A Phase III Study of Osilodrostat to Treat Cushing’s Disease

CLCI699C2302: A Phase III, Multi-center, Randomized, Double-blind, 48 Week Study with an Initial 12 Week Placebo-controlled Period to Evaluate the Safety and Efficacy of Osilodrostat in Patients with Cushing’s Disease

Purpose

In people with a disorder known as Cushing’s disease, levels of the hormone cortisol are very high in the urine and blood. Lowering cortisol levels relieves the symptoms of Cushing’s disease. Osilodrostat is an investigational drug that inhibits an enzyme needed for cortisol to be made.

In this study, researchers are assessing the safety and effectiveness of osilodrostat in patients with Cushing¿s disease and observing its ability to reduce cortisol levels. In the first 12 weeks of the study, patients will receive osilodrostat or a placebo (inactive drug). After week 12 and continuing through week 48, all patients will receive osilodrostat. Patients will then have the option to continue taking osilodrostat for up to 100 weeks into the study, if they wish.

Osilodrostat is taken orally (by mouth).

Eligibility

To be eligible for this study, patients must meet several criteria, including but not limited to the following:

  • Patients must have Cushing¿s disease with elevated levels of cortisol in the urine.
  • An acceptable amount of time must have passed between the completion of prior therapies and entry into the study, to allow for a sufficient “washout” period.
  • This study is for patients ages 18 to 75.

For more information about this study and to inquire about eligibility, please contact Dr. Eliza Geer at 646-888-2627.

Protocol

17-351

Phase

III

Investigator

Co-Investigators

Diseases

Sloan Kettering (New York City) Clinical Trials & Research

 

Clinical trials are research studies that test new treatments to see how well they work. Our Pituitary and Skull Base Tumor Center is leading clinical trials investigating new medical therapies for patients with Cushing’s disease and acromegaly. They are also involved in quality-of-life studies aimed at improving long-term follow-up care for patients who need it.

Our experts can help determine which clinical trials are right for you. The following clinical trials for pituitary tumors are currently enrolling new patients.

To learn more about a particular study, choose from the list below. For more information about our research and clinical trials, call us at 212-639-3935, or talk with your doctor.

Osilodrostat maintained cortisol control in Cushing’s syndrome

Osilodrostat, a drug that normalized cortisol in 89% of patients with Cushing’s syndrome who took it during a phase II study, continued to exert a sustained benefit during a 31-month extension phase.

In an intent-to-treat analysis, all of the 16 patients who entered the LINC-2 extension study responded well to the medication, with no lapse in cortisol control, Rosario Pivonello, MD, said at the annual meeting of the Endocrine Society.

“We also saw significant improvements in systolic and diastolic blood pressure and decreases in fasting plasma glucose,” said Dr. Pivonello of the University of Naples Federico II, Italy. “Surprisingly, after 31 months, we also observed declines in body mass index and weight.”

Osilodrostat, made by Novartis, is an oral inhibitor of 11 beta–hydroxylase. The enzyme catalyzes the last step of cortisol synthesis in the adrenal cortex. The drug was granted orphan status in 2014 by the European Medicines Agency.

In the LINC-2 study, 19 patients took osilodrostat at an initial dose of either 4 mg/day or 10 mg/day, if baseline urinary-free cortisol exceeded three times the upper normal limit. The dose was escalated every 2 weeks to up to 60 mg/day, until cortisol levels were at or below the upper limit of normal. In this study, the main efficacy endpoint was normalization of cortisol, or at least a 50% decrease from baseline at weeks 10 and 22.

Overall response was 89%. Osilodrostat treatment reduced urinary-free cortisol in all patients, and 79% had normal cortisol levels at week 22. The most common adverse events were asthenia, adrenal insufficiency, diarrhea, fatigue, headache, nausea, and acne. New or worsening hirsutism and/or acne were reported among four female patients, all of whom had increased testosterone levels.

The LINC-2 extension study enrolled 16 patients from the phase II cohort, all of whom had responded to the medication. They were allowed to continue on their existing effective dose through the 31-month period.

Dr. Pivonello presented response curves that tracked cortisol levels from treatment initiation in the LINC-2 study. The median baseline cortisol level was about 1,500 nmol per 24 hours. By the fourth week of treatment, this had normalized in all of the patients who entered the extension phase. The response curve showed continued, stable cortisol suppression throughout the entire 31-month period.

Four patients dropped out during the course of the study. Dr. Pivonello didn’t discuss the reasons for these dropouts. He did break down the results by response, imputing the missing data from these four patients. In this analysis, the majority (87.5%) were fully controlled, with urinary-free cortisol in the normal range. The remainder were partially controlled, experiencing at least a 50% decrease in cortisol from their baseline levels. These responses were stable, with no patient experiencing loss of control over the follow-up period.

The 12 remaining patients are still taking the medication, and they experienced other clinical improvements as well. Systolic blood pressure decreased by a mean of 2.2% (from 130 mm Hg to 127 mm Hg). Diastolic blood pressure also improved, by 6% (from 85 mm Hg to 80 mm Hg).

Fasting plasma glucose dropped from a mean of 89 mg/dL to 82 mg/dL. Weight decreased from a mean of 84 kg to 74 kg, with a corresponding decrease in body mass index, from 29.6 kg/m2 to 26.2 kg/m2.

