Phase I clinical and pharmacokinetic study of irinotecan in adults with recurrent malignant glioma.

PURPOSE: A preliminary evaluation of the efficacy of irinotecan in patients with malignant glioma demonstrated modest activity. A markedly lower than expected incidence of drug-related toxicity was also noted. This was consistent with pharmacokinetic data indicating that the total body clearance (CL) of irinotecan in this patient population was considerably greater than in colorectal cancer patients. Concomitant medications used chronically in brain cancer patients, especially glucocorticoids and anticonvulsants that induce hepatic enzymes involved in the metabolism or excretion of drugs, were believed to be the cause of the alteration in pharmacokinetic behavior. A Phase I study was therefore undertaken in patients with recurrent malignant gliomas to independently determine the maximum tolerated dose (MTD) of irinotecan in patients stratified according to the use of enzyme-inducing anticonvulsants (EIAs). Experimental Design: Patients with recurrent malignant gliomas received irinotecan as a weekly 90-min i.v. infusion for four consecutive weeks, with additional cycles of treatment repeated every 6 weeks. The starting dose was 125 mg/m(2)/week for both groups of patients (+/-EIA). Groups of >/==" BORDER="0">3 patients were evaluated at each dose level, and the modified continual reassessment method was used for dose adjustments. The plasma pharmacokinetics of irinotecan, its active metabolite, 7-ethyl-10-hydroxy-camptothecin (SN-38), and the glucuronide conjugate of SN-38, SN-38 glucuronide, were determined in all patients during treatment with the first weekly dose. RESULTS: Forty patients were enrolled into the study and treated with a total of 135 cycles of irinotecan. The MTD was determined to be 411 mg/m(2)/week in the +EIA cohort and 117 mg/m(2)/week in the -EIA cohort for the weekly x 4 every 6 weeks schedule. Pharmacokinetic studies showed that the CL of irinotecan was distinctly dose dependent in the patients receiving EIAs, decreasing from approximately 50 liters/h/m(2) at the lower dose levels (125-238 mg/m(2)) to a mean +/- SD value of 29.7 +/- 9.0 liters/h/m(2) (n = 7) at the MTD. The grand mean CL for a group of 13 patients who were not taking EIAs, 18.8 +/- 10.6 liters/h/m(2), was significantly different from the mean CL at the MTD of the +EIA cohort (P = 0.033). Mean values of the AUC of SN-38 (P = 0.4) and SN-38 glucuronide (P = 0.55) were not significantly different at the MTDs for the two cohorts of patients. CONCLUSIONS: The MTD of irinotecan was 3.5 times greater in patients with malignant glioma who were concurrently receiving EIAs than in those who were not. This study has also served to confirm that the concomitant administration of EIAs results in marked enhancement in the CL of irinotecan. These findings have important implications for subsequent clinical trials to further evaluate irinotecan in brain cancer patients and underscore the importance of assessing the potential for pharmacokinetic interactions between concurrent medications and chemotherapeutic agents.     

Phase I trial of irinotecan plus temozolomide in adults with recurrent malignant glioma

BACKGROUND: The authors determined the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of irinotecan (CPT-11), a topoisomerase I inhibitor, when administered with temozolomide among patients with recurrent malignant glioma (MG). METHODS: Patients with MG at any recurrence received temozolomide (TMZ) at a dose of 200 mg/m(2)/day on Days 1-5 plus CPT-11 administered as a 90-minute intravenous infusion during Weeks 1, 2, 4, and 5 of each 6-week cycle. Patients were stratified based on concurrent administration of CYP3A4-inducing anticonvulsants (enzyme-inducing antiepileptic drugs [EIAEDs]). The CPT-11 dose was escalated in successive cohorts of patients independently for each stratum. RESULTS: CPT-11, at doses ranging from 40 mg/m(2) to 375 mg/m(2), was administered with TMZ to 107 patients. Ninety-one patients (85%) had recurrent glioblastoma multiforme (GBM) and 16 (15%) had recurrent anaplastic glioma. Sixty-eight patients (64%) were given EIAEDs. The MTD of CPT-11 for patients concurrently receiving and not receiving EIAEDs was 325 mg/m(2) and 125 mg/m(2), respectively. The DLTs were hematologic, gastrointestinal, and hepatic. Fifteen patients (14%) achieved either a radiographic complete (n = 5) or partial (n = 10) response across a wide range of CPT-11 dose levels. Patients with recurrent GBM who achieved radiographic response had a median time to disease progression of 54.9 weeks. CONCLUSIONS: The current study built on preclinical observations designed to increase the clinical activity of topoisomerase I inhibitors. CPT-11, administered at full dose levels, was well tolerated in combination with TMZ. Furthermore, durable responses were observed in this recurrent population. Ongoing Phase II studies will evaluate the efficacy of this regimen and its application to other malignancies.     

