SPI-62 as a Treatment for Hypercortisolism Related to a Benign Adrenal Tumor

This is a multicenter, open-label, single-arm study, Phase 2 study to estimate SPI-62's effect on clinical features of hypercortisolism related to a benign adrenal tumor, including diabetes/impaired glucose tolerance, hyperlipidemia, hypertension, and osteopenia. Each subject who provides consent and meets all inclusion and exclusion criteria will participate in a screening period and an open-ended treatment period. Visits occur at screening/baseline, months 1, 3, 6, 9, and 12, and then quarter-annually.

Inclusion criteria

Diagnosis and main criteria for inclusion and exclusion:

The following are the main inclusion criteria:

• Adults able to provide informed consent.
• Documented characteristically benign adrenal nodule, with diameter ≤ 4 cm, homogenous texture, and non-contrast computerized tomography ≤ 20 HU attenuation or proven to be non malignant.
• Diagnosis of diabetes mellitus, pre-diabetes or impaired glucose tolerance, either untreated or on stable standard of care treatment, based on at least one of:

• HbA1c ≥ 5.7% but not > 9.5%
• 2-hour glucose level ≥ 7.8 mmol (140 mg/dL) on a 75 g OGTT
• At least one additional documented cortisol-related morbidities, either untreated or on stable standard of care treatment:

• hypercholesterolemia with total cholesterol > 3.9 mM (150 mg/dL);
• hypertriglyceridemia with triglycerides > 2.3 mM (200 mg/dL);
• osteopenia with bone densitometry Z-score < -2.0 or T-score < -1.0;
• history or evidence of minimally traumatic or osteoporotic fracture; or
• hypertension with resting supine blood pressure > 130 but < 180 mmHg systolic or > 85 but < 120 mmHg diastolic.
• Poorly suppressible hypercortisolemia:

• Morning serum cortisol > 50 nM (1.8 mcg/dL) after a 1 mg ONDST.
• Subjects with dexamethasone < 3.3 nmol/L (130 ng/dL) will undergo a high-dose (8 mg) ONDST.
• Subjects who take estrogen-containing medicines will be evaluated based on free cortisol > 2.2 nM (80 ng/dL).
• For subjects with morning serum cortisol > 138 nM (5.0 mcg/dL) after ONDST, the Investigator will assess for adrenal Cushing's syndrome.

Exclusion criteria

• Diagnosis of ACTH-dependent Cushing's syndrome, pheochromocytoma, aldosteronoma, adrenocortical carcinoma, or congenital adrenal hyperplasia, or other malignancy associated hypercortisolism including history of adrenal carcinoma.
• History of adrenalectomy or planned adrenalectomy within 4 months after randomization.
• Exogenous hypercortisolism.
• Uncontrolled, clinically significant hypo- or hyperthyroidism.
• History of idiopathic thrombocytopenia.
• Moderately impaired renal function (estimated glomerular filtration rate < 60 mL/min/1.73m2).
• History of cancer (other than non-melanoma skin, thyroid, or early-stage prostate cancer) within 3 years.
• Any major surgery, or significant post-operative sequelae, within 1 month prior to informed consent or planned during the trial.
• Pregnant or lactating.
• Positive test for severe acute respiratory syndrome coronavirus 2 infection within 4 weeks, or hospitalization for Coronavirus disease 2019 within 6 months, prior to randomization.
• Any other current or prior medical condition expected to interfere with the conduct of the trial or the evaluation of its results.
• Participation in any clinical trial within 3 months prior to the first dose of study drug, or longer depending on half-life of the investigational therapy.