Dataset Information

A multicenter phase I/II study of the BCNU implant (Gliadel(®) Wafer) for Japanese patients with malignant gliomas.

ABSTRACT: Carmustine (BCNU) implants (Gliadel(®) Wafer, Eisai Inc., New Jersey, USA) for the treatment of malignant gliomas (MGs) were shown to enhance overall survival in comparison to placebo in controlled clinical trials in the United States and Europe. A prospective, multicenter phase I/II study involving Japanese patients with MGs was performed to evaluate the efficacy, safety, and pharmacokinetics of BCNU implants. The study enrolled 16 patients with newly diagnosed MGs and 8 patients with recurrent MGs. After the insertion of BCNU implants (8 sheets maximum, 61.6 mg BCNU) into the removal cavity, various chemotherapies (including temozolomide) and radiotherapies were applied. After placement, overall and progression-free survival rates and whole blood BCNU levels were evaluated. In patients with newly diagnosed MGs, the overall survival rates at 12 months and 24 months were 100.0% and 68.8%, and the progression-free survival rate at 12 months was 62.5%. In patients with recurrent MGs, the progression-free survival rate at 6 months was 37.5%. There were no grade 4 or higher adverse events noted due to BCNU implants, and grade 3 events were observed in 5 of 24 patients (20.8%). Whole blood BCNU levels reached a peak of 19.4 ng/mL approximately 3 hours after insertion, which was lower than 1/600 of the peak BCNU level recorded after intravenous injections. These levels decreased to less than the detection limit (2.00 ng/mL) after 24 hours. The results of this study involving Japanese patients are comparable to those of previous studies in the United States and Europe.

SUBMITTER: Aoki T

PROVIDER: S-EPMC4533485 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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A multicenter phase I/II study of the BCNU implant (Gliadel(®) Wafer) for Japanese patients with malignant gliomas.

Aoki Tomokazu T Nishikawa Ryo R Sugiyama Kazuhiko K Nonoguchi Naosuke N Kawabata Noriyuki N Mishima Kazuhiko K Adachi Jun-ichi J Kurisu Kaoru K Yamasaki Fumiyuki F Tominaga Teiji T Kumabe Toshihiro T Ueki Keisuke K Higuchi Fumi F Yamamoto Tetsuya T Ishikawa Eiichi E Takeshima Hideo H Yamashita Shinji S Arita Kazunori K Hirano Hirofumi H Yamada Shinobu S Matsutani Masao M

Neurologia medico-chirurgica 20131129 4

Carmustine (BCNU) implants (Gliadel(®) Wafer, Eisai Inc., New Jersey, USA) for the treatment of malignant gliomas (MGs) were shown to enhance overall survival in comparison to placebo in controlled clinical trials in the United States and Europe. A prospective, multicenter phase I/II study involving Japanese patients with MGs was performed to evaluate the efficacy, safety, and pharmacokinetics of BCNU implants. The study enrolled 16 patients with newly diagnosed MGs and 8 patients with recurrent ...[more]

