Lysodren (mitotane)

P=N/A, N=400, Active, not recruiting, University of Wuerzburg | Recruiting --> Active, not recruiting | Trial primary completion date: Dec 2023 --> Jun 2024

Combination of TAK-243 with current ACC therapies (e.g., mitotane, etoposide, cisplatin) produced synergistic or additive effects. In addition, TAK-243 was highly synergistic with BCL2 inhibitors (Navitoclax and Venetoclax) in preclinical ACC models including patient-derived organoids...These findings provide preclinical evidence to support the initiation of a clinical trial of TAK-243 in patients with advanced-stage adrenocortical carcinoma. TAK-243 is a promising potential treatment option for ACC, either as monotherapy or in combination with existing therapies or BCL2 inhibitors.

Adrenal leiomyosarcoma derived from the smooth muscle wall of a central adrenal vein or its tributaries is rare but should be considered a differential diagnosis in the case of nonfunctioning adrenal tumors extending directly to the inferior vena cava. CT-guided biopsy is considered useful for histopathological diagnosis and clinical management of patients with inoperable advanced adrenal tumors without any hormone excess.

P2, N=30, Enrolling by invitation, National Cancer Center, Korea | Not yet recruiting --> Enrolling by invitation

In addition, our studies revealed an increase in ACSL4 and ABCG2 expression in lowly aggressive H295R cells undergoing early treatment with non-lethal concentrations of mitotane, doxorubicin and cisplatin. The increase in ACSL4 and ABCG2 expression favored tumor cell viability, proliferation and compound efflux, an effect partially offset by ACSL4 and ABCG2 inhibitors. These results provide relevant data on the undesired molecular effects of antitumor drugs and may fuel future studies on patients' early response to antitumor treatment.

Adjuvant mitotane might not be indicated in patients with low-grade, localised adrenocortical carcinoma considering the relatively good prognosis of these patients, and no significant improvement in recurrence-free survival and treatment-associated toxicity in the mitotane group. However, the study was discontinued prematurely due to slow recruitment and cannot rule out an efficacy of treatment.

No differences in PFS and OS curves were observed; the CBR was 75.0% and 60.4%, respectively. (4) The association of EDP-M + megestrol acetate in ACC pts with a low PS is feasible and well tolerated; its efficacy appeared to be non-inferior to EDP-M administered to pts with a good PS.

The response rate of advanced adrenocortical carcinoma (ACC) to standard chemotherapy with mitotane and etoposide/doxorubicin/cisplatin (EDP-M) is unsatisfactory, and benefit is frequently short lived...Here we describe three cases of patients with advanced ACC who were treated with HDR-BT and the CPI pembrolizumab...Sequential combination with CPI therapy may enhance an abscopal antitumoral effect in non-irradiated metastases in ACC. Systematic studies are required to confirm this preliminary experience and to understand underlying mechanisms.

MTT levels reached higher levels at 9 months in ACC patients with high abundance of Proteobacteria, Pseudomonas and Serratia and with low abundance of Bacteroidota, Firmicutes and Streptococcus. These findings are the first indication that human ACCs are characterised by infiltrating bacteria and their specific abundance profile seems to influence the increase in circulating MTT levels at 9 months.

The 5-year survival rate is less than 15% among patients with metastatic disease. In this article, we review the epidemiology and pathogenesis of ACC, the diagnostic procedures, the prognostic classification of ACC, and the treatment options from localized and resectable forms to advanced disease detailing recent therapeutic developments such as immunotherapy and molecularly targeted therapy.

In the two patients experiencing a further rise of mitotanemia, neurological examination was normal but P300 and electroencephalogram were altered. The results of our study highlighted the presence of neurophysiological and neuropsychological abnormalities associated with mitotane values above 18 mg/L.

P3, N=78, Completed, Children's Oncology Group | Active, not recruiting --> Completed

The combination of etoposide, doxorubicin and cisplatin with or without mitotane known as EDP/M, is recommended as first -line regimen based on FIRMACT study. Conclusions The combination of A and T showed promising clinical benefits with moderate toxicities in mACC patients. A+T might become a potential treatment option which need to be further confirmed in the randomized controlled clinical trial.

Post-hoc analyses identified predictors of lack of efficacy (no mitotane, ECOG > 1, ACC 1st diagnosis ≤9 months(mo), lesion size >125 mm, >3 organs involved, lymphopenia >grade 1); C2-post hoc group was created applying these factors. Conclusions EO2401/N was well tolerated generating durable immune responses correlating with efficacy. Based on the greater efficacy in C2-post hoc group a randomized extension is currently recruiting.

