Administration of Repurposed Ketoconazole in Glioma Patients
Administration of Repurposed Ketoconazole in Glioma Patients: Early Phase 1 Clinical Trial
調査の概要
状態
条件
介入・治療
詳細な説明
Gliomas, particularly high-grade variants like glioblastoma multiforme (WHO grade IV), represent a major challenge in neuro-oncology, comprising over 50% of gliomas and 17% of all primary brain tumors with an incidence of 5 per 100,000. These tumors exhibit marked intra-tumoral heterogeneity, aggressive angiogenesis, and reliance on aerobic glycolysis-converting glucose to lactate irrespective of oxygen levels-to fuel proliferation, invasion, and survival despite maximal safe resection followed by temozolomide-radiotherapy (Stupp protocol), which yields median survival of only 14.6 months.
Preclinical models of high-grade glioma (HGG) have demonstrated ketoconazole's disruption of this metabolic vulnerability by inhibiting hexokinase 2 (HK2), thereby curtailing glycolysis, promoting apoptosis, and curbing angiogenesis-effects achieved at pharmacologically safe doses without reliance on novel agents that struggle against the blood-brain barrier (BBB). Yet, critical gaps persist: ketoconazole's penetration into plasma and glioma tissue (both low- and high-grade) remains undocumented, precluding translation to efficacy trials amid BBB limitations that undermine many repurposed cancer therapies.
This early phase 1 trial addresses these uncertainties in primary gliomas through individualised pre-surgical dosing (single or repeated low doses) tailored to patient status and operative timing-followed by direct intra-operative sampling of tumor tissue and plasma for ketoconazole quantification. By quantifying ketoconazole concentrations directly in tumor tissue and plasma across all grade of gliomas, this early phase 1 trial determines achievable drug exposure levels and informs safe, effective dosing for subsequent efficacy studies.
研究の種類
入学 (実際)
段階
- 初期フェーズ 1
連絡先と場所
研究場所
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Jakarta Special Capital Region
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Jakarta、Jakarta Special Capital Region、インドネシア、13630
- National Brain Center Hospital Prof. Dr. dr. Mahar Mardjono
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参加基準
適格基準
就学可能な年齢
- 大人
- 高齢者
健康ボランティアの受け入れ
説明
Inclusion Criteria:
- Participants aged 18 years or older.
- Radiological confirmation of an intra-axial primary brain tumor (all grades) requiring surgical intervention.
- Karnofsky Performance Status (KPS) of ≥60 and projected life expectancy exceeding 12 weeks.
- Normal liver function, indicated by alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels within 1.5x the upper limit of normal (ULN).
- Normal renal function, defined as urea within 16.6-48.5 mg/dL, creatinine within 0.67-1.17 mg/dL, and/or eGFR ≥90 (within 1.5x the institutional ULN) .
- Capacity to take oral medications.
- Women of reproductive age and all male participants must commit to effective contraception (e.g., hormonal methods) throughout the trial.
- Willingness and ability to provide written informed consent.
- Commitment to adhere to the protocol, including treatment, procedures, and scheduled follow-ups.
Exclusion Criteria:
- Known hypersensitivity to ketoconazole.
- Prior severe reactions (e.g., agranulocytosis, neutropenia) to ketoconazole or other azole antifungals used for parasitic conditions.
- History of acute or chronic hepatitis.
- Elevated liver enzymes (ALT, AST) or impaired renal function (urea, creatinine, eGFR) exceeding 1.5x ULN per local lab standards.
- Current use of metronidazole without ability to switch to an alternative antibiotic at least 7 days prior to ketoconazole initiation.
- Azole antifungal use within the preceding 3 months.
- Pregnancy or breastfeeding.
- Any coexisting medical, psychiatric, or lab abnormality that, per investigator judgment, heightens study risks or confounds data interpretation.
- Unavailability for follow-up or inability to fulfill protocol demands.
