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

Quinn, Jennifer A.; Reardon, David A.; Friedman, Allan H.; Rich, Jeremy; Sampson, John H.; Vredenburgh, James J.; Gururangan, Sridharan; Provenzale, James M.; Walker, Amy; Schweitzer, Holly; Bigner, Darell D.; Tourt-Uhlig, Sandra; Herndon, James E.; Affronti, Mary Lou; Jackson, Susanne; Allen, Deborah H.; Ziegler, K; Bohlin, Cindy; Lentz, Christy; Friedman, Henry S.

doi:10.1215/s1152851703000498

Cited by 24 publications

(9 citation statements)

References 9 publications

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“…Antiemetic therapy with ondansetron and dexamethasone was given before each weekly dose of CPT‐11. Atropine (1 mg intravenously) was administered for acute cholinergic symptoms and loperamide was prescribed for late diarrhea as previously described 40. Hematopoietic growth factors and blood products were administered as indicated for Grade 4 hematologic toxicity.…”

Section: Methodsmentioning

confidence: 99%

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

Reardon

Quinn

Vredenburgh

et al. 2005

Cancer

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111

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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/m2 for patients receiving enzyme‐inducing antiepileptic drugs (EIAEDs) and at a dose of 125 mg/m2 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. Cancer 2005. © 2005 American Cancer Society.

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Section: Methodsmentioning

confidence: 99%

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

Reardon

Quinn

Vredenburgh

et al. 2005

Cancer

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111

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“…Irinotecan was administered weekly for 4 weeks at doses previously determined to be optimal for combination with BCNU and further stratified by EIAED status-225 mg/m 2 for those receiving and 125 mg/m 2 for those not receiving EIAEDs. 60 The phase II trial of 76 patients treated with this combination (37 newly diagnosed; 39 recurrent disease) showed the following results: five newly diagnosed patients (14%) achieved a radiographic response, including one complete response and four partial responses (95% CI, 5%-29%); five with recurrent disease (13%) demonstrated a response, including one complete response (95% CI, 4%-27%); and stable disease was demonstrated in more than 40%. 59 The median time to progression was 11.3 weeks for the recurrent GBM population and 16.9 weeks for patients with recurrent AA and anaplastic oligodendroglioma (AO).…”

Section: With Carmustinementioning

confidence: 99%

Experience with irinotecan for the treatment of malignant glioma

Vredenburgh¹,

Desjardins²,

Reardon³

et al. 2009

Neuro-Oncology

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Malignant glioma is the most commonly occurring primary malignant brain tumor. It is difficult to treat and is usually associated with an inexorable, rapidly fatal clinical course. Chemotherapy, radiotherapy, and surgical excision are core components in the management of malignant glioma. However, chemotherapy, even with the most active regimens currently available, achieves only modest improvement in overall survival. Novel agents and new approaches to therapy are required to improve clinical outcomes. Irinotecan, a first-line treatment for metastatic colorectal cancer and an agent with high activity against solid tumors of the gastrointestinal tract, is an inhibitor of topoisomerase I, a critical enzyme needed for DNA transcription. Irinotecan crosses the blood-brain barrier and, in preclinical investigations, has demonstrated cytotoxic activity against central nervous system tumor xenografts. Its antitumor activity has also been demonstrated against glioblastoma cells with multidrug resistance. Studies in adult and pediatric patients with recurrent, intractable malignant glioma have evaluated irinotecan as monotherapy and in combination with other agents, including temozolomide, carmustine, thalidomide, and bevacizumab. Studies of irinotecan in combination with other medications, particularly temozolomide and bevacizumab, have yielded promising results. Irinotecan monotherapy has demonstrated efficacy; however, its efficacy appears to be enhanced when used in combination with other chemotherapeutic agents. When administered concurrently with enzyme-inducing antiepileptic drugs, the dosage must be increased to compensate for enhanced cytochrome CY3A4/5 enzyme activity. Toxicities associated with irinotecan have been manageable; the most important dose-limiting toxicities are neutropenia and diarrhea. Irinotecan-based chemotherapy of malignant glioma merits further study.

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“…The usage of BCNU and irinotecan in combination has been described in the medical literature. The regimen seems to be active in patients with recurrent GBM and also appears to be non-crossresistant [2,15]. Recently a Phase II clinical trial involving BCNU and irinotecan showed that the activity of BCNU plus CPT-11 appears comparable to that of CPT-11 alone, and may be more toxic [17].…”

Section: Discussionmentioning

confidence: 99%

Irinotecan and BCNU-Impregnated Wafers Used in Combination, for the Treatment of Patients with Recurrent Glioblastoma Multiforme

Dewan

Stopa²,

Alderson³

et al. 2010

J Carcinogene Mutagene

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Introduction: This retrospective study examines the toxicity of the combination of intravenous irinotecan, (CPT-11; Camptosar®; Pharmacia & Upjohn, Kalamazoo, Mich.) and BCNU (1,3-bis(2-chloroethyl)-1-nitrosurea) impregnated wafers (Gliadel®) following implantation at the time of tumor recurrence in patients with glioblastoma multiforme (GBM). Method: Ten patients with recurrent GBM were examined in this study. The inclusion criteria were histologically confi rmed GBM, Karnofsky's Performance Scale (KPS) greater than or equal to 60, and a single focus of recurrent tumor. All patients underwent resection of their tumor at the time of fi rst recurrence with placement of BCNU wafers. Postoperatively, patients were treated with irinotecan. One cycle constituted of 125 mg/m 2 once weekly for 4 weeks followed by a 2-week rest. The patients were followed for toxicity, tumor progression and survival. Treatment was discontinued if intolerable side effects ensued. Results: The mean time to tumor progression was 4.35 months. The mean survival from the time of BCNU wafer placement was 12.1 months. The overall mean survival was 18.9 months. The average number of cycles of CPT-11 that patients received was 2.7. The toxicity associated with the CPT-11 was as follows: two patients reported Grade 2 diarrhea and one patient experienced grade 3 pancytopenia, three patients reported deep vein thromboses and one patient suffered a non-life threatening pulmonary embolism. Conclusions: The combination of systemic irinotecan along with local intratumoral BCNU is well tolerated and may be more effi cacious than either treatment alone. Our data support the need for a future prospective study designed to confi rm the effectiveness of this combined treatment strategy.

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

Cited by 24 publications

References 9 publications

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

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

Experience with irinotecan for the treatment of malignant glioma

Irinotecan and BCNU-Impregnated Wafers Used in Combination, for the Treatment of Patients with Recurrent Glioblastoma Multiforme

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