Phase II study of sunitinib malate in patients with recurrent high-grade glioma

Receptor tyrosine kinase signaling causes profound neo-angiogenesis in high-grade gliomas (HGG). The KIT, PDGFR-??, and VEGFR2 genes are frequently amplified and expressed in HGG and are molecular targets for therapeutic inhibition by the small-molecule kinase inhibitor sunitinib malate. Twenty-one patients with progressive HGG after prior radiotherapy and chemotherapy received a daily dose of 37.5 mg sunitinib until progression or unacceptable toxicity. Magnetic resonance imaging (MRI) and dynamic susceptibility contrast (DSC)-enhanced perfusion measurements were performed before and during therapy. Cerebral blood volume (CBV) and cerebral blood flow (CBF) lesion-to-normal-white matter ratios were measured to evaluate the antiangiogenic effects of sunitinib. The most frequent grade ??3 adverse events were skin toxicity, neutropenia, thrombocytopenia, and lymphocytopenia. None of the patients achieved an objective response, whereas a decrease in CBV and CBF within the lesion compared with the normal brain was documented in four out of 14 (29%) patients evaluable for DSC-enhanced perfusion measurements. All patients experienced progression of their disease before or after eight weeks of therapy. Median time-to-progression and overall survival were 1.6 (95%CI 0.8?C2.5) and 3.8 (95% CI 2.2?C5.3) months, respectively. No correlation could be established between VEGFR2, PDGFR-??, and KIT gene copy numbers or protein expression and the effects of sunitinib. Single-agent sunitinib at 37.5 mg/day had insufficient activity to warrant further investigation of this monotherapy regimen in recurrent HGG.     

Phase I study of RO4929097 with bevacizumab in patients with recurrent malignant glioma

Antiangiogenic therapies for malignant gliomas often result in transient response, and recurrent disease is characterized by adoption of invasive and hypoxic phenotype. The notch signaling pathway is activated in gliomas, and augments cell migration and hypoxic response. Here we report a clinical study of the combination of bevacizumab and RO4929097, an inhibitor of the notch signaling cascade. A phase I clinical trial was conducted through the Adult Brain Tumor Consortium in subjects with recurrent malignant glioma. Primary objectives were to assess safety and to define the maximum tolerated dose of RO4929097 in combination with bevacizumab. Secondary objectives were to determine overall survival, progression free survival, radiographic response, pharmacokinetic evaluation, and tissue biomarker analysis. Thirteen subjects were enrolled. Of the three subjects treated with the highest dose of RO4929097, one grade 3 toxicity and one grade 2 toxicity were observed. Definitive maximum tolerated dose of RO4929097 in combination with bevacizumab was not identified due to manufacturer’s decision to halt drug production. 2 of 12 evaluable subjects demonstrated radiographic response; one subject experienced CR and the second PR. The median overall survival was 10.9 months with a median progression-free survival of 3.7 months. Two subjects remained free of disease progression at 6 months from treatment initiation. PK evaluation did not identify clinically significant drug–drug interactions. All analyzed tissue specimens revealed activation of notch signaling. Combination of RO4929097 and bevacizumab was well-tolerated. Given the compelling scientific rationale, additional studies of antiangiogenic and notch signaling inhibitors should be considered.     

