Phase 2 Trial of Nirogacestat Doses First Patient With Ovarian Granulosa Cell Tumors

To determine the effectiveness of nirogacestat at 150mg twice a day in patients with ovarian granulosa cell tumors, the agent has been administered to the first patient in a phase 2 trial.

The first patient was dosed in a phase 2 trial (NCT05348356) evaluating nirogacestat, an investigational gamma secretase inhibitor, as a monotherapy in patients with recurrent ovarian granulosa cell tumors, according to SpringWorks Therapeutics, Inc.1

“The science behind this study is exciting because Notch signaling, a key target of gamma secretase inhibitors, is involved in the expression of FOXL2, which is an integral component of granulosa cell development, proliferation, and function,” said Panos Konstantinopoulos, MD, PhD, director of Gynecological Oncology Translational Research at Dana-Farber Cancer Center and Harvard Medical School and the principal Investigator of the phase 2 trial. “Without any FDA-approved therapies, there is a high unmet need for patients with recurrent ovarian granulosa cell tumors and I look forward to evaluating nirogacestat in this important study.”

Ovarian granulosa cell tumors make up approximately 5% of all ovarian cancers and at 70%, represent the most common subtype at 7 of ovarian sex cord tumors. A mutation in the FOXL2 gene is harbored by nearly all ovarian granulosa cell tumors. In preclinical studies, ovarian granulosa cell tumor cell lines have shown to be susceptible to gamma secretase inhibition.

Nirogacestat is a an investigational, oral, selective, small molecule gamma secretase inhibitor believed to decrease the growth and activity of ovarian granulosa tumors. The agent is currently in phase 3 clinical development for desmoid tumors and in phase 2 clinical development for ovarian granulosa cell tumors.2

In the multi-center, single-arm, phase 2 clinical trial evaluating the effectiveness of nirogacestat in ovarian granulosa cell tumors, an estimated 43 patients will be enrolled and administered 150 mg of open-label nirogacestat twice daily. The goal of the study is to determine the efficacy, safety, tolerability, and pharmacokinetics of nirogacestat in adult patients with ovarian granulosa tumors.

Enrollment in the trial is open to patients aged 18 years and older with histologically confirmed recurrent adult-type granulosa cell tumor of the ovary prior to first dose of study treatment, documented radiological evidence of relapse after 1 or more systemic therapy that is not amenable to surgery, or radiation, measurablke disease by RECIST v1.1 criteria, and adequate bone marrow, renal, hepatic function.

Patients will be excluded from the trial if they show signs of bowel obstruction requiring parental nutrition, malabsorption syndrome or preexisting gastrointestinal conditions that may impair absorption of nirogacestat, a major cardio or thromboembolic event within 6 months of signing informed consent, abnormal QT interval at the time of screening, congenital or acquired long QT syndrome, current or chronic history of liver disease or known hepatic or biliary abnormalities, or has been given treatment for ovarian granulosa cell tumors including but not limited to the following within 28 days prior to the first dose of study treatment: anti-angiogenic therapy, hormonal therapy, chemotherapy, immunotherapy, targeted therapy or any investigational treatment.

The primary end point of the trial is objective response rate with secondary end points including progression-free survival, overall survival, participant reported ovarian cancer symptoms, and duration of response,

The study, which has an estimated study completion date of December 2027, is currently recruiting patients in Canada, Poland, and at various locations across the United States, including in California, Florida, Louisiana, Maryland, Massachusetts, New York, Ohio, Texas, Washington, Wisconsin.

“Over the course of their disease, patients with ovarian granulosa cell tumors may experience severe abdominal pain associated with a large pelvic or abdominal mass, requiring surgery and subsequent systemic therapy,” said Saqib Islam, chief executive officer of SpringWorks Therapeutics, in the press release. “We are pleased to be developing a much-needed therapy for these patients and are encouraged by this new, meaningful opportunity for nirogacestat.”

1. SpringWorks Therapeutics announces dosing of first patient in phase 2 trial evaluating nirogacestat in patients with ovarian granulosa cell tumors. News release. SpringWorks Therapeutics Inc. September 29, 2022. Accessed October 3, 2022.
2. Nirogacestat in ovarian granulosa cell tumors. Updated July 15, 2022. Accessed October 3, 2022.