Phase II Trial of the Gamma-Secretase Inhibitor PF-03084014 in Adults With Desmoid Tumors/Aggressive Fibromatosis

Study Overview
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Brief Summary
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Background: Desmoid tumors (also known as aggressive fibromatosis), are rare, locally invasive, slow-growing soft-tissue tumors. The disease can be either asymptomatic or be associated with severe loss of organ function and significant morbidity. Treatment with the selective small-molecule Gamma-secretase inhibitor PF-03084014 caused significant tumor shrinkage in patients with unresectable desmoid tumors in an early phase clinical trial. The Notch pathway is a key regulator of cell differentiation, proliferation and apoptosis; aberrant signaling via the Notch pathway is associated with carcinogenesis. Objectives: Primary: Determine the response rate (Complete Response (CR)+Partial Response (PR)) of PF-03084014 in patients with desmoid tumors/aggressive fibromatosis Secondary: Assess symptom measures at baseline and on study; perform genotyping for germline and somatic mutations in adenomatous polyposis coli gene (APC) and catenin-beta 1 (CTNNB1) genes; correlate clinical response to therapy with genotyping data; and assess modulation of the Notch pathway by evaluating notch response genes in tumor biopsies at baseline and after drug administration Eligibility: Age greater than or equal to18; histologically confirmed desmoid tumor not amenable to curative resection or definitive radiation therapy that has progressed after receiving at least one line of standard treatment; adequate organ function Willingness to provide blood samples and 10 unstained slides or a tumor block for genetic research studies Study Design: This is an open-label Phase II trial of PF-03084014; study drug will be administered orally at 150 mg twice a day in 21-day cycles Optional tumor biopsies for research purposes will be performed at baseline prior to study treatment and at the beginning of cycle 7 (+/- one cycle) Restaging scans (magnetic resonance imaging (MRI) with diffusion weighting) will be performed at baseline, at the end of cycles 1 and 6, and then every 6 cycles Health-related quality of life (HRQOL)/symptom questionnaires will be administered at baseline and at each Clinical Center visit

Detailed Description
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Background: Desmoid tumors (also known as aggressive fibromatosis), are rare, locally invasive, slow-growing soft-tissue tumors. The disease can be either asymptomatic or be associated with severe loss of organ function and significant morbidity. Treatment with the selective small-molecule Gamma-secretase inhibitor PF-03084014 caused significant tumor shrinkage in patients with unresectable desmoid tumors in an early phase clinical trial. The Notch pathway is a key regulator of cell differentiation, proliferation and apoptosis; aberrant signaling via the Notch pathway is associated with carcinogenesis. Objectives: Primary: Determine the response rate (Complete Response (CR)+Partial Response (PR)) of PF-03084014 in patients with desmoid tumors/aggressive fibromatosis Exploratory: Assess symptom measures at baseline and on study; perform genotyping for germline and somatic mutations in adenomatous polyposis coli gene (APC) and catenin-beta 1 (CTNNB1) genes; correlate clinical response to therapy with genotyping data; and assess modulation of the Notch pathway by evaluating notch response genes in tumor biopsies at baseline and after drug administration Eligibility: Age greater than or equal to18; histologically confirmed desmoid tumor not amenable to curative resection or definitive radiation therapy that has progressed after receiving at least one line of standard treatment; adequate organ function Willingness to provide blood samples and 10 unstained slides or a tumor block for genetic research studies Study Design: This is an open-label Phase II trial of PF-03084014; study drug will be administered orally at 150 mg twice a day in 21-day cycles Optional tumor biopsies for research purposes will be performed at baseline prior to study treatment and at the beginning of cycle 7 (+/- one cycle) Restaging scans (computed tomography (CT) scan of the known site of disease) will be performed at baseline and then every 6 cycles (+/- one cycle) Optional magnetic resonance imaging (MRI) scans may be performed prior to start of study treatment, end of cycle 1, and every 6 cycles (at the same times as the CT scans) Health-related quality of life (HRQOL)/symptom questionnaires will be administered at baseline and at restaging

Official Title
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Phase II Trial of the Gamma-Secretase Inhibitor PF-03084014 in Adults With Desmoid Tumors/Aggressive Fibromatosis

Conditions
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Desmoid Tumors, Aggressive Fibromatosis

Intervention / Treatment
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* Drug: PF-03084014


