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

Desmoid Fibromatosis Clinical Trial

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04195399
• Other study ID #: ARST1921
• Secondary ID: NCI-2019-07498AR
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: October 7, 2020
• Est. completion date: December 31, 2024

Study information

• Verified date: March 2024
• Source: Children's Oncology Group
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This phase II trial studies the side effects and how well nirogacestat works in treating 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.

Description:

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. Patients undergo echocardiography (ECHO) and computed tomography (CT) or MRI on study. Patients may also undergo x-ray imaging and blood sample collection on study.

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

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 35
• Est. completion date: December 31, 2024
• Est. primary completion date: December 31, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 12 Months to 18 Years

Eligibility

Inclusion Criteria:

• Patients must be > 12 months and < 18 years of age at the time of enrollment

• 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

• 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 or strong inhibitors of CYP3A4 are not eligible. Strong inducers or moderate or 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)

• Adequate liver function defined as:

• 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

• Presence of non-healing fracture

• Note: patients with pathologic fracture related to tumor are eligible

• Use of corticosteroids within 21 days of enrollment, except in the following situations:

• Physiologic steroid replacement for adrenal insufficiency

• Topical, ocular, intra-articular, intranasal, or inhaled corticosteroid with minimal systemic absorption

• Short course (=< 7 days) of corticosteroid prescribed prophylactically (eg, for contrast dye allergy) or for the treatment of a non-autoimmune condition (eg, delayed-type hypersensitivity reaction caused by contact allergen), or exacerbation of asthma

• 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

Related Conditions & MeSH terms

• Desmoid Fibromatosis
• Fibroma
• Recurrent Desmoid Fibromatosis

Intervention

Procedure:
• Biospecimen Collection
Undergo blood sample collection
• Computed Tomography
Undergo CT
• Echocardiography
Undergo ECHO
• Magnetic Resonance Imaging
Undergo MRI

Drug:
• Nirogacestat
Given PO

Other:
• Quality-of-Life Assessment
Ancillary studies
• Questionnaire Administration
Ancillary studies

