Cabazitaxel Activity in Patients With Advanced AdrenoCortical-Carcinoma Progressing After Previous Chemotherapy Lines

Adrenocortical cancer (ACC) is a rare aggressive tumor. The treatment of metastatic ACC is challenging and the current available treatments are mitotane, chemotherapy or the combination of both. Prognosis in locally advanced inoperable and metastatic ACC patients still remains poor, the 5-year overall survival being \<15%. New treatment strategies are therefore needed. The taxanes are a class of drugs targeting the microtubules that have shown to be effective in the treatment of several malignancies but have not been fully developed in patients with ACC. Cabazitaxel is a new taxoid which promotes the tubulin assembly in vitro and stabilizes microtubules against cold-induced depolymerization as efficiently as docetaxel. Cabazitaxel was selected for development based on a better antiproliferative activity on resistant cell lines than docetaxel. The activity of the drug against several malignancies is currently tested in ongoing prospective studies, but to our knowledge neither preclinical nor clinical studies are currently testing cabaztaxel in ACC. This study is aimed to demonstrate that cabazitaxel is active in ACC, but the drug was never tested before in this clinical setting. A prospective, non-randomized, multicentre, open label, single arm, phase II study will be conducted in patients with advanced ACC. The phase II study will be conducted in 2 different Italian Institutions that are reference centers for ACC.

Sex

All

Minimum age

18 Years

Inclusion Criteria:

* Histologically confirmed diagnosis of ACC
* Locally advanced or metastatic disease not amenable to radical surgery resection
* Radiologically monitorised disease
* Progressing disease after one to three cytotoxic chemotherapy regimes (including a platin-based protocol)
* Eastern Cooperative Oncology Group (ECOG) performance status 0-2
* Life expectancy ≥ 3 months
* Age ≥ 18 years
* Adequate bone marrow reserve (neutrophils ≥ 1500/mm³ and platelets \> 100.000/mm³)
* Effective contraception in pre-menopausal female and male patients
* Patient´s written informed consent
* Ability to comply with the protocol procedures
* Mitotane intake should be stopped one months before the study entry

Exclusion Criteria:

* History of prior malignancy, except for cured non-melanoma skin cancer, cured in situ cervical carcinoma, or other treated malignancies with no evidence of disease for at least three years.
* Serum creatinine \> 1.5 x ULN or hepatic insufficiency, Hemoglobin \<10.0 g/dL;
* Total bilirubin \>1x ULN, Creatinine \< 1.5 ULN;
* Decompensated heart failure (ejection fraction \<45%), myocardial infarction or revascularization procedure during the last 6 months, unstable angina pectoris, uncontrolled cardiac arrhythmia
* Pregnancy or breast feeding
* Any other severe acute or chronic medical or psychiatric condition, or laboratory abnormality that would impart, in the judgment of the investigator, excess risk associated with study participation or study drug administration, or which, in the judgment of the investigator, would make the patient inappropriate for entry into this study
* Patients with serum levels of mitotane (evaluated one week before the study start) in the therapeutic range (14-20 mcg/ml).History of severe hypersensitivity reaction (≥grade 3) to docetaxel
* History of severe hypersensitivity reaction (≥grade 3) to polysorbate 80 containing drugs
* Uncontrolled severe illness or medical condition (including uncontrolled diabetes mellitus)
* Concurrent or planned treatment with strong inhibitors or strong inducers of cytochrome P450 3A4/5 (a one week wash-out period is necessary for patients who are already on these treatments) (see Annex 1 and Annex 2)
* Concomitant vaccination with yellow fever vaccine

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