Phase 1 trial of irinotecan plus BCNU in patients with progressive or recurrent malignant glioma

Irinotecan is a topoisomerase I inhibitor previously shown to be active in the treatment of malignant glioma. We now report the results of a phase 1 trial of irinotecan plus BCNU, or 1,3-bis(2-chloroethyl)-1-nitrosourea, for patients with recurrent or progressive MG. Irinotecan dose escalation occurred independently within 2 strata: patients receiving enzyme-inducing antiepileptic drugs (EIAEDs) and patients not receiving EIAEDs. BCNU was administered at a dose of 100 mg/m2 over 1 h every 6 weeks on the same day as the first irinotecan dose was administered. Irinotecan was administered intravenously over 90 min once weekly. Treatment cycles consisted of 4 weekly administrations of irinotecan followed by a 2-week rest with dose escalation in cohorts of 3 to 6 patients. Seventy-three patients were treated, including 49 patients who were on EIAEDs and 24 who were not on EIAEDs. The maximum tolerated dose for patients not on EIAEDs was 125 mg/m2. The maximum tolerated dose for patients on EIAEDs was 225 mg/m2. Dose-limiting toxicity was evenly distributed among the following organ systems: pulmonary, gastrointestinal, cardiovascular, neurologic, infectious, and hematologic, without a clear predominance of toxicity involving any one organ system. There was no evidence of increasing incidence of toxicity involving one organ system as irinotecan dose was escalated. On the basis of these results, we conclude that the recommended doses of irinotecan for a phase 2 clinical trial when given in combination with BCNU (100 mg/m2) are 225 mg/m2 for patients on EIAEDs and 125 mg/m2 for patients not on EIAEDs.     

Phase II study of topotecan in patients with recurrent malignant glioma

Background: The NCIC Clinical Trials Group has an ongoing interestin assessing investigational agents in minimally pretreatedpatients with malignant glioma. Topotecan is one of the firsttopoisomerase I inhibitors to enter clinical trials and hasshown early evidence of activity in several solid tumors. Wehave conducted a phase II trial of topotecan in patients withmalignant glioma. Methods: Adults with malignant glioma and recurrent contrastenhancing measurable disease (     

Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma.

PURPOSE: Recurrent grade III-IV gliomas have a dismal prognosis with minimal improvements in survival seen following currently available salvage therapy. This study was conducted to determine if the combination of a novel antiangiogenic therapy, bevacizumab, and a cytotoxic agent, irinotecan, is safe and effective for patients with recurrent grade III-IV glioma. EXPERIMENTAL DESIGN: We conducted a phase II trial of bevacizumab and irinotecan in adults with recurrent grade III-IV glioma. Patients with evidence of intracranial hemorrhage on initial brain magnetic resonance imaging were excluded. Patients were scheduled to receive bevacizumab and irinotecan i.v. every 2 weeks of a 6-week cycle. Bevacizumab was administered at 10 mg/kg. The dose of irinotecan was determined based on antiepileptic use: patients taking enzyme-inducing antiepileptic drugs received 340 mg/m(2), whereas patients not taking enzyme-inducing antiepileptic drugs received 125 mg/m(2). Toxicity and response were assessed. RESULTS: Thirty-two patients were assessed (23 with grade IV glioma and 9 with grade III glioma). Radiographic responses were noted in 63% (20 of 32) of patients (14 of 23 grade IV patients and 6 of 9 grade III patients). The median progression-free survival was 23 weeks for all patients (95% confidence interval, 15-30 weeks; 20 weeks for grade IV patients and 30 weeks for grade III patients). The 6-month progression-free survival probability was 38% and the 6-month overall survival probability was 72%. No central nervous system hemorrhages occurred, but three patients developed deep venous thromboses or pulmonary emboli, and one patient had an arterial ischemic stroke. CONCLUSIONS: The combination of bevacizumab and irinotecan is an active regimen for recurrent grade III-IV glioma with acceptable toxicity.     

Phase II trial of irinotecan plus celecoxib in adults with recurrent malignant glioma