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: 2.1.1.1 Patients must have histologically confirmed desmoid tumor confirmed by the Laboratory of Pathology, National Cancer Institute (NCI), that has progressed after receiving at least one line of standard treatment and that is not amenable to surgical resection or definitive radiation therapy. 2.1.1.2 Willingness to provide blood samples and 10 unstained slides or a tumor block for genetic research studies. 2.1.1.3 Any line of therapy with prior desmoid therapy, including radiotherapy, should have been completed at least 2 weeks before study entry and all toxicities must have resolved at least to eligibility levels. 2.1.1.4 Age greater than or equal 18 years; because no dosing or adverse event data are currently available on the use of PF-03084014 in patients <18 years of age, children are excluded from this study, but may be eligible for future pediatric trials. 2.1.1.5 Eastern Cooperative Oncology Group (ECOG) performance status less than or equal 2. 2.1.1.6 Life expectancy > 3 months. 2.1.1.7 Patients must have normal organ and marrow function as defined below: -absolute neutrophil count greater than or equal 1,500/mcL -platelets greater than or equal 100,000/mcL -total bilirubin less than or equal 1.5 times institutional upper limit of normal -Aspartate aminotransferase (AST) Serum Glutamic Oxaloacetic Transaminase (SGOT)/Alanine aminotransferase (ALT) Serum glutamic-pyruvic transaminase (SGPT) less than or equal 5 times institutional upper limit of normal -creatinine < 1.5 times institutional upper limit of normal OR -creatinine clearance greater than or equal 60 mL/min/1.73 m(2) for patients with creatinine levels >1.5 mg/dL -hemoglobin greater than or equal 9 g/dL 2.1.1.8 Patients must be able to swallow whole tablets or capsules with no gastrointestinal (GI) condition affecting absorption; nasogastric or G-tube administration is not allowed. 2.1.1.9 The effects of PF-03084014 on the developing human fetus are unknown. For this reason and because >=-secretase inhibitors are known to be teratogenic, women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) for the duration of study participation and for at least 6 months after dosing with study drugs ceases. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception for the duration of study participation, and 6 months after completion of study drug administration. 2.1.1.10 Ability to understand and the willingness to sign a written informed consent document. 2.1.1.11 Evidence of measurable disease by computed tomography (CT) scan. Measurable lesions are defined as those that can be accurately measured in at least one dimension (longest diameter to be recorded) as greater than or equal 20 mm by chest x-ray, as greater than or equal 10 mm with CT scan, or greater than or equal 10 mm with calipers by clinical exam. EXCLUSION CRITERIA: 2.1.2.1 Patients who are receiving any other investigational agents. Concurrent mediations that the patient is taking will be reviewed by the principal investigator (PI) to assess safety and eligibility. 2.1.2.2 Prior treatment with Gamma-secretase inhibitors or anti-notch antibody therapy. 2.1.2.3 Uncontrolled intercurrent illness including, but not limited to, serious infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. 2.1.2.4 Corrected QT interval (QTc) interval of >470 msec at study entry; congenital long QT syndrome. 2.1.2.5 Pregnant women are excluded from this study because PF-03084014 is a Gamma-secretase inhibitor with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with PF-03084014, breastfeeding should be discontinued if the mother is treated with PF-03084014. 2.1.2.6 Patients with gastrointestinal conditions that might predispose for drug intolerability or poor drug absorption (e.g., inability to take oral medication or a requirement for intravenous (IV) alimentation, prior surgical procedures affecting absorption, malabsorption syndrome, and active peptic ulcer disease) are excluded. Subjects with ulcerative colitis, inflammatory bowel disease, or a partial or complete small bowel obstruction are also excluded, as are any patients who cannot swallow the tablet whole. Tablets must not be crushed or chewed; nasogastric or gastrostomy (G)-tube administration is not allowed. 2.1.2.7 Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with PF-03084014. 2.1.3 Recruitment Strategies We have had multiple discussions with the Desmoid Tumor Research Foundation, Inc., who have various outreach efforts including patient meetings and webcasts. Senior executives of the Foundation have indicated strong interest in this trial and willingness to inform their members. We also have a network of referring physicians nationally that refers patients with solid tumors to our clinical program. Given our interest and trials for sarcomas, we have formed connections with centers that treat patients with mesenchymal malignancies. We will be informing all of these of the availability of this trial once it is open.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PF-03084014 in Desmoid Tumors/Aggressive Fibromatosis<br>PF-03084014 will be administered orally at 150 mg twice a day in 21-day cycles | Drug: PF-03084014<br>* Treatment with the selective small-molecule >=-secretase inhibitor PF- 3084014 caused significant tumor shrinkage in patients with unresectable desmoid tumors in an early-phase clinical trial.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With a Complete Response (CR) + Partial Response (PR) | Complete Response + Partial Response was determined by the Response Evaluation Criteria in Solid Tumors (RECIST). Complete Response is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD) is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progressions. Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. | 20 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Serious and Non-serious Adverse Events | Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned. | Date treatment consent signed to date off study, approximately 66 months and 27 days. | 
| Number of Participants With Somatic or Germline Mutations Identified in Adenomatous Polyposis Coli Gene (APC) or Catenin Beta-1 (CTNNB1) Genes | Tumor and blood samples were obtained from participants and genotyped for somatic and germline mutations. | Baseline | 
| Mean MD Anderson Symptom Inventory Scores After Treatment | The MD Anderson Symptoms Inventory (MDSAI) questionnaire includes questions regarding 13 symptoms commonly experienced by patients with cancer and 6 additional items that assess the extent to which these symptoms interfered with how patients felt and were able to function. The 0-10 scale (0=none, 1-4=mild, 5-6=moderate, and 7-10=severe) assesses how patients felt and were able to function over the previous 24 hours. A component score representing symptom severity is obtained by taking the average of the 13 symptom items (e.g., pain, fatigue, etc.) together. A component score representing symptom distress is obtaining by averaging the 6 symptom interference items (e.g., general activity, mood, etc.). | At baseline prior to drug administration and at least every 6 cycles of drug (18 weeks) up to 20 months of treatment. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Desmoid Tumor, Aggressive Fibromatosis, Gamma-secretase Inhibitor, Notch Pathway