Symptoms and General Pathology

All Conditions

Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Gland and Hormone Related Diseases

Rare Diseases

Recurrence

Ovarian Neoplasms

Carcinoma, Ovarian Epithelial

Granulosa Cell Tumor

Endocrine Gland Neoplasms

Ovarian Diseases

Adnexal Diseases

Genital Diseases, Female

Genital Diseases

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Genital Neoplasms, Female

Urogenital Neoplasms

Endocrine System Diseases

Gonadal Disorders

Sex Cord-Gonadal Stromal Tumors

Neoplasms by Histologic Type

Ovarian Cancer

Ovarian Epithelial Cancer

Granulosa Cell Tumor of the Ovary

All Drugs and Chemicals

Nirogacestat

Gamma Secretase Inhibitors and Modulators

Enzyme Inhibitors

All participants will receive open-label nirogacestat

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.

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.

Nirogacestat in Ovarian Granulosa Cell Tumors

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

SpringWorks Therapeutics is committed to data transparency and sharing data to further research while maintaining the privacy and confidentiality of research participants. Pertinent patient-level data from completed clinical trials will be made available by SpringWorks to qualified researchers upon approval of reasonable requests following de-identification/anonymization pursuant to applicable law.

The proportion of participants with complete response (CR) + partial response (PR) assessed using RECIST v1.1 criteria.

The number of participants without progression according to RECIST v1.1 or death at 6 months.

The number of participants who have not died of any cause.

Change from baseline as measured by Functional Assessment of Cancer Therapy - Ovarian Symptom Index (FOSI).

The time from response (CR + PR using RECIST v.1.) to disease progression and/or death

SpringWorks Therapeutics, Inc.

Leydig Cell Tumor

Sertoli-Leydig Cell Tumor

Testicular Neoplasms

Genital Neoplasms, Male

Genital Diseases, Male

Male Urogenital Diseases

Testicular Diseases

Sertoli-leydig Cell Tumors

Gynandroblastoma

Ovarian Sex Cord Tumor With Annular Tubules

Antineoplastic Agents

Anti-Infective Agents

Paclitaxel

Albumin-Bound Paclitaxel

Carboplatin

Bleomycin

Etoposide

Cisplatin

Etoposide phosphate

Tubulin Modulators

Antimitotic Agents

Anti-Bacterial Agents

Antibiotics, Antitubercular

Patients receive paclitaxel IV over 3 hours and carboplatin IV over 1 hour on day 1. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.

Patients receive bleomycin sulfate IV on day 1 and etoposide IV over 1 hour and cisplatin IV over 30 minutes on days 1-5. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.

Bleomycin Sulfate

Etoposide Phosphate

Laboratory Biomarker Analysis

Jubilee Brown

This randomized phase II trial studies paclitaxel and carboplatin to see how well they work compared with bleomycin sulfate, etoposide phosphate, and cisplatin in treating patients with sex cord-ovarian stromal tumors that have spread to other places in the body and usually cannot be cured or controlled with treatment (advanced) or has returned (recurrent). Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving more than one drug (combination chemotherapy) may kill more tumor cells. It is not yet known which chemotherapy regimen is more effective in treating sex cord-ovarian stromal tumors.

PRIMARY OBJECTIVES:

I. To assess the activity of paclitaxel and carboplatin with respect to progression free survival (using bleomycin, etoposide, and cisplatin \[BEP\] as a reference) for newly diagnosed advanced or recurrent chemonaive ovarian sex cord-stromal tumors.

SECONDARY OBJECTIVES:

I. To estimate the toxicity of paclitaxel and carboplatin, and bleomycin, etoposide, and cisplatin in this patient population.

II. To estimate overall survival for paclitaxel and carboplatin relative to that of BEP.

III. To evaluate response rate in the subset of patients with measurable disease.

TERTIARY OBJECTIVES:

I. To collect fixed and/or frozen tumor tissue for future translational research studies.

II. To explore the utility of inhibin A and inhibin B as prognostic and predictive biomarkers for ovarian sex cord-stromal tumors and to examine changes in these markers with treatment.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive paclitaxel intravenously (IV) over 3 hours and carboplatin IV over 1 hour on day 1. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive bleomycin sulfate IV on day 1 and etoposide phosphate\* IV over 1 hour and cisplatin IV over 30 minutes on days 1-5. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.

NOTE: \*Patients who have received prior radiotherapy receive etoposide phosphate on days 1-4.