BACKGROUND: In the current study, the authors report a Phase II trial of irinotecan (CPT-11), a topoisomerase I inhibitor active against malignant glioma (MG), with celecoxib, a selective COX-2 inhibitor, among MG patients with recurrent disease. METHODS: Patients with MG at any type of recurrence received CPT-11, administered as a 90-minute intravenous infusion on Weeks 1, 2, 4, and 5 of each 6-week cycle plus celecoxib, which was administered continuously at a dose of 400 mg twice a day. CPT-11 was given at a dose of 350 mg/m(2) for patients receiving enzyme-inducing antiepileptic drugs (EIAEDs) and at a dose of 125 mg/m(2) for those patients not receiving EIAEDs. Assessments were performed after every cycle. The primary endpoint was radiographic response and the secondary endpoints were progression-free survival (PFS), overall survival (OS), and therapeutic safety. RESULTS: Thirty-four of the 37 patients enrolled in the current study (92%) were diagnosed with recurrent GBM and 3 patients (8%) were diagnosed with recurrent anaplastic astrocytoma (AA). Twenty-one patients were receiving EIAEDs and 16 patients were not. The median follow-up time was 76.9 weeks. Concomitant CPT-11 plus celecoxib was found to be well tolerated and safe. Hematologic toxicities of >/= Grade 3 (according the second version of the Common Toxicity Criteria of the National Cancer Institute) reportedly complicated 8.6% of treatment courses. Grade 3 diarrhea, the most commonly reported nonhematologic toxicity, occurred with equal frequency (8%), regardless of whether the patient was receiving EIAED. Six patients (16%), all whom were diagnosed with recurrent GBM, achieved an objective radiographic response whereas an additional 13 patients (35%) achieved stable disease. The median PFS was 11.0 weeks and the 6-month PFS was reported to be 25.1%. The median OS was 31.5 weeks. CONCLUSIONS: The results of the current study confirm that CPT-11 plus celecoxib can be safely administered concurrently at full dose levels, and that this regimen has encouraging activity among heavily pretreated patients with recurrent MG.     

Phase I trial of sorafenib in patients with recurrent or progressive malignant glioma

Sorafenib is an inhibitor of multiple kinases that has demonstrated antiproliferative and antiangiogenic activity in a number of in vitro and in vivo model systems. A phase I study was conducted to determine the maximum tolerated dose (MTD) of sorafenib in patients with recurrent malignant glioma. Sorafenib was given orally, twice a day (BID), continuously in 28-day cycles. The dose was escalated in 2 groups of patients stratified by use of enzyme-inducing antiseizure drugs (± EIASDs). Dose-limiting toxicity (DLT) was defined as any grades 3-4 nonhematological toxicity, grade 4 hematological toxicity, and febrile neutropenia. The number of evaluable patients enrolled in the +EIASD and -EIASD arms were 23 and 24, respectively. DLTs were predominantly dermatological and gastrointestinal effects, as observed in previous clinical trials of sorafenib. The MTD was 600 mg BID for patients receiving EIASDs and 800 mg BID for those who were not. The plasma pharmacokinetics of sorafenib were not significantly affected by the concurrent administration of EIASDs. The MTD of sorafenib given orally BID on a continuous basis was established as 600 mg BID in patients with malignant glioma who were concurrently receiving EIASDs and 800 mg BID in those who were not. Further evaluation is warranted of sorafenib at the recommended MTD against recurrent or progressive malignant glioma in combination with other molecularly targeted drugs or in the newly diagnosed setting concurrent with chemoradiation.     

Temozolomide in combination with irinotecan for treatment of recurrent malignant glioma

The prognosis for patients with recurrent malignant glioma is poor. Both temozolomide and irinotecan have been shown to be active in this disease. A study was performed combining temozolomide 200 mg/m2 daily for 5 days and irinotecan 125 mg/m2 on days 6, 13, and 20 initially (Schedule A) and then changed to (Schedule B) temozolomide 200 mg/m2 daily for 5 days and irinotecan 350 mg/m2 on day 6. Each cycle was 28 days. All patients with recurrent tumor had to complete two cycles of therapy to be evaluable. Six cycles of treatment were provided for all responders. Thirty-two patients were treated, 6 with schedule A, 24 with schedule B, and 2 initially schedule A and then switched to schedule B. Eighteen patients (56%) had glioblastoma and 14 patients and anaplastic glioma (AOA 8, anaplastic astrocytoma 4, AO 2). Eighty-three percent (15/18) of patients with glioblastoma responded (complete response [CR] 2, partial response [PR] 3, stable disease [SD] 10). Median duration of response was 24 weeks, and 6-month progression-free survival (PFS) was 39% (7/18). Fourteen patients with anaplastic glioma were treated and all responded (CR 3, PR 2, SD 9). Median duration of response was 29 weeks and 6-month PFS was 71% (10/14). Grade IV leukopenia occurred in one patient and grade IV thrombocytopenia in two patients. Two patients were admitted to the hospital for neutropenic fever. Nonhematologic toxicity was mild and mostly gastrointestinal. These results demonstrate a favorable response and low toxicity with combined irinotecan and temozolomide therapy and warrant further clinical evaluation.     

