A Safety, Pharmacokinetic and Efficacy Study of a y-Secretase Inhibitor, Nirogacestat (PF-03084014) in Children and Adolescents With Progressive, Surgically Unresectable Desmoid Tumors

  • STATUS
    Recruiting
  • End date
    Mar 31, 2025
  • participants needed
    35
  • sponsor
    Children's Oncology Group
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Updated on 13 October 2022
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temsirolimus
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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.

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.

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

Details
Condition Desmoid Fibromatosis, Recurrent Desmoid Fibromatosis, Unresectable Desmoid Fibromatosis
Treatment questionnaire administration, quality-of-life assessment, Nirogacestat
Clinical Study IdentifierNCT04195399
SponsorChildren's Oncology Group
Last Modified on13 October 2022

Eligibility

 Yes No Not Sure

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
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)
are unable to walk because of paralysis, but who are up in a wheelchair, will
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
be considered ambulatory for the purpose of assessing performance score
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
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)
Peripheral absolute neutrophil count (ANC) >= 1000/uL (within 7 days prior to
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)
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)
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
Total bilirubin =< 1.5 x upper limit of normal (ULN) for age (unless secondary to
No history of congenital or acquired prolonged QTc syndrome
previously diagnosed Gilbert's syndrome) (within 7 days prior to enrollment)
No history of clinically significant cardiac arrhythmias, congestive heart failure, stroke or myocardial infarction within 6 months prior to study entry
All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met
All patients and/or their parents or legal guardians must sign a written informed
consent

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
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