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A Study of a New Drug, Nirogacestat, for Treating Desmoid Tumors That Cannot be Removed by Surgery

Sponsor
Children's Oncology Group (Other)
Overall Status
Recruiting
CT.gov ID
NCT04195399
Collaborator
National Cancer Institute (NCI) (NIH), SpringWorks Therapeutics, Inc. (Industry)
35
Enrollment
93
Locations
1
Arm
54.3
Anticipated Duration (Months)
0.4
Patients Per Site
0
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This phase II trial studies the side effects and how well nirogacestat works in treating patients patients less than 18 years of age with desmoid tumors that has grown after at least one form of treatment by mouth or in the vein that cannot be removed by surgery. Nirogacestat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Condition or Disease Intervention/Treatment Phase
  • Drug: Nirogacestat
  • Other: Quality-of-Life Assessment
  • Other: Questionnaire Administration
 Phase 2

Detailed Description

PRIMARY OBJECTIVES:

  1. To estimate the 2-year progression-free survival (PFS) rate in patients with progressive, surgically unresectable desmoid tumor treated with nirogacestat.

  2. To describe the toxicities of nirogacestat in children and adolescents with desmoid tumor.

  3. To characterize the pharmacokinetics (PK) of nirogacestat in children and adolescents.

SECONDARY OBJECTIVE:
  1. To determine the objective tumor response rate (ORR) of nirogacestat in children and adolescents with progressive, surgically unresectable desmoid tumor.
EXPLORATORY OBJECTIVES:

  1. To collect blood, archival tumor samples and on-study/post-treatment tumor samples (if available) from patients enrolled on this trial to correlate various CTNNB1 and APC gene mutations and genomic signatures with tumor response and PFS.

  2. To explore the effect of nirogacestat on immune cells and immunoglobulin levels in the peripheral blood.

  3. To collect blood samples for banking at baseline, during treatment, and at the time of progression for future research.

  4. To compare assessment of tumor response using Response Evaluation Criteria in Solid Tumors (RECIST), World Health Organization (WHO) criteria, and T2 and volumetric changes using magnetic resonance imaging (MRI).

  5. To utilize a tool developed to specifically assess patient reported outcomes (PROs) in adult patients with desmoid tumor (GOunder/DTRF DEsmoid Symptom/Impact Scale [GODDESS]) and the Patient Reported Outcomes Measurement Information System (PROMIS) to explore the relationship between PROs and tumor response and PFS.

OUTLINE:

Patients receive nirogacestat orally (PO) twice daily (BID) on days 1-28. Cycles repeats every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days.

Study Design

Study Type:
Interventional
Anticipated Enrollment :
35 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Safety, Pharmacokinetic and Efficacy Study of a y-Secretase Inhibitor, Nirogacestat (PF-03084014) in Children and Adolescents With Progressive, Surgically Unresectable Desmoid Tumors
Actual Study Start Date :
Sep 21, 2020
Anticipated Primary Completion Date :
Mar 31, 2025
Anticipated Study Completion Date :
Mar 31, 2025

Arms and Interventions

Arm Intervention/Treatment
Experimental: Treatment (nirogacestat)

Patients receive nirogacestat PO BID on days 1-28. Cycles repeats every 28 days in the absence of disease progression or unacceptable toxicity.

Drug: Nirogacestat
Given PO
Other Names:
  • (S)-2-(((S)-6,8-Difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide
  • PF-03084014

    • Other: Quality-of-Life Assessment
    Ancillary studies
    Other Names:
  • Quality of Life Assessment

    • Other: Questionnaire Administration
    Ancillary studies

    Outcome Measures

    Primary Outcome Measures

    1. Progression-free survival (PFS) [From initiation of treatment to occurrence of disease progression or death from any cause, assessed up to 2 years]

      Will be estimated using the Kaplan-Meier method with the 95% confidence interval estimated by the Peto-Peto method.

    2. Incidence of adverse events [Up to 2 years]

      Will be graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v.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.

    3. Pharmacokinetic (PK) parameter: systemic exposure [Up to Cycle 3 (each cycle lasts 28 days)]

      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.

    4. Pharmacokinetic (PK) parameter: drug clearance [Up to Cycle 3 (each cycle lasts 28 days)]

      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.

