PMID- 37064512
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20230418
IS  - 2589-5370 (Electronic)
IS  - 2589-5370 (Linking)
VI  - 57
DP  - 2023 Mar
TI  - Mitochondrially targeted tamoxifen in patients with metastatic solid tumours: an 
      open-label, phase I/Ib single-centre trial.
PG  - 101873
LID - 10.1016/j.eclinm.2023.101873 [doi]
LID - 101873
AB  - BACKGROUND: Mitochondria present an emerging target for cancer treatment. We have 
      investigated the effect of mitochondrially targeted tamoxifen (MitoTam), a 
      first-in-class anti-cancer agent, in patients with solid metastatic tumours. 
      METHODS: MitoTam was tested in an open-label, single-centre (Department of 
      Oncology, General Faculty Hospital, Charles University, Czech Republic), phase 
      I/Ib trial in metastatic patients with various malignancies and terminated 
      oncological therapies. In total, 75 patients were enrolled between May 23, 2018 
      and July 22, 2020. Phase I evaluated escalating doses of MitoTam in two 
      therapeutic regimens using the 3 + 3 design to establish drug safety and maximum 
      tolerated dose (MTD). In phase Ib, three dosing regimens were applied over 8 and 
      6 weeks to evaluate long-term toxicity of MitoTam as the primary objective and 
      its anti-cancer effect as a secondary objective. This trial was registered with 
      the European Medicines Agency under EudraCT 2017-004441-25. FINDINGS: In total, 
      37 patients were enrolled into phase I and 38 into phase Ib. In phase I, the 
      initial application of MitoTam via peripheral vein indicated high risk of 
      thrombophlebitis, which was avoided by central vein administration. The highest 
      dose with acceptable side effects was 5.0 mg/kg. The prevailing adverse effects 
      (AEs) in phase I were neutropenia (30%), anaemia (30%) and fever/hyperthermia 
      (30%), and in phase Ib fever/hyperthermia (58%) together with anaemia (26%) and 
      neutropenia (16%). Serious AEs were mostly related to thromboembolic (TE) 
      complications that affected 5% and 13% of patients in phase I and Ib, 
      respectively. The only statistically significant AE related to MitoTam treatment 
      was anaemia in phase Ib (p = 0.004). Of the tested regimens weekly dosing with 
      3.0 mg/kg for 6 weeks afforded the best safety profile with almost all being 
      grade 1 (G1) AEs. Altogether, five fatalities occurred during the study, two of 
      them meeting criteria for Suspected Unexpected Serious Adverse Events Reporting 
      (SUSAR) (G4 thrombocytopenia and G5 stroke). MitoTam showed benefit evaluated as 
      clinical benefit rate (CBR) in 37% patients with the largest effect in renal cell 
      carcinoma (RCC) where four out of six patients reached disease stabilisation 
      (SD), one reached partial response (PR) so that in total, five out of six (83%) 
      patients showed CBR. INTERPRETATION: In this study, the MTD was established as 
      5.0 mg/kg and the recommended dose of MitoTam as 3.0 mg/kg given once per week 
      via central vein with recommended preventive anti-coagulation therapy. The 
      prevailing toxicity included haematological AEs, hyperthermia/fever and TE 
      complications. One fatal stroke and non-fatal G4 thrombocytopenia were recorded. 
      MitoTam showed high efficacy against RCC. FUNDING: Smart Brain Ltd. TRANSLATION: 
      For the Czech translation of the abstract see Supplementary Materials section.
CI  - (c) 2023 The Author(s).
FAU - Bielcikova, Zuzana
AU  - Bielcikova Z
AD  - Department of Oncology, First Faculty of Medicine, Charles University, and 
      General University Hospital, Prague 128 08, Czech Republic.
FAU - Stursa, Jan
AU  - Stursa J
AD  - Institute of Biotechnology, Czech Academy of Sciences, Prague-West 252 50, Czech 
      Republic.
FAU - Krizova, Ludmila
AU  - Krizova L
AD  - Department of Oncology, First Faculty of Medicine, Charles University, and 
      General University Hospital, Prague 128 08, Czech Republic.
FAU - Dong, Lanfeng
AU  - Dong L
AD  - School of Pharmacy and Medical Science, Griffith University, Southport, Qld 4222, 
      Australia.
FAU - Spacek, Jan
AU  - Spacek J
AD  - Department of Oncology, First Faculty of Medicine, Charles University, and 
      General University Hospital, Prague 128 08, Czech Republic.
FAU - Hlousek, Stanislav
AU  - Hlousek S
AD  - Department of Oncology, First Faculty of Medicine, Charles University, and 
      General University Hospital, Prague 128 08, Czech Republic.
FAU - Vocka, Michal
AU  - Vocka M
AD  - Department of Oncology, First Faculty of Medicine, Charles University, and 
      General University Hospital, Prague 128 08, Czech Republic.
FAU - Rohlenova, Katerina
AU  - Rohlenova K
AD  - Institute of Biotechnology, Czech Academy of Sciences, Prague-West 252 50, Czech 
      Republic.
FAU - Bartosova, Olga
AU  - Bartosova O
AD  - Institute of Pharmacology, First Faculty of Medicine, Charles University and 
      General University Hospital, Prague 128 08, Czech Republic.