Procedure:
• X-Ray Imaging
Undergo x-ray

Locations

Country	Name	City	State
Australia	Perth Children's Hospital	Perth	Western Australia
Australia	Queensland Children's Hospital	South Brisbane	Queensland
Australia	The Children's Hospital at Westmead	Westmead	New South Wales
Canada	Alberta Children's Hospital	Calgary	Alberta
Canada	University of Alberta Hospital	Edmonton	Alberta
Canada	The Montreal Children's Hospital of the MUHC	Montreal	Quebec
New Zealand	Christchurch Hospital	Christchurch
New Zealand	Starship Children's Hospital	Grafton	Auckland
Puerto Rico	University Pediatric Hospital	San Juan
United States	Children's Hospital Medical Center of Akron	Akron	Ohio
United States	Albany Medical Center	Albany	New York
United States	C S Mott Children's Hospital	Ann Arbor	Michigan
United States	Children's Healthcare of Atlanta - Egleston	Atlanta	Georgia
United States	Children's Hospital Colorado	Aurora	Colorado
United States	Dell Children's Medical Center of Central Texas	Austin	Texas
United States	Johns Hopkins University/Sidney Kimmel Cancer Center	Baltimore	Maryland
United States	Walter Reed National Military Medical Center	Bethesda	Maryland
United States	Children's Hospital of Alabama	Birmingham	Alabama
United States	Saint Luke's Cancer Institute - Boise	Boise	Idaho
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Massachusetts General Hospital Cancer Center	Boston	Massachusetts
United States	Montefiore Medical Center - Moses Campus	Bronx	New York
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	Medical University of South Carolina	Charleston	South Carolina
United States	Carolinas Medical Center/Levine Cancer Institute	Charlotte	North Carolina
United States	Lurie Children's Hospital-Chicago	Chicago	Illinois
United States	University of Chicago Comprehensive Cancer Center	Chicago	Illinois
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	Cleveland Clinic Foundation	Cleveland	Ohio
United States	Nationwide Children's Hospital	Columbus	Ohio
United States	UT Southwestern/Simmons Cancer Center-Dallas	Dallas	Texas
United States	Dayton Children's Hospital	Dayton	Ohio
United States	Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center	Denver	Colorado
United States	Kaiser Permanente Downey Medical Center	Downey	California
United States	Michigan State University Clinical Center	East Lansing	Michigan
United States	El Paso Children's Hospital	El Paso	Texas
United States	Cook Children's Medical Center	Fort Worth	Texas
United States	University of Florida Health Science Center - Gainesville	Gainesville	Florida
United States	Helen DeVos Children's Hospital at Spectrum Health	Grand Rapids	Michigan
United States	BI-LO Charities Children's Cancer Center	Greenville	South Carolina
United States	Hackensack University Medical Center	Hackensack	New Jersey
United States	Connecticut Children's Medical Center	Hartford	Connecticut
United States	Penn State Children's Hospital	Hershey	Pennsylvania
United States	Kapiolani Medical Center for Women and Children	Honolulu	Hawaii
United States	M D Anderson Cancer Center	Houston	Texas
United States	Riley Hospital for Children	Indianapolis	Indiana
United States	University of Mississippi Medical Center	Jackson	Mississippi
United States	Nemours Children's Clinic-Jacksonville	Jacksonville	Florida
United States	Bronson Methodist Hospital	Kalamazoo	Michigan
United States	Children's Mercy Hospitals and Clinics	Kansas City	Missouri
United States	East Tennessee Childrens Hospital	Knoxville	Tennessee
United States	Alliance for Childhood Diseases/Cure 4 the Kids Foundation	Las Vegas	Nevada
United States	Summerlin Hospital Medical Center	Las Vegas	Nevada
United States	Sunrise Hospital and Medical Center	Las Vegas	Nevada
United States	University Medical Center of Southern Nevada	Las Vegas	Nevada
United States	Arkansas Children's Hospital	Little Rock	Arkansas
United States	Loma Linda University Medical Center	Loma Linda	California
United States	Children's Hospital Los Angeles	Los Angeles	California
United States	Mattel Children's Hospital UCLA	Los Angeles	California
United States	Norton Children's Hospital	Louisville	Kentucky
United States	University of Wisconsin Carbone Cancer Center	Madison	Wisconsin
United States	Saint Jude Children's Research Hospital	Memphis	Tennessee
United States	Banner Children's at Desert	Mesa	Arizona
United States	Children's Hospital of Wisconsin	Milwaukee	Wisconsin
United States	USA Health Strada Patient Care Center	Mobile	Alabama
United States	The Children's Hospital at TriStar Centennial	Nashville	Tennessee
United States	Vanderbilt University/Ingram Cancer Center	Nashville	Tennessee
United States	Children's Hospital New Orleans	New Orleans	Louisiana
United States	Ochsner Medical Center Jefferson	New Orleans	Louisiana
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center	New York	New York
United States	Children's Hospital of The King's Daughters	Norfolk	Virginia
United States	Kaiser Permanente-Oakland	Oakland	California
United States	UCSF Benioff Children's Hospital Oakland	Oakland	California
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	AdventHealth Orlando	Orlando	Florida
United States	Nemours Children's Hospital	Orlando	Florida
United States	Lucile Packard Children's Hospital Stanford University	Palo Alto	California
United States	Saint Jude Midwest Affiliate	Peoria	Illinois
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania
United States	Oregon Health and Science University	Portland	Oregon
United States	Rhode Island Hospital	Providence	Rhode Island
United States	Renown Regional Medical Center	Reno	Nevada
United States	Carilion Children's	Roanoke	Virginia
United States	University of California Davis Comprehensive Cancer Center	Sacramento	California
United States	Mercy Hospital Saint Louis	Saint Louis	Missouri
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Johns Hopkins All Children's Hospital	Saint Petersburg	Florida
United States	Primary Children's Hospital	Salt Lake City	Utah
United States	University of Texas Health Science Center at San Antonio	San Antonio	Texas
United States	Rady Children's Hospital - San Diego	San Diego	California
United States	UCSF Medical Center-Mission Bay	San Francisco	California
United States	State University of New York Upstate Medical University	Syracuse	New York
United States	Saint Joseph's Hospital/Children's Hospital-Tampa	Tampa	Florida
United States	Children's National Medical Center	Washington	District of Columbia
United States	MedStar Georgetown University Hospital	Washington	District of Columbia
United States	Alfred I duPont Hospital for Children	Wilmington	Delaware

Sponsors (3)

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

Countries where clinical trial is conducted

United States,  Australia,  Canada,  New Zealand,  Puerto Rico, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	CTNNB1 and APC gene mutations and genomic signatures	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.	Up to 2 years
Other	Changes in the levels of each of the lymphocyte subsets and immunoglobulins	Lymphocyte subsets include CD3 (total T cells), CD3+CD4+ (T helper cells), CD3+CD8+ (T cytotoxic cells), CD3+HLA-DR+ (activated T cells) percentages and absolute counts and CD4:CD8 ratio. 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.	Up to 2 years
Other	Response assessments by the RECIST criteria		Up to cycle 24
Other	Response assessment by the World Health Organization criteria		Up to cycle 24
Other	Patient reported outcomes (PROs)	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 and GOunder/DTRF DEsmoid Symptom/Impact Scale will be assessed by performing inferences on the Pearson correlation coefficients.	Up to 2 years
Primary	Progression-free survival (PFS)	Will be estimated using the Kaplan-Meier method with the 95% confidence interval estimated by the Peto-Peto method.	From initiation of treatment to occurrence of disease progression or death from any cause, assessed up to 2 years
Primary	Incidence of adverse events	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.	Up to 2 years
Primary	Pharmacokinetic (PK) parameter: systemic exposure	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.	Up to Cycle 3 (each cycle lasts 28 days)
Primary	PK parameter: drug clearance	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.	Up to Cycle 3 (each cycle lasts 28 days)
Primary	PK parameter: half-life	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.	Up to Cycle 3 (each cycle lasts 28 days)
Secondary	Objective response rate	Defined by the rate of a complete response or partial response by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.	Up to 24 months