After completion of study therapy, patients are followed up every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter.

Paclitaxel and Carboplatin or Bleomycin Sulfate, Etoposide Phosphate, and Cisplatin in Treating Patients With Advanced or Recurrent Sex Cord-Ovarian Stromal Tumors

A Randomized Phase II Trial of Paclitaxel and Carboplatin vs. Bleomycin, Etoposide, and Cisplatin for Newly Diagnosed Advanced Stage and Recurrent Chemonaive Sex Cord-Stromal Tumors of the Ovary

Pre-treatment levels of inhibin A and inhibin B will be examined in relation to OS and PFS in Cox proportional hazards models. Changes from baseline in inhibin levels will be compared between treatment groups using mixed effects models accounting for the longitudinal nature of the data. The repeated measures of inhibin will also be explored versus overall survival and PFS using time-dependent covariates in Cox proportional hazards models.

The relationship of randomized treatment to progression free survival. The RECIST 1.1 criteria are used for disease progression. This is the criteria: progression is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions).

Proportion of evaluable patients with complete or partial tumor response by RECIST 1.1 criteria.

Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. (ORR = CR + PR).

The relationship of treatment to overall survival will be assessed. The number of death events in the treatment arm is reported.

National Cancer Institute (NCI)

GOG Foundation

Patients receive paclitaxel IV over 3 hours and carboplatin IV over 1 hour on day 1. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.

Carboplatin: Given IV

Laboratory Biomarker Analysis: Correlative studies

Paclitaxel: Given IV

Arm I (Paclitaxel, Carboplatin)

Patients receive bleomycin sulfate IV on day 1 and etoposide IV over 1 hour and cisplatin IV over 30 minutes on days 1-5. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.

Bleomycin Sulfate: Given IV

Cisplatin: Given IV

Etoposide Phosphate: Given IV

Laboratory Biomarker Analysis: Correlative studies

Arm II (Bleomycin Sulfate, Etoposide Phosphate, Cisplatin)

Total

Age, Continuous

Age, Customized

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

For Performance Status, the GOG- score was used:

0 = normal activity, asymptomatic

1. = symptomatic, fully ambulatory
2. = symptomatic, in bed \< 50% of time
3. = symptomatic, in bed \> 50% of time
4. = 100% bedridden

Performance Status

Measurable Disease

Cell Type

An interim analysis was planned occur after 20 PFS events were observed in either arm (roughly 50% information time). The futility threshold for paclitaxel and carboplatin relative to BEP was HR\>1.10. Median followup time was 48 months.

The study closed at the interim analysis for futility, and difficulty with accrual. At the time of closures, 63 of a planned 128 patients had enrolled at the time of accrual suspension.

Christopher Purdy on behalf of Austin Miller PhD

Progression-free Survival (PFS)

Patients with at least one target lesion by RECIST 1.1 criteria and and at least one CT tumor assessment

Tumor Response Rate

Overall Survival (OS)

Change in Inhibin A and Inhibin B Levels

Overall Study

Antibodies

Antibodies, Monoclonal

Bevacizumab

Immunoglobulins

Immunoglobulin G

Endothelial Growth Factors

Mitogens

Immunoglobulins, Intravenous

Antineoplastic Agents, Immunological

Angiogenesis Inhibitors

Growth Inhibitors

Immunologic Factors

Patients receive bevacizumab IV over 30-90 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

This phase II trial studies how well bevacizumab works in treating patients with sex cord-stromal tumors of the ovary that have come back. Monoclonal antibodies, such as bevacizumab, may block tumor growth in different ways by targeting certain cells. Bevacizumab may also stop the growth of tumor cells by blocking blood flow to the tumor.

PRIMARY OBJECTIVES:

I. To estimate the anti-tumor activity of bevacizumab by assessing frequency of objective response in patients with recurrent sex cord-stromal tumors of the ovary who have measurable disease.

SECONDARY OBJECTIVES:

I. To determine the nature and degree of toxicity in these patients. II. To determine the overall survival and progression-free survival of these patients.

TERTIARY OBJECTIVES:

I. To quantify expression of angiogenic or lymphangiogenic markers in recurrent stromal tumors of the ovary to determine the frequency of alterations and potential utility of biologic agents directed at these proteins for inclusion in future studies.

OUTLINE:

Patients receive bevacizumab intravenously (IV) over 30-90 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed every 3 months for 2 years, every 6 months for 3 years, and then periodically thereafter.

