Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Also known as Nirogacestat Hydrobromide, Nirogacestat oral tablet
Nirogacestat · 8 trials · 10 indications
Progression will be determined radiographically using RECIST v1.1 (Eisenhauer, 2009) or clinically as assessed by the investigator. Clinical progression is defined as the onset or worsening of symptoms resulting in a global deterioration of health status causing the permanent discontinuation from study treatment and the initiation of emergent treatment (e.g., radiotherapy, surgery, or systemic therapy including chemotherapy or tyrosine kinase inhibitors) for DT/AF. Events of clinical progression will be adjudicated by an independent blinded central Endpoint Adjudication Committee (EAC) which will qualify events of clinical progression for inclusion in the PFS endpoint prior to study unblinding according to an EAC Review Charter.
Objective response rate (ORR), defined as the proportion of participants with confirmed complete response (CR) + partial response (PR) assessed by independent Central Imaging Review using RECIST v1.1 (Eisenhauer 2009).
Clinical benefit (CB) is defined as the number of participants assessed with a complete response (CR), partial response (PR), or stable disease (SD) within 1 year and with no evidence of loss of response nor progression within that year. Response \& progression will be assessed according to the Revised Response Evaluation Criteria in Solid Tumors (RECIST)v1.1, as follows: RECIST v1.1: * CR=Disappearance of all lesions * PR=≥30% decrease in diameter of target lesions * Progressive disease (PD)=20% increase in diameter of target lesion; progression of non-target lesion; or ≥1 new lesion(s) For the overall outcome: * SD=Changes not meeting above criteria * Overall Response (OR)=CR+PR * CB=CR+PR+SD
Will be estimated using the Kaplan-Meier method with the 95% confidence interval estimated by the Peto-Peto method.
Will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. All grade 3 or above toxicities deemed related to study drug will be summarized. All grade 1 and 2 toxicities observed in \> 5% of participants and deemed related to study drug will be reported.
PK parameters of nirogacestat will be defined to quantify systemic exposure, drug clearance, terminal half-life and other pharmacokinetic characteristics. These PK parameters will be summarized with descriptive statistics, including means, medians, ranges, and standard deviations.
PK parameters of nirogacestat will be defined to quantify systemic exposure, drug clearance, terminal half-life and other pharmacokinetic characteristics. These PK parameters will be summarized with descriptive statistics, including means, medians, ranges, and standard deviations.
PK parameters of nirogacestat will be defined to quantify systemic exposure, drug clearance, terminal half-life and other pharmacokinetic characteristics. These PK parameters will be summarized with descriptive statistics, including means, medians, ranges, and standard deviations.
Area under the concentration-time curve from dosing extrapolated to infinity. AUCinf = (AUClast + Clast/Kel) where Clast is the plasma concentration at the last quantifiable timepoint estimated from the log-linear regression analysis and Kel is the terminal elimination phase rate constant estimated by linear regression based on observations justified to describe the terminal phase on the log-linear concentration-time profile.
Maximum observed plasma concentration. Observed directly from the data.
Serum AUCinf of nirogacestat.
Serum Cmax of nirogacestat.
Serum AUCinf of nirogacestat.
Serum Cmax of nirogacestat.
| Arm | Type | Description |
|---|---|---|
| Double-Blind Phase - Nirogacestat | EXPERIMENTAL | Nirogacestat 150 mg by mouth, twice daily |
| Double-Blind Phase - Placebo | PLACEBO_COMPARATOR | Placebo by mouth, twice daily |
| Open-Label Phase - Nirogacestat | EXPERIMENTAL | Nirogacestat 150 mg by mouth, twice daily |
| Nirogacestat | EXPERIMENTAL | Nirogacestat 150 mg by mouth, twice daily |
| Nirogacestat 150 mg | EXPERIMENTAL | Patients will receive 3-cycle lead-in with systemic therapy with nirogacestat 150 mg po BID, given continuously. |
| Nirogacestat Open-Label | EXPERIMENTAL | Nirogacestat 150 mg by mouth, twice daily Nirogacestat oral tablet: Nirogacestat tablet |
| Treatment (nirogacestat) | EXPERIMENTAL | Patients receive nirogacestat PO BID on days 1-28. Cycles repeats every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo ECHO and CT or MRI on study. Patients may also undergo x-ray imaging and blood sample collection on study. |
