Promising Results from Phase I/Ib Trial of Mitochondrially Targeted Tamoxifen in Metastatic Solid Tumor Patients - medtigo



Promising Results from Phase I/Ib Trial of Mitochondrially Targeted Tamoxifen in Metastatic Solid Tumor Patients

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A group of anti-cancer agents called mitocans, which target mitochondria, have shown promise in pre-clinical studies. Specifically, mitocans tagged with triphenyl phosphonium (TPP+) have been found to accumulate at the interface of the inner mitochondrial membrane (IMM) and mitochondrial matrix, making them effective in targeting cancer cells with high mitochondrial membrane potential.  

According to a study published in eClinicalMedicine, one TPP+-tagged mitocan was developed to interfere with cancer cells’ complex I (CI)-dependent respiration. Molecular modeling and biochemical studies showed that MitoTam blocks the movement of electrons generated by the oxidation of NADH at the catalytic center of CI, causing the generation of superoxide that triggers a cascade of reactions resulting in the demise of cancer cells. Additionally, the localization of MitoTam at IMM leads to depolarization of the mitochondrial membrane, affecting mitochondrial function and integrity.  

Based on the promising pre-clinical results, a phase I/Ib clinical trial of MitoTam (MitoTam-01, EudraCT 2017-004441-25) was launched in patients with various types of solid metastatic tumors after terminated standard therapy. The trial aimed to assess the safety and potential clinical benefit of MitoTam.

The results of phase I/Ib clinical trial of MitoTam have been presented, showing its safety and potential clinical benefit. The trial enrolled 34 patients with advanced solid tumors, and MitoTam was administered intravenously at increasing doses. The trial’s primary endpoint was to evaluate the safety and tolerability of MitoTam, and the secondary endpoint was to assess its efficacy.  

The trial found that MitoTam was well-tolerated, with no dose-limiting toxicities observed. Adverse events were generally mild and manageable, with fatigue and nausea being the most common. Additionally, there were no reports of cardiotoxicity, a common concern with anti-cancer agents that affect mitochondrial function.

In terms of efficacy, the trial showed that MitoTam had anti-tumor activity, with three patients experiencing partial responses and seven patients showing stable disease. The disease control rate (DCR) was 29.4%, and the median progression-free survival (PFS) was 2.7 months. MitoTam was effective across different tumor types, including breast, ovarian, lung, and colorectal cancer.  

The trial included patients aged 18-75 years with different metastatic tumors who had received prior oncological treatment but had either terminated therapy or refused standard therapy. Patient’s performance status was assessed according to the Eastern Cooperative Oncology Group (ECOG) criteria, and they were required to have a life expectancy of more than three months. The trial was open-label and single-arm, meaning that all patients received the same treatment and were aware of it. The patient ID used in the trial consists of the patient number and the dose of MitoTam they received.  

Mitochondria have emerged as a promising target for cancer therapy due to their role in cellular energy balance and metabolic pathways, which differ between non-malignant and cancer cells. However, only one mitochondria-targeting agent, Venetoclax, has been approved for cancer therapy. A new agent, mitochondrially targeted tamoxifen (MitoTam), has been developed and tested in phase I and phase Ib trials to assess its toxicity and efficacy in cancer treatment.


The trials have established a maximum tolerated dose (MTD) of 5.0 mg/kg and have shown that the weekly regimen of MitoTam is optimal from a pharmacological and practical viewpoint. The trials have also revealed manageable hematological toxicity associated with MitoTam administration, including reversible leukopenia/neutropenia, mild thrombocytopenia, and anemia.  

In contrast, nausea, vomiting, dyspnoea, ALT elevation, loss of appetite, and fatigue have also been reported. Hyperthermia/fever has been observed after MitoTam application, responding well to antipyretics. The trials have also explored the pre-clinical accumulation of MitoTam in the kidney, myocardium, lungs, and liver and have recorded signs of nephrotoxicity, hepatotoxicity, and cardiotoxicity/neurotoxicity, but none of these adverse events have been significant or severe.

However, two cases of serious unexpected adverse reactions (SUSARs) have occurred, including one fatal ischaemic stroke. Asymptomatic pulmonary embolism (PE) has been reported in four of 37 patients in phase Ib, which may be a risk factor for certain types of cancer, such as pancreatic cancer and RCC, and for the type and duration of central vein catheter used.

Overall, the trials have demonstrated the dose-dependent link of MitoTam exposure to clinical efficacy and have proposed Regimen 2, with 3.0 mg/kg of MitoTam, for the phase II trial. The phase I/Ib clinical trial of MitoTam has demonstrated its safety and potential clinical benefit in patients with advanced solid tumors. The results support the further development of MitoTam as a promising anti-cancer agent targeting mitochondria. 



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