Bevacizumab in Treating Patients With Recurrent Sex Cord-Stromal Tumors of the Ovary

A Phase II Trial of NCI-Supplied Agent: Bevacizumab (rhuMAB VEGF) (NSC# 704865) for Recurrent Sex Cord-Stromal Tumors of the Ovary

Complete and Partial Tumor Response by Response Evaluation Criteria in Solid Tumors (RECIST) 1.0

Progression-Free Survival is the period from study entry until disease progression, death or date of last contact.

The observed length of life from entry into the study to death or the date of last contact.

Adverse Events at least possibly related to study agent.

NRG Oncology

Bevacizumab 15 mg/kg IV every 21 days until disease progression or adverse effects prohibit further treatment

20-29

30-39

40-49

50-59

60-69

70-79

80-89

Angela M. Kuras, Associate Director of Data Management

Tumor Response

Progression-free Survival

Overall Survival

Leukopenia

Thrombocytopenia

Anemia

Other Hematologic

Allergy/Immunology

Auditory/Ear

Cardiac

Coagulation

Constitutional

Dermatologic

Endocrine

Gastrointestinal

Genitourinary/Renal

Hemorrhage

Infection

Lymphatics

Metabolic

Musculoskeletal

Neurosensory

Other Neurological

Ocular/Visual

Pain

Pulmonary

Sexual/Reproductive

Syndromes

Vascular

Death, Not CTC coded

Number of patients who did not experience the specified AE (adverse event).

Grade 0

Number of patients who experienced a grade 1 event using Common Terminology Criteria version 3.0

Grade 1 (CTCAE v 3.0)

Number of patients who experienced a grade 2 event using Common Terminology Criteria version 3.0

Grade 2 (CTCAE v 3.0)

Number of patients who experienced a grade 3 event using Common Terminology Criteria version 3.0

Grade 3 (CTCAE v 3.0)

Number of patients who experienced a grade 4 event using Common Terminology Criteria version 3.0

Grade 4 (CTCAE v 3.0)

Number of patients who experienced a grade 5 event using Common Terminology Criteria version 3.0

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Nirogacestat in Ovarian Granulosa Cell Tumors	NCT05348356	Ovarian Granulo... Ovarian Granulo... Ovarian Cancer	Nirogacestat	18 Years -	SpringWorks Therapeutics, Inc.
Paclitaxel and Carboplatin or Bleomycin Sulfate, Etoposide Phosphate, and Cisplatin in Treating Patients With Advanced or Recurrent Sex Cord-Ovarian Stromal Tumors	NCT01042522	Ovarian Granulo... Ovarian Gynandr... Ovarian Sertoli... Ovarian Sex Cor... Ovarian Sex Cor... Ovarian Sex Cor... Ovarian Steroid...	Bleomycin Sulfa... Carboplatin Cisplatin Etoposide Phosp... Laboratory Biom... Paclitaxel	18 Years -	GOG Foundation
Bevacizumab in Treating Patients With Recurrent Sex Cord-Stromal Tumors of the Ovary	NCT00748657	Malignant Ovari... Ovarian Granulo... Ovarian Gynandr... Ovarian Sertoli... Ovarian Sex Cor... Ovarian Sex Cor... Ovarian Sex Cor... Ovarian Steroid...	Bevacizumab Laboratory Biom...	18 Years -	National Cancer Institute (NCI)
Paclitaxel and Carboplatin or Bleomycin Sulfate, Etoposide Phosphate, and Cisplatin in Treating Patients With Advanced or Recurrent Sex Cord-Ovarian Stromal Tumors	NCT01042522	Ovarian Granulo... Ovarian Gynandr... Ovarian Sertoli... Ovarian Sex Cor... Ovarian Sex Cor... Ovarian Sex Cor... Ovarian Steroid...	Bleomycin Sulfa... Carboplatin Cisplatin Etoposide Phosp... Laboratory Biom... Paclitaxel	18 Years -	GOG Foundation
Bevacizumab in Treating Patients With Recurrent Sex Cord-Stromal Tumors of the Ovary	NCT00748657	Malignant Ovari... Ovarian Granulo... Ovarian Gynandr... Ovarian Sertoli... Ovarian Sex Cor... Ovarian Sex Cor... Ovarian Sex Cor... Ovarian Steroid...	Bevacizumab Laboratory Biom...	18 Years -	National Cancer Institute (NCI)

Spots Global Cancer Trial Database for ovarian granulosa cell tumor