PMID: 24739422

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Project description:Abstract BACKGROUND FGFR mutations and translocations occur in approximately 10% of glioblastomas (GBMs). FGFR3-TACC3 fusion has been reported as predictive of response to FGFR tyrosine kinase inhibitor therapy both pre-clinically and clinically. Infigratinib (BGJ398) is a selective small-molecule pan-FGFR kinase inhibitor that has demonstrated anti-tumor activity in several solid tumors with FGFR genetic alterations. Therefore, we conducted a phase II trial to test the efficacy of infigratinib in FGFR-altered recurrent GBM (NCT01975701). METHODS This open-label trial accrued adults with recurrent high-grade gliomas following failure of initial therapy that harbored FGFR1-TACC1 or FGFR3-TACC3 fusions; activating mutations in FGFR1, 2 or 3; or FGFR1, 2, 3, or 4 amplification. Oral infigratinib was administered 125 mg on days 1–21 every 28 days. Prophylaxis for hyperphosphatemia, a common toxicity, was recommended. The primary endpoint was the 6-month progression-free survival (6mPFS) rate by RANO (locally assessed, estimated by K-M method), with a goal of >40%. RESULTS As of the Sep 2017 data cut-off, 26 patients (16 men, 10 women; median age 55 years, range 20–76 years; 50% with ≥2 prior regimens) were treated, and 24 (92.3%) discontinued for disease progression (n=21) or other reasons (n=3). All patients had FGFR1 or FGFR3 gene alterations, and 4 had >1 gene alteration. The estimated 6mPFS rate was 16% (95% CI 5.0–32.5%); median PFS was 1.7 months (95% CI 1.1–2.8 months); median OS was 6.7 months (95% CI 4.2–11.7 months); ORR was 7.7% (95% CI 1.0–25.1%). The best overall response was: partial response 7.7% (FGFR1 mutation n=1; FGFR3 amplification n=1); stable disease 26.9%; progressive disease 50.0%; missing/unknown 15.3%. The most common (>15%) all-grade treatment-related adverse events (AEs) were hyperphosphatemia, fatigue, diarrhea, hyperlipasemia, and stomatitis. There were no grade 4 treatment-related AEs. Eleven patients (42.3%) had treatment-related AEs requiring dose interruptions or reductions (most commonly hyperphosphatemia). CONCLUSIONS Infigratinib induced partial response or stable disease in approximately one-third of patients with recurrent GBM and/or other glioma subtypes harboring FGFR alterations. Most AEs were reversible and manageable. Further potential combinations are being explored in patients with proven FGFR-TACC fusion genes and analysis of biomarker data is ongoing.

Project description:Abstract INTRODUCTION FGFR mutations and translocations occur in approximately 10% of glioblastomas (GBMs). FGFR3-TACC3 fusion is predictive of response to FGFR tyrosine kinase inhibitors pre-clinically and clinically. Infigratinib (BGJ398) is a selective small-molecule pan-FGFR kinase inhibitor with anti-tumor activity in several solid tumors with FGFR genetic alterations. METHODS Open-label phase II trial of adults with recurrent high-grade gliomas following failure of initial therapy (NCT01975701). Tumors harbored FGFR1-TACC1 or FGFR3-TACC3 fusions, activating mutations in FGFR1, 2 or 3, or FGFR1, 2, 3, or 4 amplification. Oral infigratinib was administered 125 mg d1–21 q28d. Prophylaxis for hyperphosphatemia was recommended. Primary endpoint: 6-month progression-free survival (6mPFS) rate by RANO (locally assessed); goal of >40%. RESULTS As of Sep 2017, 26 patients (16 men, 10 women; median age 55 years, range 20–76 years; 50% with ≥ 2 prior regimens) were treated; 24 (92.3%) discontinued for disease progression (n=21) or other reasons (n=3). All had FGFR1 or FGFR3 gene alterations; 4 had >1 gene alteration. Estimated 6mPFS rate was 16% (95% CI 5.0–32.5%); median PFS was 1.7 months (95% CI 1.1–2.8 months); median OS was 6.7 months (95% CI 4.2–11.7 months); ORR was 7.7% (95% CI 1.0–25.1%). Best overall response was: partial response 7.7% (FGFR1 mutation n=1; FGFR3 amplification n=1); stable disease 26.9%; progressive disease 50.0%; missing/unknown 15.3%. Most common (>15%) all-grade treatment-related adverse events (AEs) were hyperphosphatemia, fatigue, diarrhea, hyperlipasemia, and stomatitis. There were no grade 4 treatment-related AEs. Eleven patients (42.3%) had treatment-related AEs requiring dose interruptions/reductions (most commonly hyperphosphatemia). CONCLUSIONS Infigratinib induced partial response or stable disease in approximately one-third of patients with recurrent GBM and/or other glioma subtypes harboring FGFR alterations. Most AEs were reversible and manageable. Further potential combinations are being explored in patients with proven FGFR-TACC fusion genes; analysis of biomarker data is ongoing.

Dataset Information

A multicenter phase I/II study of the BCNU implant (Gliadel(®) Wafer) for Japanese patients with malignant gliomas.

Publications

A multicenter phase I/II study of the BCNU implant (Gliadel(®) Wafer) for Japanese patients with malignant gliomas.

Similar Datasets

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