    5. Pharmacokinetic (PK) parameter: half-life [Up to Cycle 3 (each cycle lasts 28 days)]

      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.

    Secondary Outcome Measures

    1. Objective response rate [Up to 24 months]

      Defined by the rate of a complete response (CR) or partial response (PR) by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1.

    Other Outcome Measures

    1. CTNNB1 and APC gene mutations and genomic signatures [Up to 2 years]

      The chi-square test will be used to assess the correlation of CTNNB1 and APC gene mutations and genomic signatures with tumor response, and the long-rank test will be used to assess the correlation of CTNNB1 and APC gene mutations and genomic signatures with PFS.

    2. Changes in the levels of each of the lymphocyte subsets and immunoglobulins [Up to 2 years]

      Lymphocyte subsets include CD3 (total T cells), CD3+CD4+ (T helper cells), CD3+CD8+ (T cytotoxic cells), CD4:CD8 ratio, CD3+HLA-DR+ (activated T cells) percentages and absolute counts. The chi-square test will be used to assess the correlation of the levels of lymphocyte and immunoglobulin with tumor response, and the Cox regression will be used to assess the correlation of the levels of lymphocyte and immunoglobulin with PFS.

    3. Response assessments by the RECIST criteria [Up to cycle 24]

    4. Response assessment by the World Health Organization (WHO) criteria [Up to cycle 24]

    5. Patient reported outcomes (PROs) [Up to 2 years]

      The chi-square test will be used to assess the correlation of PROs summary scores with tumor response, and the Cox regression will be used to assess the correlation of PROs summary scores with PFS. Correlation between PRO summary scores using Patient Reported Outcomes Measurement Information System (PROMIS) and GOunder/DTRF DEsmoid Symptom/Impact Scale (GODDESS) will be assessed by performing inferences on the Pearson correlation coefficients.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    12 Months to 18 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    • Patients must have a body surface area of > 0.3 m^2 at the time of enrollment

    • Existing or recurrent desmoid tumor that is deemed not amenable to surgery without significant morbidity and progressed by >= 10% as assessed by RECIST version (v)1.1 within the 6-month period prior to study enrollment

    • Patients must have had histologic verification of the desmoid tumor

    • Patients must have measurable disease by RECIST v1.1 criteria

    • Patient must have received at least one prior course of systemic therapy for desmoid tumor

    • Patients must have a Lansky (for patients =< 16 years of age) or Karnofsky (for patients > 16 years of age) performance status score of >= 50. Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing performance score

    • Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, surgery or radiotherapy prior to entering this study. Patients may not be using or anticipate using these treatments after the observed progression or within the time period stated below

    • Cytotoxic chemotherapy: must not have received within 2 weeks of entry onto this study (4 weeks if prior nitrosourea)

    • Small molecule tyrosine kinase inhibitors (e.g., sorafenib, pazopanib, imatinib), rapalogs (e.g., temsirolimus, everolimus, sirolimus) or anti estrogen therapy (e.g., tamoxifen): may not have received within 28 days prior to the first dose of study treatment

    • Antibodies: >= 21 days must have elapsed from infusion of last dose of antibody, and toxicity related to prior antibody therapy must be recovered to grade =< 1

    • Biologic (anti-neoplastic agent): at least 7 days since the completion of therapy with a biologic agent

    • Local regional tumor directed therapy, including, but not limited to small port radiation therapy (RT), radiofrequency ablation, cryotherapy, surgery: at least 2 weeks since these therapies and all toxicity must have resolved to grade =< 1. If prior craniospinal RT or if >= 50% radiation of pelvis then >= 6 months must have elapsed. If other substantial bone marrow (BM) radiation, then >= 6 weeks must have elapsed

    • Stem cell transplant (SCT): No evidence of active graft versus (vs.) host disease. For allogeneic SCT, >= 6 months must have elapsed

    • No prior gamma-secretase, Notch or beta-catenin inhibitor

    • Investigational drugs: must not have received investigational drug within 4 weeks of study entry, and all toxicities related to prior therapy must be resolved to grade =< 1 or baseline

    • Concomitant Medication Restrictions

    • Steroids: patients who are receiving dexamethasone must be on a stable or tapering dose for at least 2 weeks prior to study entry. Use of steroids for non-tumor indications (e.g., asthma or severe allergic reaction) is permitted

