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

Trial Status: Active

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.

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

Alabama

Birmingham
Children's Hospital of Alabama
Status: ACTIVE
Contact: Site Public Contact
Phone: 205-638-9285
Mobile
USA Health Strada Patient Care Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 800-388-8721

Arkansas

Little Rock
Arkansas Children's Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 501-364-7373

California

Downey
Kaiser Permanente Downey Medical Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 626-564-3455
Loma Linda
Loma Linda University Medical Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 909-558-4050
Los Angeles
Children's Hospital Los Angeles
Status: ACTIVE
Contact: Site Public Contact
Phone: 323-361-4110
Mattel Children's Hospital UCLA
Status: ACTIVE
Contact: Site Public Contact
Phone: 310-825-6708
Oakland
Kaiser Permanente-Oakland
Status: ACTIVE
Contact: Site Public Contact
Phone: 877-642-4691
Email: Kpoct@kp.org
UCSF Benioff Children's Hospital Oakland
Status: ACTIVE
Contact: Site Public Contact
Phone: 510-428-3324
Palo Alto
Lucile Packard Children's Hospital Stanford University
Status: ACTIVE
Contact: Site Public Contact
Phone: 800-694-0012
Sacramento
University of California Davis Comprehensive Cancer Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 916-734-3089
San Diego
Rady Children's Hospital - San Diego
Status: ACTIVE
Contact: Site Public Contact
Phone: 858-966-5934
San Francisco
UCSF Medical Center-Mission Bay
Status: ACTIVE
Contact: Site Public Contact
Phone: 877-827-3222

Colorado

Aurora
Children's Hospital Colorado
Status: ACTIVE
Contact: Site Public Contact
Phone: 303-764-5056
Denver
Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 303-839-6000

Connecticut

Hartford
Connecticut Children's Medical Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 860-545-9981

Delaware

Wilmington
Alfred I duPont Hospital for Children
Status: ACTIVE
Contact: Site Public Contact
Phone: 302-651-5572

District of Columbia

Washington
Children's National Medical Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 202-884-2549
MedStar Georgetown University Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 202-444-2223

Florida

Gainesville
University of Florida Health Science Center - Gainesville
Status: ACTIVE
Contact: Site Public Contact
Phone: 352-273-8010
Jacksonville
Nemours Children's Clinic-Jacksonville
Status: ACTIVE
Contact: Site Public Contact
Phone: 302-651-5572
Orlando
AdventHealth Orlando
Status: ACTIVE
Contact: Site Public Contact
Phone: 407-303-2090
Nemours Children's Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 302-651-5572
Saint Petersburg
Johns Hopkins All Children's Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 727-767-4784

Georgia

Atlanta
Children's Healthcare of Atlanta - Egleston
Status: ACTIVE
Contact: Site Public Contact
Phone: 404-785-2025

Hawaii

Honolulu
Kapiolani Medical Center for Women and Children
Status: ACTIVE
Contact: Site Public Contact
Phone: 808-983-6090

Idaho

Boise
Saint Luke's Cancer Institute - Boise
Status: ACTIVE
Contact: Site Public Contact
Phone: 208-381-2774

Illinois

Chicago
Lurie Children's Hospital-Chicago
Status: ACTIVE
Contact: Site Public Contact
Phone: 773-880-4562
University of Chicago Comprehensive Cancer Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 773-702-8222
Peoria
Saint Jude Midwest Affiliate
Status: ACTIVE
Contact: Site Public Contact
Phone: 888-226-4343

Indiana

Indianapolis
Riley Hospital for Children
Status: ACTIVE
Contact: Site Public Contact
Phone: 800-248-1199

Kentucky

Louisville
Norton Children's Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 502-629-5500

Louisiana

New Orleans
Children's Hospital New Orleans
Status: ACTIVE
Contact: Site Public Contact
Ochsner Medical Center Jefferson
Status: ACTIVE
Contact: Site Public Contact
Phone: 504-842-8084

Maryland

Baltimore
Johns Hopkins University / Sidney Kimmel Cancer Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 410-955-8804
Bethesda
Walter Reed National Military Medical Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 301-319-2100

Massachusetts

Boston
Dana-Farber Cancer Institute
Status: ACTIVE
Contact: Site Public Contact
Phone: 877-442-3324
Massachusetts General Hospital Cancer Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 877-726-5130

Michigan

Ann Arbor
C S Mott Children's Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 800-865-1125
Grand Rapids
Helen DeVos Children's Hospital at Spectrum Health
Status: ACTIVE
Contact: Site Public Contact
Phone: 616-391-1230
Kalamazoo
Bronson Methodist Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 616-391-1230

Mississippi

Jackson
University of Mississippi Medical Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 601-815-6700

Missouri

Kansas City
Children's Mercy Hospitals and Clinics
Status: ACTIVE
Contact: Site Public Contact
Phone: 816-302-6808
Email: rryan@cmh.edu
Saint Louis
Mercy Hospital Saint Louis
Status: ACTIVE
Contact: Site Public Contact
Phone: 314-251-7066
Washington University School of Medicine
Status: ACTIVE
Contact: Site Public Contact
Phone: 800-600-3606

