Background
Adrenocortical carcinoma (ACC) is a rare and aggressive
malignancy with very limited treatment options.
Nevanimibe HCl (formerly ATR-101), a novel adrenal-specific
sterol O-acyltransferase 1 (SOAT1) inhibitor, has been shown in nonclinical studies to decrease adrenal steroidogenesis at lower doses and to cause apoptosis of adrenocortical cells at higher doses. Methods This phase 1, multicenter, open-label study assessed the safety and pharmacokinetics (PK) of
nevanimibe in adults with metastatic ACC (NCT01898715). A "3 + 3" dose-escalation design was used. Adverse events (AEs), PK, and
tumor response based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 were evaluated every 2 months. Results 63 patients with metastatic ACC, all of whom had previously failed systemic
chemotherapy and only 2 of whom were
mitotane-naïve, were dosed with oral
nevanimibe at doses ranging from 1.6 mg/kg/day to 158.5 mg/kg/day. Subjects who did not experience
tumor progression or a dose-limiting toxicity (DLT) could continue to receive additional cycles. No patients experienced a complete or partial response; however, 13 of the 48 (27%) patients who underwent imaging at 2 months had stable disease (SD), and 4 of these had SD > 4 months. In addition,
drug-related
adrenal insufficiency, considered a pharmacologic effect of
nevanimibe, was observed in two patients. The most common treatment-emergent AEs were
gastrointestinal disorders (76%), including
diarrhea (44%) and
vomiting (35%). A maximum tolerated dose (MTD) could not be defined, as very few dose-limiting toxicities (DLTs) occurred. Because the large number of
tablets required at the highest dose (i.e., ~24
tablets/day) resulted in low-grade gastrointestinal adverse effects, a maximum feasible dose of 128.2 mg/kg/day was established as a dose that could be taken on a long-term basis. Conclusions This study demonstrated the safety of
nevanimibe at doses of up to ~6000 mg BID. As the total number of
tablets required to achieve an MTD exceeded practical administration limits, a maximum feasible dose was defined. Given that the expected exposure levels necessary for an apoptotic effect could not be achieved, the current formulation of
nevanimibe had limited efficacy in patients with advanced ACC.