Forty-four patients were accrued to this study. Patient characteristics are listed in Table 2. Six patients entered the 6.5% dose level. No dose-limiting toxicities as defined above in the protocol were identified. However, one patient developed hydrocephalus and required a ventriculoperitoneal shunt, and another patient had elevated liver enzymes and four focal seizures. In the 10% and 14.5% dose level cohorts, no dose-limiting toxicities were identified. One patient developed a subdural collection requiring placement of a burr-hole, one patient developed sepsis, one had a wound infection, and another developed a CSF leak. The Data Safety Monitoring Committee deemed these events to be similar in frequency and severity to those typically observed in patients undergoing a re-exploration and resection of a recurrent malignant glioma. The 20% dose cohort had three patients who developed the following adverse events: seizures, brain edema, wound infection, wound drainage, and a bone flap infection. Although these events were believed to be consistent with patients undergoing recurrent craniotomies, the Safety Monitoring Committee recommended that an additional six patients be added to this dose level before further dose escalations were permitted. Thus, the 20% dose level cohort was expanded as recommended. Because the additional six patients did not experience these adverse events, the Safety Monitoring Committee subsequently recommended that the trial proceed to the 28% cohort.

The pharmacokinetic data obtained in this study are summarized in Fig 1. BCNU levels were not detectable in the 6.5% dose level. At higher dose levels, the peak concentrations increased into the detectable range. The highest concentration of BCNU in the serum was 27 ng/mL at 4 hours after implantation in the 20% group.

View larger version (20K): [in this window] [in a new window]   Fig 1. Serum BCNU (carmustine) levels by dose.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Standard therapy for malignant gliomas includes surgical resection, whenever possible, followed by conventional radiation therapy. This provides an average survival of 11 months for glioblastoma multiforme and 2 years for AA.⁴ Adjuvant systemic chemotherapy adds little to the length of survival and is often associated by significant side effects, such as myelosuppression.⁵ In particular, the nitrosoureas, which are the most commonly used chemotherapeutic agents in brain tumors, do not have a high therapeutic ratio (benefit-to-risk ratio).

The notion that these tumors have a high rate of local recurrence and that metastases are exceedingly rare has prompted the introduction of a number of new approaches aimed at more effective local control of the disease. These include focal radiation therapy in the form of stereotactic radiation (gamma knife, linear accelerator) or brachytherapy, immunotoxin injection, gene therapy, and interstitial chemotherapy.

Interstitial chemotherapy as an adjunct treatment for malignant gliomas has been widely used since the United States Food and Drug Administration approval of 3.8% BCNU implantable polymers in 1996. The rationale that guided the development of this form of treatment is based on the ability of these drug-impregnated polymers to circumvent the blood-brain barrier and achieve sufficiently high local concentrations of BCNU, while greatly decreasing systemic toxicity. It is estimated that currently 23% of patients affected by recurrent malignant gliomas and 15% of those affected by newly diagnosed malignant gliomas in the United States receive the commercially available BCNU polymers at the time of the surgical resection (F. Anderson, personal communication, American Association of Neurological Surgeons 2000). This treatment has been shown to be effective in prolonging survival in patients affected by recurrent and newly diagnosed gliomas in a modest but statistically significant fashion^19,21 In particular, Brem et al¹⁹ have reported survival, at the 6-month benchmark, to be 50% greater in the group of patients treated with commercially available BCNU polymers than the group of patients receiving placebo (42% v 64% mortality).

In addition, a number of clinical protocols in which the commercially available BCNU polymer is used concomitantly with other forms of treatment are currently under way in the United States and Europe. Kleinberg et al²⁴ have reported the results of a group of patients treated with the commercially available BCNU polymer and concomitant radiation treatment. A higher incidence of treatment necrosis was observed in these patients. The loading dose of BCNU in commercially available polymers is 3.85% of total weight. In an attempt to further improve the efficacy of this novel form of treatment, the present dose-escalation study was aimed at determining the MTD of BCNU incorporated into the implantable polymers.

Sipos et al²² had demonstrated that higher doses of BCNU incorporated into biodegradable polymers are more effective in the treatment of experimental tumors in rats. They studied a number of preparations and loading doses of BCNU polymers against 9L gliomas and concluded that polifeprosan 20 polymers containing 20% BCNU were the most effective in prolonging survival in rats harboring these tumors. Polymers containing 32% BCNU were also effective against the tumors but generated noticeable toxicity in the rats.

In the dose-escalation study reported here, significant adverse events were not observed until the 20% loading dose was reached. Three of the initial six patients receiving 20% loaded polymers developed adverse events that were considered more prominent than would be expected in this patient population. A careful review by the Safety Monitoring Committee of each case resulted in the recommendation to repeat treatment testing in six additional patients. No significant side effects were observed in this additional group. When the dose was escalated to 28%, however, serious episodes of severe postoperative edema and seizures were observed in three of the four patients. One patient required reoperation and polymer removal with subsequent clinical improvement of the brain edema. It appeared clear that the dose was associated with dose-limiting toxicity. Ten additional patients were enrolled (as per protocol) at the lower dose (20%). Of these, only nine patients were assessed because one received the commercially available 3.85% BCNU polymer instead of the 20% polymers. No dose-limiting toxicities were observed in this final group of patients, confirming that the MTD was 20%. This study demonstrates that doses of BCNU in excess of five times the current commercially available BCNU dose in the polymer are tolerated.

Of note, the experimental studies previously carried out in animals were accurate in predicting the MTD of the BCNU polymers subsequently established in our patients. In addition, our study demonstrated that even with the highest loading dose, the systemic exposure to BCNU was minimal, thus underscoring one of the main advantages of this form of local treatment. In our pharmacokinetic studies, BCNU could be measured systemically but the concentrations were 500 times lower than those known to cause acute systemic toxicity.

As a phase I study, our protocol was not designed to determine the efficacy of polymers containing BCNU in the treatment of malignant gliomas. However, optimizing the dose of a treatment that has already shown evidence of clinical effectiveness might provide an additional tool in developing better therapies for a disease that remains uniformly fatal. A phase III trial comparing commercially available polymer, which is loaded with 3.85% BCNU, with a polymer containing higher doses of BCNU is needed to determine the benefit of increasing the local delivery of this chemotherapeutic agent in patients with malignant gliomas.

	ACKNOWLEDGMENTS

 
We thank the members of the Safety Monitoring Committee (Michael Walker, MD, Ed Laws, MD, Phil Gutin, MD, and Frank Dorsey, MD). We thank Pamela Talalay, PhD, for her assistance in the preparation of the manuscript.

	NOTES

 
Supported in part by a grant from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, which funds the NABTT CNS Consortium (NIH/NCI CA-62475), and Guilford Pharmaceuticals.

	REFERENCES

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Submitted September 6, 2002; accepted February 12, 2003.

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