Ovarian Granulosa-Stromal Tumor, Ovarian Granulosa Cell Tumor, Ovarian Cancer
Conditions
Brief summary
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.
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.
Interventions
DRUGNirogacestat
nirogacestat oral tablet
Sponsors
SpringWorks Therapeutics, Inc., a healthcare company of Merck KGaA, Darmstadt, Germany
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | 2.5 years | The percentage of participants with complete response (CR) + partial response (PR) assessed using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival at 6 Months (PFS-6) | First day of cycle 7 (approximately 6 months after the first dose of study treatment). Each cycle is 28 days. | The number of participants without progression according to RECIST v1.1 or death at 6 months. |
| Overall Survival at Year 2 | 2 years after first dose of study treatment | The number of participants who have not died of any cause by Year 2. |
| Duration of Response | 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). | 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. |
| Change From Baseline at Cycle 2 Day 1 in the Functional Assessment of Cancer Therapy - Ovarian Symptom Index (FOSI) Score. | Baseline and at Cycle 2 Day 1 (cycle length is 28 days). | 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. |
| Change From Baseline at Cycle 3 Day 1 Treatment in the Functional Assessment of Cancer Therapy - Ovarian Symptom Index (FOSI) Score | Baseline and at Cycle 3 Day 1 (cycle length is 28 days). | 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. |
| Change From Baseline at Cycle 4 Day 1 in the Functional Assessment of Cancer Therapy - Ovarian Symptom Index (FOSI) Score | Baseline and at Cycle 4 Day 1 (cycle length is 28 days). | 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. |
| Change From Baseline at Cycle 5 Day 1 in the Functional Assessment of Cancer Therapy - Ovarian Symptom Index (FOSI) Score | Baseline and at Cycle 5 Day 1 (cycle length is 28 days). | 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. |
| Change From Baseline at End of Treatment in the Functional Assessment of Cancer Therapy - Ovarian Symptom Index (FOSI) Score | Baseline and at end of treatment (estimated to be an average of 5.5 months [minimum of 0 month and maximum of 33 months]). | 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. |
| Change From Baseline at Safety Follow-up in the Functional Assessment of Cancer Therapy - Ovarian Symptom Index (FOSI) Score | Baseline and at safety follow-up (up to a maximum of 34 months). | 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. |
Countries
Canada, Poland, United States
Contacts
STUDY_DIRECTORMedical Responsible
SpringWorks Therapeutics, Inc., a healthcare company of Merck KGaA, Darmstadt, Germany
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 55.1 years STANDARD_DEVIATION 12.85 |
| Age, Customized <45 years | 13 Participants |
| Age, Customized >=45 years | 40 Participants |
| Baseline Height | 1.632 meter STANDARD_DEVIATION 0.0611 |
| Baseline Weight | 82.48 kilogram STANDARD_DEVIATION 19.672 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 43 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 4 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants |
| Race (NIH/OMB) More than one race | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 7 Participants |
| Race (NIH/OMB) White | 37 Participants |
| Region of Enrollment Poland | 3 Participants |
| Region of Enrollment United States | 50 Participants |
| Sex: Female, Male Female | 53 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 7 / 53 |
| other Total, other adverse events | 52 / 53 |
| serious Total, serious adverse events | 12 / 53 |
Outcome results
None listed