    • Growth factor(s): must not have received within 1 week of entry onto this study

    • Patients who are currently receiving drugs that are strong inducers or moderate to strong inhibitors of CYP3A4 are not eligible. Strong inducers or moderate to strong inhibitors of CYP3A4 are not allowed from 14 days prior to enrollment to the end of protocol therapy. Note: CYP3A4 inducing anti-epileptic drugs on a stable dose, are allowed

    • Must not be receiving non-steroidal anti-inflammatory drugs (NSAIDs) as treatment for desmoid tumor after the observed progression and patient agrees to not use NSAIDs while on study. Occasional use (defined as =< 3 times per week) for treatment of pain is permitted

    • Peripheral absolute neutrophil count (ANC) >= 1000/uL (within 7 days prior to enrollment)

    • Platelet count >= 100,000/uL (transfusion independent) (within 7 days prior to enrollment)

    • Hemoglobin >= 9.0 g/dL (may receive red blood cell [RBC] transfusions) (within 7 days prior to enrollment)

    • Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 or a serum creatinine based on age/gender as follows (within 7 days prior to enrollment):

    • Age: Maximum serum creatinine (mg/dL)

    • Age: 1 to < 2 years; Maximum serum creatinine (mg/dL): 0.6 (male and female)

    • Age: 2 to < 6 years; Maximum serum creatinine (mg/dL): 0.8 (male and female)

    • Age: 6 to < 10 years; Maximum serum creatinine (mg/dL): 1 (male and female)

    • Age: 10 to < 13 years; Maximum serum creatinine (mg/dL): 1.2 (male and female)

    • Age: 13 to < 16 years; Maximum serum creatinine (mg/dL): 1.5 (male); 1.4 (female)

    • Age: >= 16 years; Maximum serum creatinine (mg/dL): 1.7 (male); 1.4 (female)

    • Total bilirubin =< 1.5 x upper limit of normal (ULN) for age (unless secondary to previously diagnosed Gilbert's syndrome) (within 7 days prior to enrollment)

    • Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L

    • Note: For the purpose of this study, the ULN for SGPT (ALT) has been set to the value of 45 U/L (within 7 days prior to enrollment)

    • Adequate cardiac function defined as:

    • Corrected QT (QTc) interval < 470 ms

    • No history of congenital or acquired prolonged QTc syndrome

    • No history of clinically significant cardiac arrhythmias, congestive heart failure, stroke or myocardial infarction within 6 months prior to study entry

    • All patients and/or their parents or legal guardians must sign a written informed consent

    • All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

    Exclusion Criteria:

    • Active or chronic infection within 7 days prior to study entry

    • Patients with gastrointestinal conditions that might predispose for drug intolerability or poor drug absorption (e.g., inability to take oral medication, prior surgical procedures affecting absorption (e.g., gastric bypass), malabsorption syndrome, and active peptic ulcer disease)

    • Patients with ulcerative colitis, inflammatory bowel disease, or a partial or complete small bowel obstruction

    • Known active infection with hepatitis B, hepatitis C or human immunodeficiency virus (HIV)

    • Patients with a prior history of malignancy, with the exceptions of desmoid tumor(s) and non-melanoma skin cancer, who are not in remission for more than 3 years

    • Patients who are unable to swallow tablets. Tablets must not be crushed or chewed. Administration of nirogacestat via gastrostomy tube or nasogastric tube is not allowed

    • Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study

    • Sexually active female patients of reproductive potential who have not agreed to use 1 method of highly effective contraceptive (including copper-containing intrauterine device, condom with spermicidal foam/gel/film/cream/suppository, bilateral tubal ligation, established use of inserted, injected or implanted hormonal method of contraception, abstinence, or male sterilization) for the duration of their study participation and for at least 6 months after last dose of nirogacestat. A second form of contraception (i.e. barrier method) is required for patients who are using hormonal contraception as nirogacestat may reduce the efficacy of hormonal contraceptives

    • Sexually active male patients of reproductive potential who have not agreed to use a condom and their female partner who have not agreed to use one of the highly effective methods of contraception mentioned above during treatment and for at least 90 days after the last dose of nirogacestat