Our study suggests that patients with metastatic ACC benefit from inclusion in early clinical trials in second line. As recommended, if a clinical trial is available, it should be the first choice for suitable patients.

Adjuvant mitotane remains the most commonly used adjuvant therapy in ACC based on clinical practice guidelines, though emerging data from ADIUVO trial (mitotane vs observation in low-risk ACC) suggest that mitotane use in low-risk patients may not be needed...A prospective study is needed to study the role of adjuvant radiation in ACC as radiation is expected to help only with local control without impact on distant microscopic metastases. There are no recommendations or published data about using adjuvant immunotherapy in ACC, but this may be a future study after establishing the efficacy and safety profile of immunotherapy in metastatic ACC.

MTT negatively affects the male reproductive system, including changes in the morphology of testicular tissue and reductions in sperm concentration and quality.

P2, N=80, Recruiting, Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia

We have recently proposed a new method analogous to what is established for the anticoagulant warfarin, the time in target range (TTR). Conclusions The present findings show that the patients who are exposed to plasma mitotane >14 mg/L for longer periods have better RFS. These findings provide indirect evidence of the value of adjuvant therapy with mitotane and support the importance of drug monitoring to guide dose adjustment in clinical practice and improve patient outcome.

A subsequent CT adrenals demonstrated a 12.8 x 13.2 x 10.6cm left adrenal mass and she failed a 1mg overnight dexamethasone suppression test. This is a rare case of ACC secreting multiple hormones, resulting in post-menopausal bleeding and IGF-2 mediated hypoglycaemia.

All 13 patients were taking glucocorticoid replacement therapy and 5 were able to completely withdraw hydrocortisone 39 ± 14.5 months after stopping mitotane treatment. Mitotane can take up to 13 months to become undetectable in patients' plasma after cessation. In our cohort, it is mainly influenced by increased weight but not by duration of exposure to the drug.

We have recently proposed a new method analogous to what is established for the anticoagulant warfarin, the time in target range (TTR). Conclusions The present findings show that the patients who are exposed to plasma mitotane >14 mg/L for longer periods have better RFS. These findings provide indirect evidence of the value of adjuvant therapy with mitotane and support the importance of drug monitoring to guide dose adjustment in clinical practice and improve patient outcome.

No ACC patients studied had been treated with mitotane... Significant differences in plasma steroids were observed in ACC vs ACA patients, with more steroids altered in female patients. Serum steroid profiles, particularly steroid sulfates, might serve as an adjunct, easy to obtain diagnostic tool to differentiate ACA and ACC.

He underwent radiotherapy and mitotane as adjuvant therapies...After six courses of EDP (a combination of etoposide, doxorubicin and cisplatin), CT showed widespread metastases in the retroperitoneum and he chose to receive the best supportive care...Complete resection is needed to improve prognosis and this was not achieved in our case. We therefore recommend careful selection of the operative procedure.

In the real-life setting, we observe a response comparable to other second-line therapies and an acceptable safety profile in ACC patients receiving different ICI. The relevance of PD-L1 as a marker of response and the potentially more favourable outcome in nivolumab-treated patients require confirmation.

In addition, mitotane being the only pharmacological agent approved for the treatment of ACC...Similar findings have been shown in the literature for other 3D cancer cell culture models. All were steroidogenic in nature.ConclusionIn the current study, we successfully developed 3D cell culture models for ACC.This model will be used in the future studies to test novel and traditional therapeutics to test the translational relevance of this model to ACC, as a reliable, animal sparing model.

No ACC patients studied had been treated with mitotane... Significant differences in plasma steroids were observed in ACC vs ACA patients, with more steroids altered in female patients. Serum steroid profiles, particularly steroid sulfates, might serve as an adjunct, easy to obtain diagnostic tool to differentiate ACA and ACC.*Unless otherwise noted, all abstracts presented at ENDO must not be released to the press or the public until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins.

Additionally, he started IV dexamethasone while inpatient. He was discharged once euvolemic on PO furosemide and follow-up was scheduled with cardiology, oncology, and endocrinology. At discharge, he transitioned to PO hydrocortisone (HC) and was placed on trimethoprim/sulfamethoxazole for PJP prophylaxis, doxazosin, and ketoconazole...Subsequently, he started and failed carboplatin plus etoposide palliative chemotherapy with a continued increase in adrenal mass size. Now, he is on second line pembrolizumab with an ECOG score of 2... ACC is a rare and often aggressive tumor that should be considered in the setting of hypercortisolism and cushingoid features. This is particularly important for patients with a relatively unremarkable history and new onset heart failure with dyspnea on exertion. In these cases, mitotane can be used for hypercortisolism associated with ACC.

