A Safety, Pharmacokinetic and Efficacy Study of a y-Secretase Inhibitor, Nirogacestat (PF-03084014), in Children and Adolescents With Progressive, Surgically Unresectable Desmoid Tumors
Overview
- Phase
- Phase 2
- Intervention
- Quality-of-Life Assessment
- Conditions
- Desmoid Fibromatosis
- Sponsor
- Children's Oncology Group
- Enrollment
- 31
- Locations
- 126
- Primary Endpoint
- Progression-free survival (PFS)
- Status
- Active, not recruiting
- Last Updated
- 17 days ago
Overview
Brief 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.
Detailed 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.
Investigators
Eligibility Criteria
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 \>=
- •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)
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)
Arms & Interventions
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. Patients undergo ECHO and CT or MRI on study. Patients may also undergo x-ray imaging and blood sample collection on study.
Intervention: Quality-of-Life Assessment
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. Patients undergo ECHO and CT or MRI on study. Patients may also undergo x-ray imaging and blood sample collection on study.
Intervention: Biospecimen Collection
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. Patients undergo ECHO and CT or MRI on study. Patients may also undergo x-ray imaging and blood sample collection on study.
Intervention: Computed Tomography
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. Patients undergo ECHO and CT or MRI on study. Patients may also undergo x-ray imaging and blood sample collection on study.
Intervention: Echocardiography Test
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. Patients undergo ECHO and CT or MRI on study. Patients may also undergo x-ray imaging and blood sample collection on study.
Intervention: Magnetic Resonance Imaging
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. Patients undergo ECHO and CT or MRI on study. Patients may also undergo x-ray imaging and blood sample collection on study.
Intervention: Questionnaire Administration
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. Patients undergo ECHO and CT or MRI on study. Patients may also undergo x-ray imaging and blood sample collection on study.
Intervention: X-Ray Imaging
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. Patients undergo ECHO and CT or MRI on study. Patients may also undergo x-ray imaging and blood sample collection on study.
Intervention: Nirogacestat
Outcomes
Primary Outcomes
Progression-free survival (PFS)
Time Frame: 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.
PK parameter: drug clearance
Time Frame: 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.
PK parameter: half-life
Time Frame: 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.
Pharmacokinetic (PK) parameter: systemic exposure
Time Frame: 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.
Incidence of adverse events
Time Frame: Up to 2 years
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.
Secondary Outcomes
- Objective response rate(Up to 24 months)