Phase I study of temozolomide and escalating doses of oral etoposide for adults with recurrent malignant glioma

BACKGROUND: Although temozolomide is active against recurrent malignant glioma, responses in many patients are modest and short-lived. Temozolomide may prove more effective in combination with other agents. Therefore, combination oral chemotherapy for these patients is a particularly attractive approach. METHODS: The authors conducted a Phase I study of temozolomide in combination with escalating doses of oral etoposide (VP-16) to determine the maximum tolerated doses of these two agents when given together. The temozolomide dose was fixed at 150 mg/m(2) per day on Days 1-5. The oral VP-16 was escalated in cohorts of 3 to 6 patients by numbers of days of VP-16 administered: 50 mg/m(2) per day, Days 1-5 (dose level 1), Days 1-8 (dose level 2), Days 1-12 (dose level 3), Days 1-16 (dose level 4), and Days 1-20 (dose level 5). Therapy was given in 28-day cycles. RESULTS: Of the 29 patients enrolled, 26 were fully evaluable and 3 were partially evaluable for toxicity. The 29 patients received a total of 92 cycles. The median age of the patients was 49 years (range, 28-76 years). Diagnoses included glioblastoma (n = 19), gliosarcoma (n = 3), anaplastic astrocytoma (n = 5), and anaplastic oligoastrocytoma (n = 2). The median time from diagnosis to disease recurrence was 8 months (3-188 months). Twenty patients were treated at the first disease recurrence, seven at the second, and two at the third. Twenty-four patients (83%) were receiving anticonvulsants and 24 were receiving dexamethasone. All patients had received previous radiation, and 25 of 29 had been treated with chemotherapy previously. Of the 3 patients at dose level 1, none had dose-limiting toxicity (DLT). Of the 6 patients at dose level 2, 1 patient had DLT: Grade 3 thrombocytopenia resulting in a > 2-week delay in starting the next cycle of chemotherapy. Of the 6 patients at dose level 3, 1 patient had DLT: death due to pneumonia. There were 2 DLTs in the 7 patients at dose level 4: fever, neutropenia, and herpes zoster infection in 1 patient and death due to pneumonia in another. Seven patients had been started at dose level 5 when DLT was established at dose level 4: of the 5 fully evaluable and 2 partially evaluable patients at dose level 5, there was no DLT. CONCLUSIONS: The maximum tolerated dose of temozolomide and oral VP-16 in this heavily treated group of patients with recurrent malignant glioma is temozolomide 150 mg/m(2) per day for 5 days and oral VP-16 50 mg/m(2) per day for 12 days.     

Phase I safety study of escalating doses of atrasentan in adults with recurrent malignant glioma

Atrasentan is an oral selective endothelin-A receptor antagonist that may inhibit cell proliferation and interfere with angiogenesis during glioma growth. We conducted a dose-finding study to assess atrasentan's safety and toxicity and to gather preliminary evidence of efficacy. Patients with recurrent malignant glioma received oral atrasentan at >or=10 mg/day. We increased the dose among cohorts until the maximum tolerated dose (MTD) was defined. Patients were evaluated for response every 8 weeks and remained on the study until the tumor progressed or toxicities occurred. Twenty-five patients were enrolled, with a median age of 53 years (range, 25-70) and a median KPS of 90% (range, 60-100%). Twenty-two patients had glioblastoma multiforme (GBM), 2 had anaplastic astrocytoma, and 1 had an anaplastic oliogodendroglioma; 24 patients had received one prior chemo therapy regimen before being enrolled in the study. The most common atrasentan-related toxicities were grade 1 or 2 rhinitis, fatigue, and edema. One patient developed grade 3 hypoxia and peripheral edema at a dose of 90 mg/day. We observed no dose-limiting toxicities in an expanded cohort of 10 patients at 70 mg/day, which was declared the MTD. Two partial responses (8%) were seen in patients with GBM at the 70- and 90-mg/day dose levels, and 4 patients had stable disease before progressing. Nineteen patients have died, and median survival was 6.0 months (95% confidence interval, 4.2-9.5 months). We conclude that the MTD of daily oral atrasentan in patients with recurrent malignant glioma is 70 mg/day. Further study of atrasentan with radiation therapy and temozolomide in newly diagnosed GBM is warranted to evaluate the efficacy of this novel agent.     

