Early Use of mTOR Inhibitors in Tuberous Sclerosis: Current State and Plan for a Prospective Clinical Trial of Early Prophylactic mTOR Inhibitor Treatment (PROTECT)

2021 ◽  
Author(s):  
S. Syrbe ◽  
A. Saffari
Keyword(s):  
Clinical Trial ◽  
Tuberous Sclerosis ◽  
Mtor Inhibitor ◽  
Mtor Inhibitors ◽  
Prospective Clinical Trial ◽  
Current State ◽  
Early Use ◽  
Inhibitor Treatment

scholarly journals Conceptual Framework to Support Clinical Trial Optimization and End-to-End Enrollment Workflow

2019 ◽  
pp. 1-10 ◽  
Author(s):  
Neha M. Jain ◽  
Alison Culley ◽  
Teresa Knoop ◽  
Christine Micheel ◽  
Travis Osterman ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Knowledge Representation ◽  
Conceptual Framework ◽  
Trial Design ◽  
Clinical Trial Design ◽  
Prospective Clinical Trial ◽  
Future Trends ◽  
Current State ◽  
Evaluation Strategies

In this work, we present a conceptual framework to support clinical trial optimization and enrollment workflows and review the current state, limitations, and future trends in this space. This framework includes knowledge representation of clinical trials, clinical trial optimization, clinical trial design, enrollment workflows for prospective clinical trial matching, waitlist management, and, finally, evaluation strategies for assessing improvement.

scholarly journals Frequency, Progression, and Current Management: Report of 16 New Cases of Nonfunctional Pancreatic Neuroendocrine Tumors in Tuberous Sclerosis Complex and Comparison With Previous Reports

2021 ◽  
Vol 12 ◽  
Author(s):  
Kate Mowrey ◽  
Hope Northrup ◽  
Peyton Rougeau ◽  
S. Shahrukh Hashmi ◽  
Darcy A. Krueger ◽  
...  
Keyword(s):  
Tuberous Sclerosis ◽  
Neuroendocrine Tumors ◽  
Tuberous Sclerosis Complex ◽  
Clinical Management ◽  
Mtor Inhibitor ◽  
Mtor Inhibitors ◽  
Surgical Removal ◽  
Pancreatic Neuroendocrine Tumors ◽  
Serial Imaging ◽  
Pathogenic Variants

Background: Tuberous sclerosis complex (TSC) is a genetic condition that causes benign tumors to grow in multiple organ systems. Nonfunctional pancreatic neuroendocrine tumors (PNETs) are a rare clinical feature of TSC with no specific guidelines outlined for clinical management at this time. Our purpose is to calculate the frequency of nonfunctional PNETs as well as characterize the presentation, current clinical management, and assess the impact of systemic mammalian target of rapamycin (mTOR) on nonfunctional PNETs in TSC.Methods: This retrospective chart review was performed by a query of the TS Alliance's Natural History Database and the Cincinnati Children's Hospital TSC Database for patients with nonfunctional PNET. Clinical data from these two groups was summarized for patients identified to have a nonfunctional PNET and compared to previously reported cases with TSC and nonfunctional PNETs.Results: Our calculated frequency of nonfunctional PNETs is 0.65%. We identified 16 individuals, nine males and seven females, with a median age of 18.0 years (interquartile range: −15.5 to 25.5). Just over half (56.3%, n = 9) of the patients provided results from genetic testing. Six had pathogenic variants in TSC2 whereas three had pathogenic variants in TSC1. The average age at PNET diagnosis was 15.0 years (range: 3–46 years). Almost all individuals were diagnosed with a PNET during routine TSC surveillance, 56.3% (n = 9) by MRI, 12.5% (n = 2) by CT, 25% (n = 4) by ultrasound, and 6.2% (n = 1) through a surgical procedure. Follow up after diagnosis involved 68.8% (n = 11) having serial imaging and nine of the sixteen individuals proceeding with surgical removal of the PNET. Eight individuals had a history of using systemic mTOR inhibitors. Tumor growth rate was slightly less in individuals taking an mTOR inhibitor (−0.8 mm/yr, IQR: −2.3 to 2.2) than those without (1.6 mm/yr; IQR: −0.99 to 5.01, p > 0.05).Conclusions: Nonfunctional PNETs occurred at younger ages in our TSC cohort and more commonly compared to ages and prevalence reported for the general population. PNETs in patients on systemic mTOR inhibitors had lower rates of growth. The outcome of this study provides preliminary evidence supporting the use of mTOR inhibitor therapy in conjunction with serial imaging as medical management for nonfunctional PNETs as an alternative option to invasive surgical removal.

