Clinical Activity of the γ-Secretase Inhibitor PF-03084014 in Adults With Desmoid Tumors (Aggressive Fibromatosis)

Abstract

Purpose Desmoid tumors (aggressive fibromatosis) arise from connective tissue cells or fibroblasts. In general, they are slow growing and do not metastasize; however, locally aggressive desmoid tumors can cause severe morbidity and loss of function. Disease recurrence after surgery and/or radiation and diagnosis of multifocal desmoid tumors highlight the need to develop effective systemic treatments for this disease. In this study, we evaluate objective response rate after therapy with the γ-secretase inhibitor PF-03084014 in patients with recurrent, refractory, progressive desmoid tumors. Patients and Methods Seventeen patients with desmoid tumors received PF-03084014 150 mg orally twice a day in 3-week cycles. Response to treatment was evaluated at cycle 1 and every six cycles, that is, 18 weeks, by RECIST (Response Evaluation Criteria in Solid Tumors) version 1.1. Patient-reported outcomes were measured at baseline and at every restaging visit by using the MD Anderson Symptoms Inventory. Archival tumor and blood samples were genotyped for somatic and germline mutations in APC and CTNNB1. Results Of 17 patients accrued to the study, 15 had mutations in APC or CTNNB1 genes. Sixteen patients (94%) were evaluable for response; five (29%) experienced a confirmed partial response and have been on study for more than 2 years. Another five patients with prolonged stable disease as their best response remain on study. Patient-reported outcomes confirmed clinician reporting that the investigational agent was well tolerated and, in subgroup analyses, participants who demonstrated partial response also experienced clinically meaningful and statistically significant improvements in symptom burden. Conclusion PF-03084014 was well tolerated and demonstrated promising clinical benefit in patients with refractory, progressive desmoid tumors who receive long-term treatment.

Identification and assessment of health-related quality of life issues in patients with sporadic desmoid-type fibromatosis: a literature review and focus group study

“…n  = 2 pain with use of medicationTESS[28]14 (1) a UESGNA n  = 1 MSTS 50 (pain 3, function 2, acceptance 5, hand positioning 0, dexterity 5, lifting 0), TESS 62 a EORTC QLQ-C30[19]14AWSGNAMean global health status b : 97 (± 5.9); physical functioning 93 (± 11.1); role functioning 89 (± 16.7); emotional functioning 87 (± 19.1); cognitive functioning 94 (± 8.3); social functioning 93 (± 14.7)MDASI – [32]17ASGSINAMean symptom severity: partial responders ( n  = 5): 1.65 point improvement, stable disease ( n  = 5): 0.8 point improvement, no response/dropout ( n  = 7) 0.04 point improvementModified Johnstone scale – [34]40 (24)ASSGARTxCT n  = 24 amputation required (grade 0): n  = 1 (4%), severe functional deficit (grade 1): n  = 1 (4%), major functional limitations (grade 2): n  = 4 (17%), mild functional limitations (grade 3): n  = 7 (29%), no functional limitations (grade 4): n  = 9 (38%), NA: n  = 2 (8%) n  = 24 grade 0: n  = 5 (21%); grade 1: n  = 0; grade 2: n  = 6 (25%); grade 3: n  = 3 (13%); grade 4: n  = 8 (33%) not recorded: n  = 2 (8%)NRS – [37]15 (6)EAMRgFUSCTCA n  = 6 NRS 7.5 (± 1.9) (worst daily NRS); n  = 6 NRS 6 (± 2.3) (average daily NRS) n  = 6 NRS 2.7 (± 2.6) (worst daily NRS); n  = 6 NRS 1.3 (± 2) (average daily NRS) – [38]44ASSTMedian NRS 6 (IQR 2–7) group B: median NRS 7/10; n  = 7 moderate pain, n  = 17 severe pain; group C: n  = 8 severe pain c Group B n  = 12 (75%) pain improvement, n  = 1 (6%) pain worsening, n  = 3 (19%) stable symptoms; group C: n  = 8 (100%) pain relief c Other scoresFunctional outcome[43]21HN<...>…”

“…The European Organisation for Research and Treatment of Cancer quality of life questionnaire C30 (EORTC QLQ-C30) is a 30-item, cancer-specific questionnaire designed for evaluating quality of life incorporating five functional scales, symptom scales, and global health and quality of life scales [19, 31]. The MD Anderson Symptom Inventory (MDASI) measures the severity of 13 cancer-related symptoms experienced by the patient during the previous 24 h. The score rates symptoms on an 11-point scale; higher scores reflect more severe symptoms [32, 33]. The (modified) Johnstone scale provides a functional grading system with grades ranging from 0 to 4; higher scores reflect fewer limitations [34, 35].…”

“…Functional scores like the DASH score [26], the Enneking score/MSTS [24, 27, 28, 30], the TESS [28], and the Johnstone scale [34] are used for extremity diseases but are not suitable for patients who have sites of disease other than the extremities. Symptoms scores including the MDASI score [32] and the NRS [37, 38] are quite specific for measuring the severity of symptoms, and could be useful in combination with HRQL tools measuring issues like emotional or social well-being. The EORTC QLQ-C30 [19] is designed to cover issues relevant for cancer patients and may be a good generic measure to be completed by an item list consisting of the key DTF-specific issues identified in our focus groups, in order to create a more holistic perspective of HRQL issues in patients with DTF.…”

Functional analyses of major cancer-related signaling pathways in Alzheimer's disease etiology

“…Nevertheless, the other oral BACE1 inhibitor Lanabecestat has recently gained support from FDA to further expand its phase III trial, following the data analysis based on early results [326]. On the other hand, PF-03084014, a γ-secretase inhibitor found curative in solid and hematological malignancies, remains in preclinical stage for AD field [327, 328]. At present, immunotherapy is believed to have the ability to clear the redundant Aβ by specific antigen-antibody reactions, irrespective of active or passive mechanisms [329].…”

Assessment of Physician's Systemic Treatment Preferences for Patients with Advanced Desmoid-Type Fibromatosis: Experience-Based Medicine in the Absence of High-Level Evidence

“…As an illustration, www.clinicaltrials.gov (accessed July 27, 2017) refers to only 2 actively recruiting systemic treatment trials: NCT01265030, a nonrandomized phase II trial with the mammalian target of rapamycin (mTOR) inhibitor sirolimus in recurrent or advanced DF, and NCT01876082, a randomized phase II trial comparing the kinase inhibitor pazopanib with methotrexate-vinblastine in adults with progressive DF. Another non-randomized phase II trial studied the γ-secretase inhibitor PF-03084014 in 17 patients, with a response rate of 29% and another 65% of patients achieving stable disease (NCT01981551) [11]. A randomized phase III trial with the kinase inhibitor sorafenib is no longer actively recruiting new patients (NCT02066181).…”