    • Female patients who are breastfeeding

    • Female patients who are pregnant. These patients are excluded because there is no available information regarding the effects of nirogacestat on the developing human fetus and inhibition of gamma-secretase is known to be teratogenic

    • Female patients of childbearing potential unless a negative pregnancy test result has been obtained

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Children's Hospital of Alabama Birmingham Alabama United States 35233
    2 USA Health Strada Patient Care Center Mobile Alabama United States 36604
    3 Arkansas Children's Hospital Little Rock Arkansas United States 72202-3591
    4 Kaiser Permanente Downey Medical Center Downey California United States 90242
    5 Loma Linda University Medical Center Loma Linda California United States 92354
    6 Children's Hospital Los Angeles Los Angeles California United States 90027
    7 Mattel Children's Hospital UCLA Los Angeles California United States 90095
    8 UCSF Benioff Children's Hospital Oakland Oakland California United States 94609
    9 Kaiser Permanente-Oakland Oakland California United States 94611
    10 Lucile Packard Children's Hospital Stanford University Palo Alto California United States 94304
    11 University of California Davis Comprehensive Cancer Center Sacramento California United States 95817
    12 Rady Children's Hospital - San Diego San Diego California United States 92123
    13 UCSF Medical Center-Mission Bay San Francisco California United States 94158
    14 Children's Hospital Colorado Aurora Colorado United States 80045
    15 Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center Denver Colorado United States 80218
    16 Connecticut Children's Medical Center Hartford Connecticut United States 06106
    17 Alfred I duPont Hospital for Children Wilmington Delaware United States 19803
    18 MedStar Georgetown University Hospital Washington District of Columbia United States 20007
    19 Children's National Medical Center Washington District of Columbia United States 20010
    20 University of Florida Health Science Center - Gainesville Gainesville Florida United States 32610
    21 Nemours Children's Clinic-Jacksonville Jacksonville Florida United States 32207
    22 AdventHealth Orlando Orlando Florida United States 32803
    23 Nemours Children's Hospital Orlando Florida United States 32827
    24 Johns Hopkins All Children's Hospital Saint Petersburg Florida United States 33701
    25 Children's Healthcare of Atlanta - Egleston Atlanta Georgia United States 30322
    26 Kapiolani Medical Center for Women and Children Honolulu Hawaii United States 96826
    27 Saint Luke's Cancer Institute - Boise Boise Idaho United States 83712
    28 Lurie Children's Hospital-Chicago Chicago Illinois United States 60611
    29 University of Chicago Comprehensive Cancer Center Chicago Illinois United States 60637
    30 Saint Jude Midwest Affiliate Peoria Illinois United States 61637
    31 Riley Hospital for Children Indianapolis Indiana United States 46202
    32 Norton Children's Hospital Louisville Kentucky United States 40202
    33 Children's Hospital New Orleans New Orleans Louisiana United States 70118
    34 Ochsner Medical Center Jefferson New Orleans Louisiana United States 70121
    35 Johns Hopkins University/Sidney Kimmel Cancer Center Baltimore Maryland United States 21287
    36 Walter Reed National Military Medical Center Bethesda Maryland United States 20889-5600
    37 Massachusetts General Hospital Cancer Center Boston Massachusetts United States 02114
    38 Dana-Farber Cancer Institute Boston Massachusetts United States 02215
    39 C S Mott Children's Hospital Ann Arbor Michigan United States 48109
    40 Michigan State University Clinical Center East Lansing Michigan United States 48824-7016
    41 Helen DeVos Children's Hospital at Spectrum Health Grand Rapids Michigan United States 49503
    42 Bronson Methodist Hospital Kalamazoo Michigan United States 49007
    43 University of Mississippi Medical Center Jackson Mississippi United States 39216
    44 Children's Mercy Hospitals and Clinics Kansas City Missouri United States 64108
    45 Washington University School of Medicine Saint Louis Missouri United States 63110
    46 Mercy Hospital Saint Louis Saint Louis Missouri United States 63141
    47 University Medical Center of Southern Nevada Las Vegas Nevada United States 89102
    48 Sunrise Hospital and Medical Center Las Vegas Nevada United States 89109