Nevada

Las Vegas
Alliance for Childhood Diseases / Cure 4 the Kids Foundation
Status: ACTIVE
Contact: Site Public Contact
Phone: 702-384-0013
Summerlin Hospital Medical Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 702-384-0013
Sunrise Hospital and Medical Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 702-384-0013
University Medical Center of Southern Nevada
Status: ACTIVE
Contact: Site Public Contact
Phone: 702-384-0013
Reno
Renown Regional Medical Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 702-384-0013

New Jersey

Hackensack
Hackensack University Medical Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 201-996-2879

New York

Albany
Albany Medical Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 518-262-5513
Bronx
Montefiore Medical Center - Moses Campus
Status: ACTIVE
Contact: Site Public Contact
Phone: 718-379-6866
Buffalo
Roswell Park Cancer Institute
Status: ACTIVE
Contact: Site Public Contact
Phone: 800-767-9355
New York
Memorial Sloan Kettering Cancer Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 212-639-7592
NYP / Columbia University Medical Center / Herbert Irving Comprehensive Cancer Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 212-305-6361
Syracuse
State University of New York Upstate Medical University
Status: ACTIVE
Contact: Site Public Contact
Phone: 315-464-5476

North Carolina

Charlotte
Carolinas Medical Center / Levine Cancer Institute
Status: ACTIVE
Contact: Site Public Contact
Phone: 800-804-9376

Ohio

Akron
Children's Hospital Medical Center of Akron
Status: ACTIVE
Contact: Site Public Contact
Phone: 330-543-3193
Cincinnati
Cincinnati Children's Hospital Medical Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 513-636-2799
Cleveland
Cleveland Clinic Foundation
Status: ACTIVE
Contact: Site Public Contact
Phone: 866-223-8100
Columbus
Nationwide Children's Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 614-722-6039
Dayton
Dayton Children's Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 800-228-4055

Oklahoma

Oklahoma City
University of Oklahoma Health Sciences Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 405-271-8777

Oregon

Portland
Oregon Health and Science University
Status: ACTIVE
Contact: Site Public Contact
Phone: 503-494-1080

Pennsylvania

Hershey
Penn State Children's Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 717-531-6012
Philadelphia
Children's Hospital of Philadelphia
Status: ACTIVE
Contact: Site Public Contact
Phone: 267-425-5544
Pittsburgh
Children's Hospital of Pittsburgh of UPMC
Status: ACTIVE
Contact: Site Public Contact
Phone: 412-692-8570

Rhode Island

Providence
Rhode Island Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 401-444-1488

South Carolina

Charleston
Medical University of South Carolina
Status: ACTIVE
Contact: Site Public Contact
Phone: 843-792-9321
Greenville
BI-LO Charities Children's Cancer Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 864-241-6251

Tennessee

Knoxville
East Tennessee Childrens Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 865-541-8266
Memphis
Saint Jude Children's Research Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 888-226-4343
Nashville
The Children's Hospital at TriStar Centennial
Status: ACTIVE
Contact: Site Public Contact
Phone: 615-342-1919
Vanderbilt University / Ingram Cancer Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 800-811-8480

Texas

Austin
Dell Children's Medical Center of Central Texas
Status: ACTIVE
Contact: Site Public Contact
Phone: 512-628-1902
Dallas
UT Southwestern / Simmons Cancer Center-Dallas
Status: ACTIVE
Contact: Site Public Contact
Phone: 214-648-7097
El Paso
El Paso Children's Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 915-298-5444
Fort Worth
Cook Children's Medical Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 682-885-2103
Houston
M D Anderson Cancer Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 877-632-6789
San Antonio
University of Texas Health Science Center at San Antonio
Status: ACTIVE
Contact: Site Public Contact
Phone: 210-450-3800

Utah

Salt Lake City
Primary Children's Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 801-585-5270

Virginia

Norfolk
Children's Hospital of The King's Daughters
Status: ACTIVE
Contact: Site Public Contact
Phone: 757-668-7243

Wisconsin

Madison
University of Wisconsin Carbone Cancer Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 800-622-8922
Milwaukee
Children's Hospital of Wisconsin
Status: ACTIVE
Contact: Site Public Contact
Phone: 414-955-4727

Alberta

Calgary
Alberta Children's Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 403-220-6898

Quebec

Montreal
The Montreal Children's Hospital of the MUHC
Status: ACTIVE
Contact: Site Public Contact
Phone: 514-412-4445

Australia

Perth
Perth Children's Hospital
Status: ACTIVE
Contact: Site Public Contact
South Brisbane
Queensland Children's Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 61 7 3068 1111
Westmead
The Children's Hospital at Westmead
Status: ACTIVE
Contact: Site Public Contact
Phone: 61-2-9845 1400

New Zealand

Grafton
Starship Children's Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 0800 728 436

PRIMARY OBJECTIVES:

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

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

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

SECONDARY OBJECTIVE:

I. To determine the objective tumor response rate (ORR) of nirogacestat in children and adolescents with progressive, surgically unresectable desmoid tumor.

EXPLORATORY OBJECTIVES:

I. 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.

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

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

IV. 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).

V. 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.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
Children's Oncology Group

Principal Investigator
Fariba Navid

  • Primary ID ARST1921
  • Secondary IDs NCI-2019-07498
  • Clinicaltrials.gov ID NCT04195399