Nirogacestat in Ovarian Granulosa Cell Tumors

A Phase 2 Trial of Nirogacestat in Patients With Recurrent Ovarian Granulosa Cell Tumors

This phase 2 clinical trial will study the effectiveness of nirogacestat in ovarian granulosa cell tumors (OvGCTs). Nirogacestat is a gamma secretase inhibitor (GSI) which is hypothesized to decrease the growth and activity of ovarian granulosa tumors.

Study Overview

• Status: Completed
• Conditions: Ovarian Cancer; Ovarian Granulosa Cell Tumor; Ovarian Granulosa-Stromal Tumor
• Intervention / Treatment: Drug: Nirogacestat

Detailed Description

Ovarian granulosa cell tumors (OvGCTs) represent 5-7% of all ovarian cancers (~1.5 to 2k newly diagnosed patients/year in the United States) and are the most common subtype of ovarian sex cord tumors (70%). Treatment of granulosa cell tumors with nirogacestat is expected to inhibit Notch-induced granulosa cell proliferation.

This is a multi-center, single-arm, Phase 2 open label treatment study to determine the efficacy, safety, tolerability, and pharmacokinetics of nirogacestat in adult participants with relapsed/refractory OvGCT. The participants will continue treatment until disease progression as determined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 (unless the participants meet criteria for continued treatment) or unacceptable toxicity.

• Study Type: Interventional
• Enrollment (Actual): 53
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 1Z2
      • Cross Cancer Institute
• Poland
  • Bialystok, Poland, 15-027
    • Maria Sklodowska-Curie Bialystok Oncology Center
  • Krakow, Poland, 30-348
    • Jagiellonian Innovation Centre Clinical Research Centre
  • Poznan, Poland, 60-569
    • University Teaching Hospital Poznan, Department of Oncological Gynaecology
  • Warsaw, Poland, 02-781
    • Maria Sklodowska-Curie National Institute of Oncology-National Research Institute, Clinic of Oncological Gynecology
• United States
  • California
    • Los Angeles, California, United States, 90033
      • USC/Norris Comprehensive Cancer Center
    • Los Angeles, California, United States, 90095
      • UCLA-JCCC Dept. of OBGYN - Women's Health Clinical Research Unit
  • Florida
    • Orlando, Florida, United States, 32806
      • Orlando Health Cancer Institute
    • Orlando, Florida, United States, 32804
      • AdventHealth Orlando
    • Tampa, Florida, United States, 33612
      • H. Lee Moffitt Cancer Center and Research Institute
  • Louisiana
    • Covington, Louisiana, United States, 70433
      • Women's Cancer Care
  • Maryland
    • Baltimore, Maryland, United States, 21204
      • Greater Baltimore Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana-Farber Cancer Institute
  • Missouri
    • St Louis, Missouri, United States, 63141
      • David C. Pratt Cancer Center
  • New Mexico
    • Albuquerque, New Mexico, United States, 87102
      • University of New Mexico Comprehensive Cancer Center
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical center
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Institute
  • Ohio
    • Kettering, Ohio, United States, 45429
      • Women's Cancer Center at Kettering
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • OU Health Stephenson Cancer Center
  • Washington
    • Seattle, Washington, United States, 98109
      • UW/Fred Hutch Cancer Center
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Froedtert and Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

• Has histologically confirmed recurrent adult-type granulosa cell tumor of the ovary prior to first dose of study treatment
• Have documented radiological evidence of relapse after at least one systemic therapy that is not amenable to surgery, or radiation and have measurable disease by RECIST v1.1 criteria
• Have adequate bone marrow, renal and hepatic function as defined by screening visit laboratory values

Key Exclusion Criteria:

• Has signs of bowel obstruction requiring parenteral nutrition, malabsorption syndrome or preexisting gastrointestinal conditions that may impair absorption of nirogacestat
• Has had a major cardiac or thrombo-embolic event within 6 months of signing informed consent
• Has abnormal QT interval at Screening, or has congenital or acquired long QT syndrome or a history of additional risk factors for Torsades de Pointes
• Has current or chronic history of liver disease or known hepatic or biliary abnormalities
• Has received bevacizumab treatment or other monoclonal antibody therapy with targeted anti-angiogenic activity for OvGCT within 28 days (or 5 half-lives, whichever is shorter) prior to the first dose of study treatment;
• Has received treatment for OvGCT including but not limited to the following within 28 days (or 5 half-lives, whichever is longer) prior to the first dose of study treatment: hormonal therapy, chemotherapy, immunotherapy, targeted therapy or any investigational treatment