| Nirogacestat and CYP cocktail | EXPERIMENTAL | Nirogacestat 100 mg BID will be administered orally from Day 1 through Day 17 and an oral dose of CYP cocktail (CYP2B6 \[bupropion 20 mg\], CYP2C8 \[repaglinide 0.05 mg\], CYP2C9 \[flurbiprofen 10 mg\], CYP2C19 \[omeprazole 10 mg\], and CYP3A4 \[midazolam 1 mg\]) will be administered on Day -3, and again on Day 15. |
| Period 1 - Nirogacestat Dose (Reference) | ACTIVE_COMPARATOR | Nirogacestat will be administered, after at least a 10-hour fast, in the morning on Day 1, Day 6, and Day 17 |
| Period 2 - Nirogacestat and Famotidine (Test) | ACTIVE_COMPARATOR | Famotidine will be administered as an oral tablet 2 hours after the administration of nirogacestat on Day 6. |
| Period 3 Nirogacestat and Rabeprazole (Test) | ACTIVE_COMPARATOR | Rabeprazole will be administered as an oral tablet in the evenings on Day 10 through Day 16. |
| Name | Type | Description |
|---|---|---|
| Nirogacestat oral tablet | DRUG | Nirogacestat tablet |
| Placebo Oral Tablet | DRUG | Sugar pill manufactured to mimic nirogacestat 50 mg tablet |
| Nirogacestat | DRUG | Given by PO |
| Cryoablation | PROCEDURE | Cryoablation procedure (single session) of one tumor mass between Cycles 3 and 4 of nirogacestat treatment |
| Biospecimen Collection | PROCEDURE | Undergo blood sample collection |
| Computed Tomography | PROCEDURE | Undergo CT |
| Echocardiography Test | PROCEDURE | Undergo ECHO |
| Magnetic Resonance Imaging | PROCEDURE | Undergo MRI |
| Nirogacestat Hydrobromide | DRUG | Given PO |
| Quality-of-Life Assessment | OTHER | Ancillary studies |
| Questionnaire Administration | OTHER | Ancillary studies |
| X-Ray Imaging | PROCEDURE | Undergo x-ray |
| Nirogacestat and Cocktail of CYP Specific Probe Substrates | DRUG | Drug: Nirogacestat 100 mg tablet Day 1 through Day 17 and Drug: Cocktail of CYP Specific Probe Substrates administered Day 15. |
| Nirogacestat and Famotidine | DRUG | oral dose of 150 mg nirogacestat \& oral dose of 40 mg famotidine |
| Nirogacestat and Rabeprazole | DRUG | oral dose of 150 mg nirogacestat and oral dose of 20 mg rabeprazole |
Double-Blind Key Inclusion Criteria: * Participant has histologically confirmed DT/AF (by local pathologist prior to informed consent) that has progressed by ≥ 20% as measured by RECIST v1.1 within 12 months of the screening visit scan. * Participant has: 1. Treatment naïve, measurably progressi...
Nirogacestat is an investigational small molecule being developed by SpringWorks Therapeutics, Inc. (ticker SWTX). It is being studied in desmoid fibromatosis, also called desmoid tumor or aggressive fibromatosis, as well as in ovarian granulosa-stromal tumors. It has received FDA designations including Priority Review, Fast Track, Orphan Drug, and Breakthrough Therapy.
Nirogacestat is being studied for the treatment of desmoid tumors, also known as desmoid fibromatosis or aggressive fibromatosis. Clinical trials are evaluating it both as a single agent in Japanese adults and in combination with cryoablation in the United States. It is also being investigated in ovarian granulosa-stromal tumors.
Nirogacestat is an inhibitor that targets the gamma-secretase complex components APH1A, APH1B, PSEN1, PSEN2, PSENEN, and NCSTN. By inhibiting these presenilin and nicastrin subunits, it interferes with gamma-secretase mediated signaling. This mechanism underlies its investigation in desmoid tumors and other conditions.
Nirogacestat is developed by SpringWorks Therapeutics, Inc., which trades under the ticker SWTX. The company is running clinical trials of the drug in desmoid tumors and related conditions, including studies in Japan and the United States.
Nirogacestat is in Phase 2 clinical development. Two Phase 2 trials are ongoing, one active but not recruiting in Japanese adults with desmoid tumors and one recruiting in the United States studying cryoablation plus Nirogacestat. Two Phase 1 trials in healthy volunteers have been completed.
Nirogacestat has been studied in several trials. NCT07170644 is a Phase 2 study in Japanese adults with desmoid tumors and is active but not recruiting. NCT05949099 is a recruiting Phase 2 study of cryoablation plus Nirogacestat in desmoid tumor. Completed Phase 1 trials include NCT07259330 and NCT07171619 in healthy volunteers.
Yes, Nirogacestat Hydrobromide is another name for Nirogacestat, which is also described as a Nirogacestat oral tablet. These names refer to the same small molecule developed by SpringWorks Therapeutics, Inc. (SWTX) for desmoid tumors and related conditions.