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    Summary
    EudraCT Number:2022-001816-25
    Sponsor's Protocol Code Number:NIR-OGT-201
    National Competent Authority:Poland - Office for Medicinal Products
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2022-10-11
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedPoland - Office for Medicinal Products
    A.2EudraCT number2022-001816-25
    A.3Full title of the trial
    A Phase 2 trial of Nirogacestat in Patients with Recurrent Ovarian Granulosa Cell Tumors
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Nirogacestat in Ovarian Granulosa Cell Tumors
    A.4.1Sponsor's protocol code numberNIR-OGT-201
    A.5.4Other Identifiers
    Name:IND NumberNumber:159545
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorSpringWorks Therapeutics, Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportSpringWorks Therapeutics, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationSpringWorks Therapeutics, Inc.
    B.5.2Functional name of contact pointResearch and Development - CO dpt.
    B.5.3 Address:
    B.5.3.1Street Address100 Washington Blvd
    B.5.3.2Town/ cityStamford
    B.5.3.3Post codeCT 06902
    B.5.3.4CountryUnited States
    B.5.6E-mailNIROGT201-Clinical@springworkstx.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product namenirogacestat
    D.3.2Product code PF-03084014
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNirogacestat
    D.3.9.1CAS number 1962925-29-6
    D.3.9.2Current sponsor codePF-03084014
    D.3.9.3Other descriptive nameNirogacestat hydrobromide
    D.3.9.4EV Substance CodeSUB197065
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Ovarian Granulosa Cell Tumor
    E.1.1.1Medical condition in easily understood language
    Ovarian tumor
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 27.0
    E.1.2Level PT
    E.1.2Classification code 10073260
    E.1.2Term Ovarian granulosa cell tumour
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 27.0
    E.1.2Level LLT
    E.1.2Classification code 10073273
    E.1.2Term Ovarian granulosa cell tumor
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To determine the anti-tumor activity of nirogacestat in adult participants with relapsed/refractory OvGCT
    E.2.2Secondary objectives of the trial
    - To determine if nirogacestat delays progression or death in OvGC
    - To describe overall survival in participants treated with nirogacestat
    - To determine the effect of nirogacestat on ovarian cancer symptoms measured by Functional Assessment of Cancer Therapy – Ovarian Symptom Index (FOSI)
    - To determine the duration of response
    - To determine the pharmacokinetics (PK) of nirogacestat
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Participant must be aged ≥ 18 years of age inclusive
    2. Participant has histologically confirmed recurrent adult-type granulosa cell tumor of the ovary prior to first dose of study treatment and agrees to provide archival or fresh tumor tissue.
    3. Participant must 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. Prior systemic therapy is not limited to therapy type nor is any specific prior line of therapy required.
    4. Participant must have a ECOG performance Grade of 0, 1, or 2 at Screening.
    5. Participant must have adequate bone marrow, renal and hepatic function as defined by the following Screening laboratory values:
    a. Absolute neutrophil count (ANC) ≥1,000 cells/μL;
    b. Platelets ≥ 75,000/μL;
    c. Estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73 m2 calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation (Grade ≤ 1).
    d. Total bilirubin ≤ 1.5 ×ULN (isolated total bilirubin > 1.5 × ULN is acceptable if bilirubin is fractionated and direct bilirubin < 35% of total);
    e. Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase)/alanine
    aminotransferase (ALT) (serum glutamic pyruvate transaminase) ≤ 2 x ULN; and
    f. Alkaline phosphatase < 2.5 × ULN.
    6. Participant can swallow tablets (delivery of nirogacestat via nasogastric tube or gastrostomy tube is not allowed).
    7. A female participant is eligible to participate if not pregnant or breastfeeding, and at least one of the following conditions applies:
    a. Is not of childbearing potential (WOCBP);
    OR
    b. Is of childbearing potential but is abstinent or using 1 highly effective contraceptive method, as described in Appendix 6 during the treatment period and for at least 1 week after the last dose of study treatment. A second method of contraception is required if the participant is using hormonal contraception, as coadministration with nirogacestat may alter the plasma concentrations of hormonal contraceptives resulting in reduced efficacy.
    • Additionally, the participant agrees not to harvest or donate eggs (ova, oocytes) for the purpose of reproduction during the treatment period and for at least 1 week after the last dose of study treatment. The Investigator should evaluate the effectiveness of the contraceptive method in relationship to the first dose of study treatment.
    • A WOCBP must have a negative serum pregnancy test result at Screening and a negative urine pregnancy test result at Baseline (C1D1) prior to the first dose of study treatment.
    • Investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
    E.4Principal exclusion criteria
    1. Participant has any of the following:
    • Signs of bowel obstruction who require parenteral nutrition.
    • Malabsorption syndrome or preexisting gastrointestinal conditions that may impair absorption of nirogacestat (e.g., gastric bypass, lap band, or other gastric procedures that would alter absorption).
    2.Participant has experienced any of the following within 6 months of signing informed consent:
    • Clinically significant cardiac disease (New York Heart Association Class III or IV);
    • Myocardial infarction;
    • Severe/unstable angina;
    • Coronary/peripheral artery bypass graft;
    • Symptomatic congestive heart failure;
    • Cerebrovascular accident;
    • Transient ischemic attack; or
    • Symptomatic pulmonary embolism.
    3. Participant has abnormal QT interval corrected by Fridericia’s formula (> 470 msec for female participants, or > 480 msec for participants with bundle branch block) after electrolytes have been corrected at Screening.
    4. Participant has congenital or acquired long QT syndrome or a history of additional risk factors for Torsades de Pointes (TdP) (e.g., heart failure, hypokalemia, family history of Long QT Syndrome).
    5. Participant has current or chronic history of liver disease or known hepatic or biliary abnormalities (except for Gilbert’s syndrome or asymptomatic gallstones).
    6. Participant has had a major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to the first dose of study treatment.
    7. Participant has a history of other invasive malignancies, with the exception of nonmelanoma skin cancer, are excluded if there is any evidence of other malignancy being present within the last 5 years. Participants are also excluded if their previous cancer treatment contraindicates this protocol therapy.
    8. Participant has CTCAE v5.0 Grade > 1 toxicity from prior therapy (except alopecia, anorexia or CTCAE grade 2 peripheral neuropathy).
    9. Palliative radiotherapy with a limited field of radiation within 14 days or with wide field of radiation or to more than 30% of bone marrow within 28 days prior to the first dose of study treatment.
    10. Participant previously received or is currently receiving therapy with GS inhibitors (i.e., nirogacestat) or anti-Notch antibody therapy.
    11. Previous or current treatment for OvGCT:
    a. Participant previously received or is currently receiving bevacizumab (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; or

    b. Participant has received the following treatment types for OvGCT within 28 days (or 5 half-lives, whichever is longer) prior to the first dose of study treatment:
    • hormonal therapy;
    • chemotherapy;
    • immunotherapy;
    • targeted therapy (e.g., tyrosine kinase inhibitors [TKIs], small molecule inhibitors); or
    • any other investigational treatment.
    12. Participant is currently using or anticipates using food or drugs that are known strong/moderate cytochrome P450 3A4 (CYP3A4) inhibitors, or strong CYP3A inducers within 14 days prior to the first dose of study treatment.
    13. Participant is using concomitant medications that are known to prolong the QT/QTcF interval including Class Ia (e.g., quinidine, procainamide, disopromide) and Class III (e.g., dofetilide, ibutilide, sotalol) antiarrhythmics at the time of informed consent.
    Non-antiarrhythmic medications which may prolong the QT/QTcF interval are allowed provided the participant does not have additional risk factors for Torsades de Pointes (TdP).
    E.5 End points
    E.5.1Primary end point(s)
    Objective response rate, defined as the proportion of participants with Complete Response (CR) + Partial Response (PR) using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
    E.5.1.1Timepoint(s) of evaluation of this end point
    There is not any defined timepoint.
    E.5.2Secondary end point(s)
    - Estimate of proportion of participants who have not progressed or died at 6 months follow-up: PFS-6. Progression is defined by RECIST v1.1
    - Estimate of 2-year overall survival, defined as the proportion of participants who have not died after 2 years of follow-up after their first dose of nirogacestat
    - Change from baseline in FOSI
    - Duration of response, (DoR), defined as the time from first assessment of response (CR + PR using RECIST v1.1) to first disease progression defined by RECIST v1.1 or death, whichever comes first
    - Serum concentrations of nirogacestat will be measured to evaluate system exposures (Cmax, Ctrough and other PK parameters as data allow)
    E.5.2.1Timepoint(s) of evaluation of this end point
    There is not any defined timepoint.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA15
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Canada
    United States
    France
    Poland
    Spain
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    Last visit of the last subject
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months8
    E.8.9.1In the Member State concerned days20
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 28
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 15
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male No
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients No
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state6
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 13
    F.4.2.2In the whole clinical trial 43
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2022-12-07
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-10-06
    P. End of Trial
    P.End of Trial StatusCompleted
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