Mitochondrially targeted tamoxifen in patients with metastatic solid tumours: an open-label, phase I/Ib single-centre
Zuzana Bielcikova1, Jan Stursa2, Ludmila Krizova1
1Department of Oncology, First Faculty of Medicine, Charles University, and General University Hospital, Prague 128 08, Czech Republic.
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.
Insights
Mitochondria-targeted tamoxifen (MitoTam) shows promise in treating solid tumors, particularly renal cell carcinoma. The recommended dose is 3.0 mg/kg weekly, with careful monitoring for side effects like anemia and thromboembolic events.
Area of Science:
- Oncology
- Pharmacology
- Mitochondrial Biology
Background:
- Mitochondria are increasingly recognized as a therapeutic target in cancer treatment.
- Mitochondrially targeted tamoxifen (MitoTam) is a novel agent designed to exploit this vulnerability.
- This study investigates the safety and efficacy of MitoTam in patients with advanced solid tumors.
Purpose of the Study:
- To determine the safety profile and maximum tolerated dose (MTD) of MitoTam in a Phase I/Ib clinical trial.
- To evaluate the anti-cancer effects and long-term toxicity of MitoTam in patients with metastatic solid tumors.
Main Methods:
- An open-label, single-centre Phase I/Ib trial involving 75 patients with metastatic solid tumors and completed oncological therapies.
- Phase I utilized a 3+3 dose escalation design to establish MTD and safety.
- Phase Ib assessed long-term toxicity and anti-cancer effects with three different dosing regimens.
Main Results:
- The MTD was determined to be 5.0 mg/kg. The recommended dose is 3.0 mg/kg weekly via central vein administration.
- Common adverse events included neutropenia, anemia, and fever/hyperthermia. Serious adverse events were primarily thromboembolic complications.
- MitoTam demonstrated a clinical benefit rate of 37%, with notable efficacy in renal cell carcinoma (83% benefit).
Conclusions:
- MitoTam is a potential anti-cancer agent targeting mitochondria, with a recommended dose of 3.0 mg/kg weekly.
- Hematological toxicities, hyperthermia, and thromboembolic events are key safety considerations.
- MitoTam exhibits significant anti-cancer activity, particularly in renal cell carcinoma, warranting further investigation.
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