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Nirogacestat Open-Label; Nirogacestat 150 mg by mouth, twice daily Nirogacestat oral tablet: Nirogacestat tablet	Drug: Nirogacestat; nirogacestat oral tablet; Other Names: PF-03084014

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate (ORR)	The percentage of participants with complete response (CR) + partial response (PR) assessed using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria.	2.5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival at 6 Months (PFS-6)	The number of participants without progression according to RECIST v1.1 or death at 6 months.	First day of cycle 7 (approximately 6 months after the first dose of study treatment). Each cycle is 28 days.
Overall Survival at Year 2	The number of participants who have not died of any cause by Year 2.	2 years after first dose of study treatment
Duration of Response	The time from response (Complete Response [CR] + Partial Response [PR] using RECIST v.1.) to disease progression and/or death, in participants with CR or PR.	First day of every other cycle (each cycle is 28 days) for the first year, and then every 3 cycles thereafter until study completion (estimated to be an average of 2.5 years).
Change From Baseline at Cycle 2 Day 1 in the Functional Assessment of Cancer Therapy - Ovarian Symptom Index (FOSI) Score.	Participant reported ovarian cancer symptoms as measured by Functional Assessment of Cancer Therapy - Ovarian Symptom Index (FOSI). The FOSI is an 8-question evaluation scored on a Likert scale of 0-4 from not at all to very much. Metrics assessed include lack of energy, vomiting, pain, nausea, swelling in stomach area, concern condition will get worse, quality of life assessment and stomach cramps. Higher score means worse outcome. The responses to the statements except for statement 7 (I am content with the quality of my life right now) were reversed and the sum of non-missing responses is calculated. The FOSI score is the sum multiplied by 8, then divided by the number of responded statements. The FOSI score was missing if a participants had 5 or more missing values in the 8 individual symptom scores at a visit.	Baseline and at Cycle 2 Day 1 (cycle length is 28 days).
Change From Baseline at Cycle 3 Day 1 Treatment in the Functional Assessment of Cancer Therapy - Ovarian Symptom Index (FOSI) Score	Participant reported ovarian cancer symptoms as measured by Functional Assessment of Cancer Therapy - Ovarian Symptom Index (FOSI). The FOSI is an 8-question evaluation scored on a Likert scale of 0-4 from not at all to very much. Metrics assessed include lack of energy, vomiting, pain, nausea, swelling in stomach area, concern condition will get worse, quality of life assessment and stomach cramps. Higher score means worse outcome. The responses to the statements except for statement 7 (I am content with the quality of my life right now) were reversed and the sum of non-missing responses is calculated. The FOSI score is the sum multiplied by 8, then divided by the number of responded statements. The FOSI score was missing if a participants had 5 or more missing values in the 8 individual symptom scores at a visit.	Baseline and at Cycle 3 Day 1 (cycle length is 28 days).
Change From Baseline at Cycle 4 Day 1 in the Functional Assessment of Cancer Therapy - Ovarian Symptom Index (FOSI) Score	Participant reported ovarian cancer symptoms as measured by Functional Assessment of Cancer Therapy - Ovarian Symptom Index (FOSI). The FOSI is an 8-question evaluation scored on a Likert scale of 0-4 from not at all to very much. Metrics assessed include lack of energy, vomiting, pain, nausea, swelling in stomach area, concern condition will get worse, quality of life assessment and stomach cramps. Higher score means worse outcome. The responses to the statements except for statement 7 (I am content with the quality of my life right now) were reversed and the sum of non-missing responses is calculated. The FOSI score is the sum multiplied by 8, then divided by the number of responded statements. The FOSI score was missing if a participants had 5 or more missing values in the 8 individual symptom scores at a visit.	Baseline and at Cycle 4 Day 1 (cycle length is 28 days).
Change From Baseline at Cycle 5 Day 1 in the Functional Assessment of Cancer Therapy - Ovarian Symptom Index (FOSI) Score	Participant reported ovarian cancer symptoms as measured by Functional Assessment of Cancer Therapy - Ovarian Symptom Index (FOSI). The FOSI is an 8-question evaluation scored on a Likert scale of 0-4 from not at all to very much. Metrics assessed include lack of energy, vomiting, pain, nausea, swelling in stomach area, concern condition will get worse, quality of life assessment and stomach cramps. Higher score means worse outcome. The responses to the statements except for statement 7 (I am content with the quality of my life right now) were reversed and the sum of non-missing responses is calculated. The FOSI score is the sum multiplied by 8, then divided by the number of responded statements. The FOSI score was missing if a participants had 5 or more missing values in the 8 individual symptom scores at a visit.	Baseline and at Cycle 5 Day 1 (cycle length is 28 days).
Change From Baseline at End of Treatment in the Functional Assessment of Cancer Therapy - Ovarian Symptom Index (FOSI) Score	Participant reported ovarian cancer symptoms as measured by Functional Assessment of Cancer Therapy - Ovarian Symptom Index (FOSI). The FOSI is an 8-question evaluation scored on a Likert scale of 0-4 from not at all to very much. Metrics assessed include lack of energy, vomiting, pain, nausea, swelling in stomach area, concern condition will get worse, quality of life assessment and stomach cramps. Higher score means worse outcome. The responses to the statements except for statement 7 (I am content with the quality of my life right now) were reversed and the sum of non-missing responses is calculated. The FOSI score is the sum multiplied by 8, then divided by the number of responded statements. The FOSI score was missing if a participants had 5 or more missing values in the 8 individual symptom scores at a visit.	Baseline and at end of treatment (estimated to be an average of 5.5 months [minimum of 0 month and maximum of 33 months]).
Change From Baseline at Safety Follow-up in the Functional Assessment of Cancer Therapy - Ovarian Symptom Index (FOSI) Score	Participant reported ovarian cancer symptoms as measured by Functional Assessment of Cancer Therapy - Ovarian Symptom Index (FOSI). The FOSI is an 8-question evaluation scored on a Likert scale of 0-4 from not at all to very much. Metrics assessed include lack of energy, vomiting, pain, nausea, swelling in stomach area, concern condition will get worse, quality of life assessment and stomach cramps. Higher score means worse outcome. The responses to the statements except for statement 7 (I am content with the quality of my life right now) were reversed and the sum of non-missing responses is calculated. The FOSI score is the sum multiplied by 8, then divided by the number of responded statements. The FOSI score was missing if a participants had 5 or more missing values in the 8 individual symptom scores at a visit.	Baseline and at safety follow-up (up to a maximum of 34 months).