Phase II trial of continuous low-dose temozolomide for patients with recurrent malignant glioma

Background

In this phase II trial, we investigated the efficacy of a metronomic temozolomide schedule in the treatment of recurrent malignant gliomas (MGs).

Methods

Eligible patients received daily temozolomide (50 mg/m²) continuously until progression. The primary endpoint was progression-free survival rate at 6 months in the glioblastoma cohort (N = 37). In an exploratory analysis, 10 additional recurrent grade III MG patients were enrolled. Correlative studies included evaluation of 76 frequent mutations in glioblastoma (iPLEX assay, Sequenom) aiming at establishing the frequency of potentially “drugable” mutations in patients entering recurrent MG clinical trials.

Results

Among glioblastoma patients, median age was 56 y; median Karnofsky Performance Score (KPS) was 80; 62% of patients had been treated for ≥2 recurrences, including 49% of patients having failed bevacizumab. Treatment was well tolerated; clinical benefit (complete response + partial response + stable disease) was seen in 10 (36%) patients. Progression-free survival rate at 6 months was 19% and median overall survival was 7 months. Patients with previous bevacizumab exposure survived significantly less than bevacizumab-naive patients (median overall survival: 4.3 mo vs 13 mo; hazard ratio = 3.2; P = .001), but those patients had lower KPS (P = .04) and higher number of recurrences (P < .0001). Mutations were found in 13 of the 38 MGs tested, including mutations of EGFR (N = 10), IDH1 (N = 5), and ERBB2 (N = 1).

Conclusions

In spite of a heavily pretreated population, including nearly half of patients having failed bevacizumab, the primary endpoint was met, suggesting that this regimen deserves further investigation. Results in bevacizumab-naive patients seemed particularly favorable, while results in bevacizumab-failing patients highlight the need to develop further treatment strategies for advanced MG.

Clinical trials.gov identifier

{"type":"clinical-trial","attrs":{"text":"NCT00498927","term_id":"NCT00498927"}}NCT00498927 (available at http://clinicaltrials.gov/ct2/show/{"type":"clinical-trial","attrs":{"text":"NCT00498927","term_id":"NCT00498927"}}NCT00498927)     

Phase 2 study of weekly irinotecan in adults with recurrent malignant glioma: final report of NABTT 97-11

The primary objective of this study was to determine the proportion of patients exhibiting a radiographic response in a cohort of patients with recurrent malignant glioma who were treated with irinotecan. Secondary objectives were to determine progression-free survival, overall survival, and toxicity. The trial was terminated after the first 18 patients were enrolled in this multicenter, 2-stage, phase 2 study. Twelve patients received concurrent enzyme-inducing antiepileptic drugs, and 6 did not. Each cycle consisted of a 90-min i.v. infusion of irinotecan every week for 4 consecutive weeks, followed by 2 weeks off. One patient had a complete response, 5 patients had stable disease, 5 patients had radiographic progression, 6 patients were removed from the study because of toxicity, and 1 patient refused further therapy and was removed from the study. The response rate in this study was 6% (1/18), and 28% (5/18) of these patients progressed while receiving irinotecan. Dose-limiting toxicities consisted of diarrhea in 5 patients, neutropenia in 1 patient, infection in 1 patient, and respiratory failure in 1 patient. Irinotecan had minimal efficacy in this cohort of 18 patients with recurrent malignant glioma. Toxicity was significant but similar to that reported in other patient populations.     

Phase 1 trial of irinotecan (CPT-11) in patients with recurrent malignant glioma: a North American Brain Tumor Consortium study