Post-adrenalectomy, the patient's starting dose was 1g mitotane each day with replacement hydrocortisone. While some studies show hypertriglyceridemia secondary to mitotane, others only show elevated cholesterol at 6 and 3 months, respectively. We describe an ACC patient with a history of fatty liver disease and mixed hyperlipidemia who developed severe hypertriglyceridemia and acute pancreatitis leading to multiorgan failure about one month after starting mitotane. This case highlights hypertriglyceridemia as a serious complication of mitotane in a patient with preexisting dyslipidemia.*Unless otherwise noted, all abstracts presented at ENDO must not be released to the press or the public until the date and time of presentation.

The patient failed a 8mg dexamethasone suppression test with AM cortisol levels of 57.8 mcg/dL (5-25 mcg/dL) with a dexamethasone drug level of 2713 ng/dL (reference range >200 ng/dL), excluding elevated metabolism as cause of failed suppression...Patient was taken off ketoconazole two weeks after prior discharge, not knowing it was temporary treatment for his Cushing's syndrome...Patient was then discharged from our care to an outpatient endocrinologist.This case shows that cortisol levels in ectopic Cushing Syndrome can be effectively lowered through fluconazole treatment. This medication has a more favorable side effect profile than other steroidogenesis inhibitors such as metyrapone and mitotane.Fluconazole monotherapy or dual therapy should be investigated further as a viable option for ectopic Cushing Syndrome therapy prior to bilateral adrenalectomy.

She underwent a new chemotherapy regimen with gemcitabine, docetaxel and fluorouracil + M. She presented a complete response confirmed by radiological exams and hormonal data. Mitotane was discontinued in 2016 due to bladder bleeding...Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.*

Her other home medications included mitotane 500mg QID and hydrocortisone 180mg (40mg-40mg-30mg -20mg QID)...Due to the temporal relation of her transaminitis and rash to recent pembrolizumab infusion with an otherwise negative work-up, the patient was diagnosed with immune-mediated liver injury from checkpoint inhibitors (ILICI)...Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.*

Our results give support to the role of progesterone in ACC. The involvement of its analog (megestrol acetate) in reducing ACC progression in ACC patients undergoing EDP-M therapy is now under investigation in the PESETA phase II clinical study.

Mitotane induces GDF-15 both in vivo and in vitro and potentially contributes to the poor response rates to ICI in ACC.

m7G risk score was a potential biomarker for predicting the efficacy of ICBs and mitotane...Finally, miR-885-5p and CEBPB were predicted as the upstream regulators of METTL1 through data mining of the public databases. In conclusions, m7G regulatory genes well represented by METTL1 profoundly affected the prognosis, tumor immune, therapeutic outcomes, and malignant progression of ACC.

Consistent with the findings in our study, low expression of RRM1, CYP2W1 and SOAT1 was associated with worse DFS with antitumor therapy. The results of the work indicate the need to assess the levels of immunoreactivity of these markers in patients with ACC before starting treatment with mitotane in order to predict the efficiency of therapy.

GMNN is a novel tumor marker for predicting the malignant progression, metastasis and prognosis of ACC, and may be a potential therapeutic target for ACC.

The pharmacological approach to adrenocortical carcinoma (ACC) is based on mitotane with/without etoposide, doxorubicin, and cisplatin, according to the disease stage. Our results indicate that trabectedin interferes with invasiveness and metastasis processes, both dramatic feature of ACC. Furthermore, these results support those previously published in providing the rationale for a clinical evaluation of the efficacy of trabectedin in ACC patients.

Current treatment protocols are derived from adult ACC and consist of surgery and/or chemotherapy with etoposide, doxorubicin, and cisplatin (EDP) with mitotane. Limited research has been reported on other treatment modalities for pediatric ACC, including mitotane, pembrolizumab, cabozantinib, and chimeric antigen receptor autologous cell (CAR-T) therapy.

CDK1 could be exploited as an essential therapeutic target of ACC via regulating the EMT, the G2/M checkpoint, and PANoptosis. Thus, CurE may be a potential candidate drug for ACC therapy with good safety and efficacy, which will meet the great need of patients with ACC.