Collaborators and Investigators

• Sponsor: SpringWorks Therapeutics, Inc., a healthcare company of Merck KGaA, Darmstadt, Germany
• Investigators: Study Director: Medical Responsible, SpringWorks Therapeutics, Inc., a healthcare company of Merck KGaA, Darmstadt, Germany

Publications and helpful links

General Publications

• Grisham RN, Hopp E, Pennington K, Holloway R, Wenham RM, Blecharz P, Dockery L, Matsuo K, Salani R, Bidzinski M, Braly P, Celano P, Reid T, Seward S, Lewis J, Johnson M, DuBose R, Ahn S, Cheng S, Alvero C, Konstantinopoulos PA. Phase II clinical trial of nirogacestat in patients with relapsed ovarian granulosa cell tumours. Clin Transl Med. 2026 Jan;16(1):e70568. doi: 10.1002/ctm2.70568.

Helpful Links

• US Medical Information website, Medical Resources
• Trial Awareness and Transparency website

Study record dates

Study Major Dates

• Study Start (Actual): August 30, 2022
• Primary Completion (Actual): July 8, 2025
• Study Completion (Actual): July 14, 2025

Study Registration Dates

• First Submitted: April 13, 2022
• First Submitted That Met QC Criteria: April 20, 2022
• First Posted (Actual): April 27, 2022

Study Record Updates

• Last Update Posted (Actual): August 25, 2026
• Last Update Submitted That Met QC Criteria: July 31, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Endocrine System Diseases; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Genital Diseases, Female; Endocrine Gland Neoplasms; Ovarian Diseases; Adnexal Diseases; Genital Neoplasms, Female; Gonadal Disorders; Ovarian Neoplasms; Granulosa cell tumor of the ovary; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Gamma Secretase Inhibitors and Modulators; nirogacestat
• Other Study ID Numbers: NIR-OGT-201; 2022-001816-25 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: IPD supporting publicly available results will be evaluated for sharing.

IPD Sharing Time Frame

IPD from completed trials will be publicly available within 6 months after all of the following events:

• Approval of a product/new indication by major authorities (FDA, EMA, PMDA if requested) with no pending submissions
• Public results via primary manuscript or trial registry disclosure
• Legal authority to share data
• Privacy protections are in place If approval is not sought or development is globally discontinued, data will be publicly available within 18 months after global trial completion. Further information on how to request data can be found on our website bit.ly/IPD21

• IPD Sharing Access Criteria: Qualified researchers may propose access to IPD from sponsored trials via https://vivli.org/members/ourmembers/.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No