This study was conducted to determine the maximum tolerated dose and dose-limiting toxicity of irinotecan (CPT-11) administered every 3 weeks to adults with progressive malignant glioma who were treated with enzyme inducing antiepileptic drug (EIAED) therapy, and to compare the pharmacokinetics with those in patients not on EIAED therapy treated at the recommended phase 2 dose for other cancers. The CPT-11 dose was 350 mg/m(2) i.v. every 3 weeks and remained fixed in patients not on EIAED therapy, but the dose was escalated by 50-mg/m(2) increments in patients on EIAED therapy. CPT-11 and its metabolites SN-38, SN-38 glucuronide (SN-38G), and APC (7-ethyl-10[4-N-(5 aminopentanoic acid)-1-piperidine]-carbonyloxycamptothecin) were characterized in both groups. Patients on EIAEDs received 350 to 800 mg/m(2) of CPT-11. Dose-limiting toxicity was due to grade 3 diarrhea despite maximal doses of loperamide. The systemic levels of CPT-11, APC, SN-38G, and SN-38 were all lower in the EIAED group. There was a moderate-to-fair relationship between CPT-11 dose and the area under the curve (AUC) for CPT-11 and APC over the 2, but no relationship dosage range of 350 to 800 mg/m between CPT-11 dose and the AUC for SN-38 or SN-38G. At the 750-mg/m(2) dose, the AUC for CPT-11 (21.6 microg x h/ml) matched the AUC (21.6 microg x h/ml) in the non-EIAED group treated with 350 mg/m(2) of CPT-11. We conclude that the recommended phase 2 dose of CPT-11 for patients on EIAEDs is 750 mg/m(2) when given every 3 weeks. A phase 2 study of patients with recurrent malignant glioma is ongoing to assess the efficacy of CPT-11 when the dose is stratified according to the use of EIAEDs.     

Phase I and pharmacokinetic study of karenitecin in patients with recurrent malignant gliomas

Karenitecin is a highly lipophilic camptothecin analogue with a lactone ring that is relatively resistant to inactivating hydrolysis under physiologic conditions. This phase I clinical trial was conducted to determine the maximum tolerated dose (MTD) of karenitecin in adults with recurrent malignant glioma (MG), to describe the effects of enzyme-inducing antiseizure drugs (EIASDs) on its pharmacokinetics, and to obtain preliminary evidence of activity. Karenitecin was administered intravenously over 60 min daily for 5 consecutive days every 3 weeks to adults with recurrent MG who had no more than one prior chemotherapy regimen. The continual reassessment method was used to escalate doses, beginning at 1.0 mg/m(2)/day, in patients stratified by EIASD use. Treatment was continued until disease progression or treatment-related dose-limiting toxicity (DLT). Plasma pharmacokinetics was determined for the first daily dose of karenitecin. Thirty-two patients (median age, 52 years; median KPS score, 90) were accrued. Seventy-eight percent had glioblastoma, and 22% had anaplastic glioma. DLT was reversible neutropenia or thrombocytopenia. The MTD was 2.0 mg/m(2) in daggerEIASD patients and 1.5 mg/m(2) in -EIASD patients. The mean (+/-SD) total body clearance of karenitecin was 15.9 +/- 9.6 liters/h/m(2) in daggerEIASD patients and 10.2 +/- 3.5 liters/h/m(2) in -EIASD patients (p = 0.02). No objective responses were observed in 11 patients treated at or above the MTD. The total body clearance of karenitecin is significantly enhanced by the concurrent administration of EIASDs. This schedule of karenitecin, a novel lipophilic camptothecin analogue, has little activity in recurrent MG.     

A prospective phase II single-institution trial of sunitinib for recurrent malignant glioma

Single-agent sunitinib, an oral small molecule inhibitor of multiple tyrosine kinase receptors, was evaluated for treatment of patients with recurrent glioblastoma (GB) and anaplastic astrocytoma (AA). Fourteen AA and 16?GB patients, all previously treated with surgery, radiotherapy, and temozolomide, were enrolled in a prospective phase II study at either first or second relapse. Patients were treated with daily sunitinib for 4 consecutive weeks, followed by a 2-week break. For AA patients, the most common side effects were fatigue (86?%), diarrhea (43?%), hand-foot syndrome (36?%), neutropenia (36?%), thrombocytopenia (36?%), and nausea (29?%). In the GB cohort, the most common side effects were fatigue (56?%), diarrhea (44?%), neutropenia (31?%), and thrombocytopenia (25?%). Six of 14 (43?%) AA and 5 of 16 (31?%) GB patients experienced grade 3 or greater toxicities. Five patients discontinued study due to drug toxicities. There were no partial or complete responses in either cohort; 8/14 (57?%) AA and 5/16 (31?%) GB patients had stable disease at the first planned assessment. Progression-free survival at 6?months was 21.5?% (AA) and 16.7?% (GB). Median overall survival was 12.1?months (AA) and 12.6?months (GB). These results are comparable to those reported in the literature in patients treated with standard cytotoxic therapies. This is the largest reported trial of sunitinib in recurrent malignant astrocytic gliomas to date, as well as contains the largest AA cohort. Nonetheless, sunitinib did not demonstrate significant anti-glioma activity in patients with recurrent malignant astrocytic gliomas.     

