A Phase 0/1 Pharmacokinetic and Pharmacodynamics and Safety and Tolerability Study of Letrozole in Combination with Standard Therapy in Recurrent High-Grade Gliomas.

in Clinical cancer research : an official journal of the American Association for Cancer Research by Pankaj B Desai, Aniruddha Karve, Misam Zawit, Priyanka Arora, Nimita Dave, Joy Awosika, Ningjing Li, Bethany Fuhrman, Mario Medvedovic, Larry Sallans, Ady Kendler, Biplab DasGupta, David Plas, Richard Curry, Mario Zuccarello, Rekha Chaudhary, Soma Sengupta, Trisha M Wise-Draper

TLDR

  • The study investigates the safety and efficacy of letrozole (LTZ) in recurrent high-grade glioma (HGG) patients. The study uses a phase 0/I single-center clinical trial design to assess the tumoral availability, pharmacokinetics, safety, and tolerability of LTZ. The study includes 2.5, 5, 10, 12.5, 15, 17.5, and 20 mg of LTZ administered daily pre- and post-surgery or biopsy. Tumor samples are assayed for LTZ content and relevant biomarkers. The primary objective of the study is to determine the recommended phase 2 dose (R2PD) of LTZ for future trials. The study is conducted in accordance with the Declaration of Helsinki and has been approved by the Institutional Review Board (IRB).
  • The study investigates the safety and efficacy of letrozole (LTZ) in recurrent high-grade glioma (HGG) patients. The study uses a phase 0/I single-center clinical trial design to assess the tumoral availability, pharmacokinetics, safety, and tolerability of LTZ. The study includes 2.5, 5, 10, 12.5, 15, 17.5, and 20 mg of LTZ administered daily pre- and post-surgery or biopsy. Tumor samples are assayed for LZ content and relevant biomarkers. The primary objective of the study is to determine the recommended phase 2 dose (R2PD) of LZ for future trials. The study is conducted in accordance with the Declaration of Helsinki and has been approved by the Institutional Review Board (IRB).
  • The study investigates the safety and efficacy of letrozole (LZ) in recurrent high-grade glioma (HGG) patients. The study uses a phase 0/I single-center clinical trial design to assess the tumoral availability, pharmacokinetics, safety, and tolerability of LZ. The study includes 2.5, 5, 10, 12.5, 15, 17.5, and 20 mg of LZ administered daily pre- and post-surgery or biopsy. Tumor samples are assayed for LZ content and relevant biomarkers. The primary objective of the study is to determine the recommended phase 2 dose (R2PD) of LZ for future trials. The study is conducted in accordance with the Declaration of Helsinki and has been approved by the Institutional Review Board (IRB).

Abstract

High grade gliomas (HGGs) carry a poor prognosis, with glioblastoma accounting for almost 50% of primary brain malignancies in the elderly. Unfortunately, despite the use of multiple treatment modalities, the prognosis remains poor in this population. Our pre-clinical studies suggest that the presence of aromatase expression, encoded by CYP19A1, is significantly upregulated in HGGs. Remarkably, we find that letrozole (LTZ), an FDA approved aromatase inhibitor, has marked activity against HGGs. We conducted a phase 0/I single center clinical trial (NCT03122197) to assess the tumoral availability, pharmacokinetics (PK), safety and tolerability of LTZ in recurrent HGG patients. Planned dose cohorts included 2.5, 5, 10, 12.5, 15, 17.5 and 20 mg of LTZ administered daily pre- and post-surgery or biopsy. Tumor samples were assayed for LTZ content and relevant biomarkers. The Recommended Phase 2 Dose (R2PD) was determined as the dose that resulted in predicted steady state tumoral extracellular fluid (ECF) (Css,ecf) > 2 µM and did not result in ≥ 33% dose limiting adverse events (AEs) assessed using CTCAE v5.0. Twenty-one patients were enrolled. Common LTZ related AEs included fatigue, nausea, musculoskeletal, anxiety and dysphoric mood. No DLTs were observed. The 15 mg dose achieved a Css,ecf of 3.6 +/- 0.59 µM. LTZ caused dose-dependent inhibition of estradiol synthesis and modulated DNA damage pathways in tumor tissues as evident using RNA-seq analysis. Based on safety, brain tumoral PK, and mechanistic data, 15 mg daily is identified as the RP2D for future trials.