Serum aldosterone decreased along with cortisol, dropping from a mean of 168 pmol/L to just 19 pmol/L. Adrenocorticotropic hormone increased, as did 11-deoxycortisol, 11-deoxycorticosterone, and testosterone.

Pituitary tumor size was measured in six patients. It increased in three and decreased in three. Dr. Pivonello didn’t discuss why this might have occurred.

The most common adverse events were asthenia, adrenal insufficiency, diarrhea, fatigue, headache, nausea, and acne. These moderated over time in both number and severity.

However, there were eight serious adverse events among three patients, including prolonged Q-T interval on electrocardiogram, food poisoning, gastroenteritis, headache, noncardiac chest pain, symptoms related to pituitary tumor (two patients), and uncontrolled Cushing’s syndrome.

Two patients experienced hypokalemia. Six experienced mild events related to hypocortisolism.

Novartis is pursuing the drug with two placebo-controlled phase III studies (LINC-3 and LINC-4), Dr. Pivonello said. An additional phase II study is being conducted in Japan.

Dr. Pivonello has received consulting fees and honoraria from Novartis, which sponsored the study.

Medical Therapies in Cushing’s Syndrome

Chapter

The Hypothalamic-Pituitary-Adrenal Axis in Health and Disease

pp 165-179

Date: 03 December 2016

Medical Therapies in Cushing’s Syndrome

Abstract

Medical therapy has an important, albeit secondary, role in patients with Cushing’s syndrome. While medications are not currently used as definitive therapy of this condition, they can be very effective in controlling hypercortisolism in patients who fail surgery, those who are not surgical candidates, or those whose tumor location is unknown. Medical therapies can be particularly helpful to control hypercortisolism in patients with Cushing’s disease who underwent radiation therapy and are awaiting its salutary effects.

Currently available treatment options include several steroidogenesis inhibitors (ketoconazole, metyrapone, mitotane, etomidate), which block one or several steps in cortisol synthesis in the adrenal glands, centrally acting agents (cabergoline, pasireotide), which decrease ACTH secretion, and glucocorticoid receptor antagonists, which are represented by a single agent (mifepristone). With the exception of pasireotide and mifepristone, available agents are used “off-label” to manage hypercortisolism. Several other medications are at various stages of development and may offer additional options for the management of this serious condition.

As more potential molecular targets become known and our understanding of the pathogenesis of Cushing’s syndrome improves, it is anticipated that novel, rationally designed medical therapies may emerge. Clinical trials are needed to further investigate the relative risks and benefits of currently available and novel medical therapies and examine the potential role of combination therapy in the management of Cushing’s syndrome.

Keywords

Cabergoline, Etomidate, Ketoconazole, Levoketoconazole, Metyrapone, Mifepristone, Mitotane, Osilodrostat, Pasireotide, Pituitary adenoma

Osilodrostat for Cushing’s

The study looked at a drug to treat Cushing’s disease. The article, in the journal Pituitary, is called Osilodrostat, a potent oral 11β-hydroxylase inhibitor: 22-week, prospective, Phase II study in Cushing’s disease.
Fleseriu M, Pivonello R, Young J, Hamrahian AH, Molitch ME, Shimizu C, Tanaka T, Shimatsu A, White T, Hilliard A, Tian C, Sauter N, Biller BM, Bertagna X.
Pituitary. 2015 Nov 5. [Epub ahead of print]

Abstract

PURPOSE:
In a 10-week proof-of-concept study (LINC 1), the potent oral 11β-hydroxylase inhibitor osilodrostat (LCI699) normalized urinary free cortisol (UFC) in 11/12 patients with Cushing’s disease. The current 22-week study (LINC 2; NCT01331239) further evaluated osilodrostat in patients with Cushing’s disease.

METHODS:
Phase II, open-label, prospective study of two patient cohorts. Follow-up cohort: 4/12 patients previously enrolled in LINC 1, offered re-enrollment if baseline mean UFC was above ULN. Expansion cohort: 15 newly enrolled patients with baseline UFC > 1.5 × ULN. In the follow-up cohort, patients initiated osilodrostat twice daily at the penultimate efficacious/tolerable dose in LINC 1; dose was adjusted as needed. In the expansion cohort, osilodrostat was initiated at 4 mg/day (10 mg/day if baseline UFC > 3 × ULN), with dose escalated every 2 weeks to 10, 20, 40, and 60 mg/day until UFC ≤ ULN. Main efficacy endpoint was the proportion of responders (UFC ≤ ULN or ≥50 % decrease from baseline) at weeks 10 and 22.

RESULTS:
Overall response rate was 89.5 % (n/N = 17/19) at 10 weeks and 78.9 % (n/N = 15/19) at 22 weeks; at week 22, all responding patients had UFC ≤ ULN. The most common AEs observed during osilodrostat treatment were nausea, diarrhea, asthenia, and adrenal insufficiency (n = 6 for each). New or worsening hirsutism (n = 2) and/or acne (n = 3) were reported among four female patients, all of whom had increased testosterone levels.

CONCLUSIONS:
Osilodrostat treatment reduced UFC in all patients; 78.9 % (n/N = 15/19) had normal UFC at week 22. Treatment with osilodrostat was generally well tolerated.

KEYWORDS:
11β-hydroxylase; Cortisol; Cushing’s; LCI699; Osilodrostat

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