Phase I trial of temozolomide plus O6-benzylguanine for patients with recurrent or progressive malignant glioma.

PURPOSE: We conducted a two-phase clinical trial in patients with progressive malignant glioma (MG). The first phase of this trial was designed to determine the dose of O6-BG effective in producing complete depletion of tumor AGT activity for 48 hours. The second phase of the trial was designed to define the maximum tolerated dose (MTD) of a single dose of temozolomide when combined with O6-BG. In addition, plasma concentrations of O6-BG and O6-benzyl-8-oxoguanine were evaluated after O6-BG. PATIENTS AND METHODS: For our first phase of the clinical trial, patients were scheduled to undergo craniotomy for AGT determination after receiving a 1-hour O6-BG infusion at 120 mg/m2 followed by a continuous infusion at an initial dose of 30 mg/m2/d for 48 hours. The dose of the continuous infusion of O6-BG escalated until tumor AGT was depleted. Once the O6-BG dose was established a separate group of patients was enrolled in the second phase of clinical trial, in which temozolomide, administered as a single dose at the end of the 1-hour O6-BG infusion, was escalated until the MTD was determined. RESULTS: The O6-BG dose found to be effective in depleting tumor AGT activity at 48 hours was an IV bolus of 120 mg/m2 over 1 hour followed by a continuous infusion of 30 mg/m2/d for 48 hours. On enrolling 38 patients in six dose levels of temozolomide, the MTD was established at 472 mg/m2 with dose-limiting toxicities limited to myelosuppression. CONCLUSION: This study provides the foundation for a phase II trial of O6-BG plus temozolomide in temozolomide-resistant MG.     

Phase I trial of carmustine plus O6-benzylguanine for patients with recurrent or progressive malignant glioma.

PURPOSE: The major mechanism of resistance to alkylnitrosourea therapy involves the DNA repair protein O(6)-alkylguanine-DNA alkyltransferase (AGT), which removes chloroethylation or methylation damage from the O(6) position of guanine. O(6)-benzylguanine (O(6)-BG) is an AGT substrate that inhibits AGT by suicide inactivation. We conducted a phase I trial of carmustine (BCNU) plus O(6)-BG to define the toxicity and maximum-tolerated dose (MTD) of BCNU in conjunction with the preadministration of O(6)-BG with recurrent or progressive malignant glioma. PATIENTS AND METHODS: Patients were treated with O(6)-BG at a dose of 100 mg/m(2) followed 1 hour later by BCNU. Cohorts of three to six patients were treated with escalating doses of BCNU, and patients were observed for at least 6 weeks before being considered assessable for toxicity. Plasma samples were collected and analyzed for O(6)-BG, 8-oxo-O(6)-BG, and 8-oxoguanine concentration. RESULTS: Twenty-three patients were treated (22 with glioblastoma multiforme and one with anaplastic astrocytoma). Four dose levels of BCNU (13.5, 27, 40, and 55 mg/m(2)) were evaluated, with the highest dose level being complicated by grade 3 or 4 thrombocytopenia and neutropenia. O(6)-BG rapidly disappeared from plasma (elimination half-life = 0. 54 +/- 0.14 hours) and was converted to a longer-lived metabolite, 8-oxo-O(6)-BG (elimination half-life = 5.6 +/- 2.7 hours) and further to 8-oxoguanine. There was no detectable O(6)-BG 5 hours after the start of the O(6)-BG infusion; however, 8-oxo-O(6)-BG and 8-oxoguanine concentrations were detected 25 hours after O(6)-BG infusion. The mean area under the concentration-time curve (AUC) of 8-oxo-O(6)-BG was 17.5 times greater than the mean AUC for O(6)-BG. CONCLUSION: These results indicate that the MTD of BCNU when given in combination with O(6)-BG at a dose of 100 mg/m(2) is 40 mg/m(2) administered at 6-week intervals. This study provides the foundation for a phase II trial of O(6)-BG plus BCNU in nitrosourea-resistant malignant glioma.