PMID- 38530160
OWN - NLM
STAT- Publisher
LR  - 20240326
IS  - 1557-3265 (Electronic)
IS  - 1078-0432 (Linking)
DP  - 2024 Mar 26
TI  - A Phase 0/1 Pharmacokinetic and Pharmacodynamics and Safety and Tolerability 
      Study of Letrozole in Combination with Standard Therapy in Recurrent High-Grade 
      Gliomas.
LID - 10.1158/1078-0432.CCR-23-3341 [doi]
AB  - PURPOSE: 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. METHODS: 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 microM and did not result in >/= 33% dose 
      limiting adverse events (AEs) assessed using CTCAE v5.0. RESULTS: 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 microM. LTZ caused dose-dependent inhibition 
      of estradiol synthesis and modulated DNA damage pathways in tumor tissues as 
      evident using RNA-seq analysis. CONCLUSION: Based on safety, brain tumoral PK, 
      and mechanistic data, 15 mg daily is identified as the RP2D for future trials.
FAU - Desai, Pankaj B
AU  - Desai PB
AUID- ORCID: 0000-0002-3001-1603
AD  - University of Cincinnati, Cincinnati, OH, United States.
FAU - Karve, Aniruddha
AU  - Karve A
AUID- ORCID: 0000-0002-1617-4828
AD  - University of Cincinnati, Cincinnati, OH, United States.
FAU - Zawit, Misam
AU  - Zawit M
AUID- ORCID: 0000-0003-2991-4386
AD  - University of Cincinnati, Cincinnati, United States.
FAU - Arora, Priyanka
AU  - Arora P
AUID- ORCID: 0009-0003-8894-892X
AD  - University of Cincinnati, United States.
FAU - Dave, Nimita
AU  - Dave N
AUID- ORCID: 0009-0009-5434-0696
AD  - University of Cincinnati, Boston, MA, United States.
FAU - Awosika, Joy
AU  - Awosika J
AUID- ORCID: 0000-0001-6074-4771
AD  - University of Cincinnati Cancer Center, Cincinnati, OH, United States.
FAU - Li, Ningjing
AU  - Li N
AUID- ORCID: 0000-0002-1170-7971
AD  - The University of Texas Health Science Center at Houston, Houston, Texas, United 
      States.
FAU - Fuhrman, Bethany
AU  - Fuhrman B
AUID- ORCID: 0009-0002-2200-8751
AD  - University of Cincinnati, United States.
FAU - Medvedovic, Mario
AU  - Medvedovic M
AUID- ORCID: 0000-0003-4510-3102
AD  - University of Cincinnati, Cincinnati, OH, United States.
FAU - Sallans, Larry
AU  - Sallans L
AUID- ORCID: 0000-0002-8521-8951
AD  - University of Cincinnati, United States.
FAU - Kendler, Ady
AU  - Kendler A
AUID- ORCID: 0009-0008-1327-8796
AD  - University of Cincinnati, Cincinnati, Ohio, United States.
FAU - DasGupta, Biplab
AU  - DasGupta B
AUID- ORCID: 0000-0002-5809-7779
AD  - Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States.
FAU - Plas, David
AU  - Plas D
AUID- ORCID: 0000-0001-7568-1400
AD  - University of Cincinnati, Cincinnati, OH, United States.
FAU - Curry, Richard
AU  - Curry R
AUID- ORCID: 0000-0002-2951-5687
AD  - CTI, United States.
FAU - Zuccarello, Mario
AU  - Zuccarello M
AUID- ORCID: 0000-0002-7892-7450
AD  - University of Cincinnati, United States.
FAU - Chaudhary, Rekha
AU  - Chaudhary R
AUID- ORCID: 0000-0002-8068-8129
AD  - University of Cincinnati, cincinnati, oh, United States.
FAU - Sengupta, Soma
AU  - Sengupta S
AUID- ORCID: 0000-0003-4577-1397
AD  - University of North Carolina Chapel Hill, Chapel Hill, United States.
FAU - Wise-Draper, Trisha M
AU  - Wise-Draper TM
AUID- ORCID: 0000-0002-7279-4028
AD  - University of Cincinnati, Cincinnati, OH, United States.
LA  - eng
PT  - Journal Article
DEP - 20240326
PL  - United States
TA  - Clin Cancer Res
JT  - Clinical cancer research : an official journal of the American Association for 
      Cancer Research
JID - 9502500
SB  - IM
EDAT- 2024/03/26 12:44
MHDA- 2024/03/26 12:44
CRDT- 2024/03/26 10:04
PHST- 2024/03/18 00:00 [accepted]
PHST- 2023/11/18 00:00 [received]
PHST- 2024/01/24 00:00 [revised]
PHST- 2024/03/26 12:44 [medline]
PHST- 2024/03/26 12:44 [pubmed]
PHST- 2024/03/26 10:04 [entrez]
AID - 741887 [pii]
AID - 10.1158/1078-0432.CCR-23-3341 [doi]
PST - aheadofprint
SO  - Clin Cancer Res. 2024 Mar 26. doi: 10.1158/1078-0432.CCR-23-3341.