Pulse mTOR inhibitor treatment effectively controls cyst growth but leads to severe parenchymal and glomerular hypertrophy in rat polycystic kidney disease

2009 ◽  
Vol 297 (6) ◽  
pp. F1597-F1605 ◽  
Author(s):  
Ming Wu ◽  
Alexandre Arcaro ◽  
Zsuzsanna Varga ◽  
Alexander Vogetseder ◽  
Michel Le Hir ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Kidney Function ◽  
Mtor Inhibitor ◽  
Autosomal Dominant ◽  
Mtor Inhibitors ◽  
Glomerular Hypertrophy ◽  
Polycystic Kidney ◽  
Autosomal Dominant Polycystic Kidney ◽  
Inhibitor Treatment

The efficacy of mammalian target of rapamycin (mTOR) inhibitors is currently tested in patients affected by autosomal dominant polycystic kidney disease. Treatment with mTOR inhibitors has been associated with numerous side effects. However, the renal-specific effect of mTOR inhibitor treatment cessation in polycystic kidney disease is currently unknown. Therefore, we compared pulse and continuous everolimus treatment in Han:SPRD rats. Four-week-old male heterozygous polycystic and wild-type rats were administered everolimus or vehicle by gavage feeding for 5 wk, followed by 7 wk without treatment, or continuously for 12 wk. Cessation of everolimus did not result in the appearance of renal cysts up to 7 wk postwithdrawal despite the reemergence of S6 kinase activity coupled with an overall increase in cell proliferation. Pulse everolimus treatment resulted in striking noncystic renal parenchymal enlargement and glomerular hypertrophy that was not associated with compromised kidney function. Both treatment regimens ameliorated kidney function, preserved the glomerular-tubular connection, and reduced proteinuria. Pulse treatment at an early age delays cyst development but leads to striking glomerular and parenchymal hypertrophy. Our data might have an impact when long-term treatment using mTOR inhibitors in patients with autosomal dominant polycystic kidney disease is being considered.

Safety and Efficacy of mTOR Inhibitor Treatment in Patients with Tuberous Sclerosis Complex under 2 Years of Age

2019 ◽  
Author(s):  
Afshin Saffari ◽  
Ines Brösse ◽  
Adelheid Wiemer-Kruel ◽  
Bernd Wilken ◽  
Paula Kreuzaler ◽  
...  
Keyword(s):  
Tuberous Sclerosis ◽  
Tuberous Sclerosis Complex ◽  
Mtor Inhibitor ◽  
Safety And Efficacy ◽  
Inhibitor Treatment

A multicenter phase II study of bevacizumab (B) and temsirolimus (T) in women with recurrent epithelial ovarian cancer (OC): A study of the Mayo, Chicago, California, New York, Southeast, and Princess Margaret Phase II Consortia.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 5517-5517
Author(s):  
Robert Morgan ◽  
Amit M. Oza ◽  
Rui Qin ◽  
Briant Fruth ◽  
Hal Hirte ◽  
...  
Keyword(s):  
Clinical Trial ◽  
New York ◽  
Phase Ii ◽  
Mtor Inhibitor ◽  
Phase Ii Study ◽  
Mtor Inhibitors ◽  
Stage Design ◽  
Angiogenic Therapy ◽  
Platinum Sensitive ◽  
Clinical Trial Evaluation

5517 Background: Anti-angiogenic therapy is active in OC; the combination of VEGF and mTOR inhibitors is hypothesized to further improve activity. This report is the OC cohort of a multi-histology phase II study assessing the activity and toxicity of B/T. Methods: Patients (Pts) with recurrent epithelial OC who had received ≤ 2 chemotherapy regimens and no prior treatment with a VEGF or mTOR inhibitor were eligible. A two-stage design was used with second stage accrual if >6 pts had objective responses (OR) or >10 pts of the first 25 remained progression-free (PF) at six months (mo). Pre-defined end-points for a recommendation for further clinical trial evaluation included at least 15/50 with OR or 26/50 PF at six mo. Treatment included T 25 mg IV wkly and B 10 mg/kg IV q14 days on 28 day cycles. Results: 58 pts were enrolled (the first 50 pts are used to determine a final recommendation). Median age=62 (range 35-82). A median of 4 (range 1-23) cycles were administered. 24 were platinum-sensitive, 34 resistant. Off-study reasons included 13 adverse events and disease progression in 38. 3 refused further therapy due to toxicity. 14 of the first 50 pts had partial response (PR) (9 platinum-resistant); 25/50 remained PF (8 PR, 15 SD, 2 non-progressing) at 6 mo. Grade (gr) 3/4 toxicities occurring >2 events include: fatigue (4), stomatitis (7), hypertension (5), neutropenia (4), thrombocytopenia (4), hypokalemia (3). One rectal and one vaginal fistula, and two colonic perforations (one gr 2 and one gr 3 during cycles 3 and 1 respectively) were observed. Episodes of gr 1/2 oral, nasal, pulmonary, vaginal and gastrointestinal hemorrhage were also observed. Conclusions: Although the OR and PFS did not reach pre-defined standards, the numbers of OR and 6 mo PFS suggest potential enhanced activity with a combination of mTOR inhibitor with anti-angiogenic therapy. Other combinations of these targeted agents may result in more satisfactory activity with less toxicity. N01-CM-62203 (PMH) N01-CM-62208 (Southeast Phase 2) N01 CM-62209 (CCCP) N01-CM-62204 (NYCC) N01-CM-2011-0071C (Chicago) N01-CM62205 (Mayo) Clinical trial information: NCT01010126.

Sign in / Sign up

Export Citation Format

Share Document