- Concurrent use of ketoconazole metabolic inducers (e.g., isoniazid, nevirapine, rifampin, rifabutin) without discontinuation option.
研究計画
研究はどのように設計されていますか？
デザインの詳細
- 主な目的：処理
- 割り当て：なし
- 介入モデル：単一グループの割り当て
- マスキング：なし（オープンラベル）
武器と介入
参加者グループ / アーム |
介入・治療 |
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実験的：Ketoconazole Administration
Eligible patients undergo baseline assessments including liver function tests, renal function, metabolic panel, medical history review, and current medication inventory to ensure safety. Participants receive a single oral dose of ketoconazole 400 mg, administered 4-24 hours prior to scheduled surgery. Oral intake with food optimizes dissolution in acidic gastric conditions and alcohol avoidance for 3 days post-treatment to mitigates hepatotoxicity risks. Dosing is adjusted or withheld based on clinical tolerance: ketoconazole can be given with Dexamethasone 4mg PO QID; if adverse effects occur, dose is reduced to 200 mg; administration is discontinued if patient condition precludes dosing. |
Dose: 400 mg (two 200 mg tablets) orally.
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この研究は何を測定していますか？
主要な結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
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Difference in Ketoconazole Concentrations Between Tumor Tissue and Plasma in Primary All-Grade Gliomas
時間枠：Preoperative administration to intraoperative sampling (4-120 hours post-dose)
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Mean concentrations of ketoconazole measured in plasma and intratumoral tissue samples collected intraoperatively from patients with primary all-grade gliomas (grade I to IV) after preoperative single or fixed-dose administration. Ketoconazole concentrations in tumor and plasma will be summarized using descriptive statistics. The 400 mg preoperative dose was chosen in accordance with published pharmacokinetic safety data supporting its established tolerability across varying clinical conditions [1-3].
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Preoperative administration to intraoperative sampling (4-120 hours post-dose)
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二次結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
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Time Interval vs Ketoconazole Concentration in Tumor Tissue and Plasma
時間枠：Preoperative administration to intraoperative sampling (4-120 hours post-dose)
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Correlation between time from ketoconazole administration to tumor resection and ketoconazole concentrations in glioma tissue and plasma.
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Preoperative administration to intraoperative sampling (4-120 hours post-dose)
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Glioma Grade vs Ketoconazole Concentration in Tumor Tissue and Plasma
時間枠：Preoperative administration to intraoperative sampling (4-120 hours post-dose)
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Correlation between glioma grade (grade I-IV) and ketoconazole concentrations in tumor tissue and plasma
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Preoperative administration to intraoperative sampling (4-120 hours post-dose)
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Effect of Glioma Grade and Time Interval on Ketoconazole Concentrations in Tumor Tissue and Plasma
時間枠：Preoperative administration to intraoperative sampling (4-120 hours post-dose)
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This multivariable analysis evaluates how glioma grade (LGG vs. HGG) and time interval from dosing to sampling independently influence ketoconazole concentrations in tumor tissue and plasma, after controlling for both covariates to quantify these effects and reveal penetration patterns.
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Preoperative administration to intraoperative sampling (4-120 hours post-dose)
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協力者と研究者
スポンサー
捜査官
- 主任研究者：Selfy Oswari, MD、Universitas Padjadjaran
研究記録日
主要日程の研究
研究開始 (実際)
一次修了 (実際)
研究の完了 (推定)
試験登録日
最初に提出
QC基準を満たした最初の提出物
最初の投稿 (実際)
学習記録の更新
投稿された最後の更新 (実際)
QC基準を満たした最後の更新が送信されました
最終確認日
詳しくは
本研究に関する用語
追加の関連 MeSH 用語
その他の研究ID番号
- NC-202604.01
個々の参加者データ (IPD) の計画
個々の参加者データ (IPD) を共有する予定はありますか?
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米国FDA規制医薬品の研究
米国FDA規制機器製品の研究
米国で製造され、米国から輸出された製品。
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