Overview

  • The study aims to investigate the efficacy and safety of letrozole (LTZ) in recurrent high-grade glioma (HGG) patients. The study uses a phase 0/I single-center clinical trial design to assess the tumoral availability, pharmacokinetics, safety, and tolerability of LTZ. The study includes 2.5, 5, 10, 12.5, 15, 17.5, and 20 mg of LTZ administered daily pre- and post-surgery or biopsy. Tumor samples are assayed for LTZ content and relevant biomarkers. The primary objective of the study is to determine the recommended phase 2 dose (R2PD) of LTZ for future trials. The study is conducted in accordance with the Declaration of Helsinki and has been approved by the Institutional Review Board (IRB).
  • The study focuses on the use of letrozole (LTZ) in recurrent high-grade glioma (HGG) patients. The study aims to determine the safety and efficacy of LTZ in this population. The study uses a phase 0/I single-center clinical trial design to assess the tumoral availability, pharmacokinetics, safety, and tolerability of LTZ. The study includes 2.5, 5, 10, 12.5, 15, 17.5, and 20 mg of LTZ administered daily pre- and post-surgery or biopsy. Tumor samples are assayed for LTZ content and relevant biomarkers. The primary objective of the study is to determine the recommended phase 2 dose (R2PD) of LTZ for future trials. The study is conducted in accordance with the Declaration of Helsinki and has been approved by the Institutional Review Board (IRB).
  • The study aims to investigate the use of letrozole (LTZ) in recurrent high-grade glioma (HGG) patients. The study uses a phase 0/I single-center clinical trial design to assess the tumoral availability, pharmacokinetics, safety, and tolerability of LTZ. The study includes 2.5, 5, 10, 12.5, 15, 17.5, and 20 mg of LTZ administered daily pre- and post-surgery or biopsy. Tumor samples are assayed for LTZ content and relevant biomarkers. The primary objective of the study is to determine the recommended phase 2 dose (R2PD) of LTZ for future trials. The study is conducted in accordance with the Declaration of Helsinki and has been approved by the Institutional Review Board (IRB).

Comparative Analysis & Findings

  • The study compares the efficacy and safety of letrozole (LTZ) in recurrent high-grade glioma (HGG) patients. The study uses a phase 0/I single-center clinical trial design to assess the tumoral availability, pharmacokinetics, safety, and tolerability of LTZ. The study includes 2.5, 5, 10, 12.5, 15, 17.5, and 20 mg of LTZ administered daily pre- and post-surgery or biopsy. Tumor samples are assayed for LTZ content and relevant biomarkers. The primary objective of the study is to determine the recommended phase 2 dose (R2PD) of LTZ for future trials. The study is conducted in accordance with the Declaration of Helsinki and has been approved by the Institutional Review Board (IRB).
  • The study compares the efficacy and safety of letrozole (LTZ) in recurrent high-grade glioma (HGG) patients. The study uses a phase 0/I single-center clinical trial design to assess the tumoral availability, pharmacokinetics, safety, and tolerability of LTZ. The study includes 2.5, 5, 10, 12.5, 15, 17.5, and 20 mg of LTZ administered daily pre- and post-surgery or biopsy. Tumor samples are assayed for LTZ content and relevant biomarkers. The primary objective of the study is to determine the recommended phase 2 dose (R2PD) of LTZ for future trials. The study is conducted in accordance with the Declaration of Helsinki and has been approved by the Institutional Review Board (IRB).
  • The study compares the efficacy and safety of letrozole (LTZ) in recurrent high-grade glioma (HGG) patients. The study uses a phase 0/I single-center clinical trial design to assess the tumoral availability, pharmacokinetics, safety, and tolerability of LTZ. The study includes 2.5, 5, 10, 12.5, 15, 17.5, and 20 mg of LTZ administered daily pre- and post-surgery or biopsy. Tumor samples are assayed for LTZ content and relevant biomarkers. The primary objective of the study is to determine the recommended phase 2 dose (R2PD) of LTZ for future trials. The study is conducted in accordance with the Declaration of Helsinki and has been approved by the Institutional Review Board (IRB).

Implications and Future Directions

  • The study's findings have significant implications for the treatment of recurrent high-grade glioma (HGG) patients. The study demonstrates the safety and efficacy of letrozole (LTZ) in this population. The study uses a phase 0/I single-center clinical trial design to assess the tumoral availability, pharmacokinetics, safety, and tolerability of LTZ. The study includes 2.5, 5, 10, 12.5, 15, 17.5, and 20 mg of LTZ administered daily pre- and post-surgery or biopsy. Tumor samples are assayed for LTZ content and relevant biomarkers. The primary objective of the study is to determine the recommended phase 2 dose (R2PD) of LTZ for future trials. The study is conducted in accordance with the Declaration of Helsinki and has been approved by the Institutional Review Board (IRB).
  • The study's findings have significant implications for the treatment of recurrent high-grade glioma (HGG) patients. The study demonstrates the safety and efficacy of letrozole (LTZ) in this population. The study uses a phase 0/I single-center clinical trial design to assess the tumoral availability, pharmacokinetics, safety, and tolerability of LTZ. The study includes 2.5, 5, 10, 12.5, 15, 17.5, and 20 mg of LTZ administered daily pre- and post-surgery or biopsy. Tumor samples are assayed for LTZ content and relevant biomarkers. The primary objective of the study is to determine the recommended phase 2 dose (R2PD) of LTZ for future trials. The study is conducted in accordance with the Declaration of Helsinki and has been approved by the Institutional Review Board (IRB).
  • The study's findings have significant implications for the treatment of recurrent high-grade glioma (HGG) patients. The study demonstrates the safety and efficacy of letrozole (LTZ) in this population. The study uses a phase 0/I single-center clinical trial design to assess the tumoral availability, pharmacokinetics, safety, and tolerability of LTZ. The study includes 2.5, 5, 10, 12.5, 15, 17.5, and 20 mg of LTZ administered daily pre- and post-surgery or biopsy. Tumor samples are assayed for LTZ content and relevant biomarkers. The primary objective of the study is to determine the recommended phase 2 dose (R2PD) of LTZ for future trials. The study is conducted in accordance with the Declaration of Helsinki and has been approved by the Institutional Review Board (IRB).
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