    49 Alliance for Childhood Diseases/Cure 4 the Kids Foundation Las Vegas Nevada United States 89135
    50 Summerlin Hospital Medical Center Las Vegas Nevada United States 89144
    51 Renown Regional Medical Center Reno Nevada United States 89502
    52 Hackensack University Medical Center Hackensack New Jersey United States 07601
    53 Albany Medical Center Albany New York United States 12208
    54 Montefiore Medical Center - Moses Campus Bronx New York United States 10467
    55 Roswell Park Cancer Institute Buffalo New York United States 14263
    56 NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center New York New York United States 10032
    57 Memorial Sloan Kettering Cancer Center New York New York United States 10065
    58 State University of New York Upstate Medical University Syracuse New York United States 13210
    59 Carolinas Medical Center/Levine Cancer Institute Charlotte North Carolina United States 28203
    60 Children's Hospital Medical Center of Akron Akron Ohio United States 44308
    61 Cincinnati Children's Hospital Medical Center Cincinnati Ohio United States 45229
    62 Cleveland Clinic Foundation Cleveland Ohio United States 44195
    63 Nationwide Children's Hospital Columbus Ohio United States 43205
    64 Dayton Children's Hospital Dayton Ohio United States 45404
    65 University of Oklahoma Health Sciences Center Oklahoma City Oklahoma United States 73104
    66 Oregon Health and Science University Portland Oregon United States 97239
    67 Penn State Children's Hospital Hershey Pennsylvania United States 17033
    68 Children's Hospital of Philadelphia Philadelphia Pennsylvania United States 19104
    69 Children's Hospital of Pittsburgh of UPMC Pittsburgh Pennsylvania United States 15224
    70 Rhode Island Hospital Providence Rhode Island United States 02903
    71 Medical University of South Carolina Charleston South Carolina United States 29425
    72 BI-LO Charities Children's Cancer Center Greenville South Carolina United States 29605
    73 East Tennessee Childrens Hospital Knoxville Tennessee United States 37916
    74 Saint Jude Children's Research Hospital Memphis Tennessee United States 38105
    75 The Children's Hospital at TriStar Centennial Nashville Tennessee United States 37203
    76 Vanderbilt University/Ingram Cancer Center Nashville Tennessee United States 37232
    77 Dell Children's Medical Center of Central Texas Austin Texas United States 78723
    78 UT Southwestern/Simmons Cancer Center-Dallas Dallas Texas United States 75390
    79 El Paso Children's Hospital El Paso Texas United States 79905
    80 Cook Children's Medical Center Fort Worth Texas United States 76104
    81 M D Anderson Cancer Center Houston Texas United States 77030
    82 University of Texas Health Science Center at San Antonio San Antonio Texas United States 78229
    83 Primary Children's Hospital Salt Lake City Utah United States 84113
    84 Children's Hospital of The King's Daughters Norfolk Virginia United States 23507
    85 University of Wisconsin Carbone Cancer Center Madison Wisconsin United States 53792
    86 Children's Hospital of Wisconsin Milwaukee Wisconsin United States 53226
    87 The Children's Hospital at Westmead Westmead New South Wales Australia 2145
    88 Queensland Children's Hospital South Brisbane Queensland Australia 4101
    89 Perth Children's Hospital Perth Western Australia Australia 6009
    90 Alberta Children's Hospital Calgary Alberta Canada T3B 6A8
    91 The Montreal Children's Hospital of the MUHC Montreal Quebec Canada H3H 1P3
    92 Starship Children's Hospital Grafton Auckland New Zealand 1145
    93 University Pediatric Hospital San Juan Puerto Rico 00926

    Sponsors and Collaborators

    • Children's Oncology Group
    • National Cancer Institute (NCI)
    • SpringWorks Therapeutics, Inc.

    Investigators

    • Principal Investigator: Fariba Navid, Children's Oncology Group

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Children's Oncology Group
    ClinicalTrials.gov Identifier:
    NCT04195399
    Other Study ID Numbers:
    • ARST1921
    • NCI-2019-07498
    • ARST1921
    • ARST1921
    • U10CA180886
    First Posted:
    Dec 11, 2019
    Last Update Posted:
    Aug 18, 2022
    Last Verified:
    Aug 1, 2022
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Product Manufactured in and Exported from the U.S.:
    Yes
    Additional relevant MeSH terms:
    Fibromatosis, Aggressive
    Fibroma
    Imidazole

    Study Results

    No Results Posted as of Aug 18, 2022