FAU - Cerny, Vladimir
AU  - Cerny V
AD  - Department of Radiodiagnostics, First Faculty of Medicine, Charles University, 
      and General University Hospital, Prague 128 08, Czech Republic.
FAU - Padrta, Tomas
AU  - Padrta T
AD  - Department of Radiodiagnostics, First Faculty of Medicine, Charles University, 
      and General University Hospital, Prague 128 08, Czech Republic.
FAU - Pesta, Michal
AU  - Pesta M
AD  - Department of Probability and Mathematical Statistics, Faculty of Mathematics and 
      Physics, Charles University, Prague 121 06, Czech Republic.
FAU - Michalek, Pavel
AU  - Michalek P
AD  - Department of Anesthesiology and Intensive Care, First Faculty of Medicine, 
      Charles University and General University Hospital, Prague 128 08, Czech 
      Republic.
FAU - Hubackova, Sona Stemberkova
AU  - Hubackova SS
AD  - Institute of Biotechnology, Czech Academy of Sciences, Prague-West 252 50, Czech 
      Republic.
AD  - Centre for Experimental Medicine, Institute for Clinical and Experimental 
      Medicine, Prague 4 140 21, Czech Republic.
FAU - Kolostova, Katarina
AU  - Kolostova K
AD  - Laboratory of Personalized Medicine, Oncology Clinic, Faculty Hospital Kralovske 
      Vinohrady, Prague 10 100 34, Czech Republic.
FAU - Pospisilova, Eliska
AU  - Pospisilova E
AD  - Laboratory of Personalized Medicine, Oncology Clinic, Faculty Hospital Kralovske 
      Vinohrady, Prague 10 100 34, Czech Republic.
FAU - Bobek, Vladimir
AU  - Bobek V
AD  - Laboratory of Personalized Medicine, Oncology Clinic, Faculty Hospital Kralovske 
      Vinohrady, Prague 10 100 34, Czech Republic.
FAU - Klezl, Peter
AU  - Klezl P
AD  - Laboratory of Personalized Medicine, Oncology Clinic, Faculty Hospital Kralovske 
      Vinohrady, Prague 10 100 34, Czech Republic.
AD  - Urology Clinic, Third Faculty of Medicine, Charles University and Faculty 
      Hospital Kralovske Vinohrady, Prague 10 100 34, Czech Republic.
FAU - Zobalova, Renata
AU  - Zobalova R
AD  - Institute of Biotechnology, Czech Academy of Sciences, Prague-West 252 50, Czech 
      Republic.
FAU - Endaya, Berwini
AU  - Endaya B
AD  - Institute of Biotechnology, Czech Academy of Sciences, Prague-West 252 50, Czech 
      Republic.
AD  - Department of Pediatrics and Inherited Metabolic Diseases, First Faculty of 
      Medicine, Charles University, Prague 2 128 08, Czech Republic.
FAU - Rohlena, Jakub
AU  - Rohlena J
AD  - Institute of Biotechnology, Czech Academy of Sciences, Prague-West 252 50, Czech 
      Republic.
FAU - Petruzelka, Lubos
AU  - Petruzelka L
AD  - Department of Oncology, First Faculty of Medicine, Charles University, and 
      General University Hospital, Prague 128 08, Czech Republic.
FAU - Werner, Lukas
AU  - Werner L
AD  - Institute of Biotechnology, Czech Academy of Sciences, Prague-West 252 50, Czech 
      Republic.
FAU - Neuzil, Jiri
AU  - Neuzil J
AD  - Institute of Biotechnology, Czech Academy of Sciences, Prague-West 252 50, Czech 
      Republic.
AD  - School of Pharmacy and Medical Science, Griffith University, Southport, Qld 4222, 
      Australia.
AD  - Department of Pediatrics and Inherited Metabolic Diseases, First Faculty of 
      Medicine, Charles University, Prague 2 128 08, Czech Republic.
AD  - Department of Physiology, Faculty of Science, Charles University, Prague 2 128 
      00, Czech Republic.
LA  - eng
PT  - Journal Article
DEP - 20230223
PL  - England
TA  - EClinicalMedicine
JT  - EClinicalMedicine
JID - 101733727
PMC - PMC10102891
OTO - NOTNLM
OT  - Cancer
OT  - Mitochondrially targeted tamoxifen
OT  - Phase I/Ib clinical trial
OT  - Renal cell carcinoma
COIS- J.N., J.S and L.W. are owners of MitoTax s.r.o. that co-owns the MitoTam 
      intellectual property.
EDAT- 2023/04/18 06:00
MHDA- 2023/04/18 06:01
PMCR- 2023/02/23
CRDT- 2023/04/17 03:44
PHST- 2022/10/04 00:00 [received]
PHST- 2023/01/10 00:00 [revised]
PHST- 2023/01/31 00:00 [accepted]
PHST- 2023/04/18 06:01 [medline]
PHST- 2023/04/17 03:44 [entrez]
PHST- 2023/04/18 06:00 [pubmed]
PHST- 2023/02/23 00:00 [pmc-release]
AID - S2589-5370(23)00050-0 [pii]
AID - 101873 [pii]
AID - 10.1016/j.eclinm.2023.101873 [doi]
PST - epublish
SO  - EClinicalMedicine. 2023 Feb 23;57:101873. doi: 10.1016/j.eclinm.2023.101873. 
      eCollection 2023 Mar.