Pilot study of dovitinib in patients with VHL disease.

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 587-587 ◽  
Author(s):  
Patrick Glen Pilie ◽  
Surena F. Matin ◽  
Ashley Henriksen Woodson ◽  
Valerie D. Marcott ◽  
Shelly Bird ◽  
...  
Keyword(s):  
Pilot Study ◽  
Kinase Inhibitor ◽  
Pilot Trial ◽  
Stopping Rule ◽  
Response To Treatment ◽  
Pancreatic Cysts ◽  
Inherited Disease ◽  
Patients Âgés ◽  
Vhl Disease ◽  
Efficacy Profile

587 Background: Von Hippel-Lindau (VHL) is an autosomal dominant inherited disease occurring in 1 in 35,000 births. Individuals with germline mutations in the VHL gene may phenotypically express a variety of lesions including hemangioblastomas (HBs), pancreatic cysts, renal cysts, and renal cell carcinomas (RCC). Previous studies have shown differentially increased FGFR3 levels in HBs compared to RCC. In this pilot trial, we investigated the safety and efficacy profile of TKI 258 (dovitinib), a tyrosine kinase inhibitor of VEGF and FGF receptors, in VHL related lesions, focusing on HBs. Methods: A MDACC IRB-approved protocol planned to enroll 25 subjects who had genetically confirmed VHL disease or clinical diagnosis of VHL, and measurable HBs with no immediate risk of needing intervention. Dovitinib 500mg/day was given in a 4 week cycle on 5 day on/2 day off schedule. In the absence of adverse events (AE), treatment lasted 6 cycles or until disease progression. Evaluation of response to treatment was done every 8 weeks including imaging, laboratory, and clinical evaluation. The trial design used a continuous Bayesian stopping rule based on toxicities that resulted in discontinuation of dovitinib and another for lack of efficacy. Signed informed consent completed on all patients enrolled. Results: Trial stopped after six patients enrolled due to toxicity stopping rule. Patients’ ages ranged 18-61 with 5/6 being male. With regards to safety, 6/6 subjects had at least one AE with the most common AEs being rash, diarrhea, and fatigue including a grade 3 AE (severe rash) in one patient. 1/6 was stopped due to noncompliance, 1/6 stopped due to progression, 3/6 stopped due to side effects despite dose reduction, and 1/6 completed full six cycles at full dose. Best response in 6/6 subjects was stable disease (SD) in HBs. Conclusions: This pilot study of dovitinib in patients with VHL disease with measureable HBs did not show a favorable safety or efficacy profile for this dose and schedule. Half of the patients discontinued the drug due to AEs before study completion, and the best achieved response was SD. Further investigation into alternative scheduling and other FGFR inhibitors in the treatment of HBs is warranted given the strong pre-clinical data. Clinical trial information: NCT01266070.

Molecular Targeting of Platelet-Derived Growth Factor B by Imatinib Mesylate in a Patient With Metastatic Dermatofibrosarcoma Protuberans

2002 ◽  
Vol 20 (17) ◽  
pp. 3586-3591 ◽  
Author(s):  
Brian P. Rubin ◽  
Scott M. Schuetze ◽  
Janet F. Eary ◽  
Thomas H. Norwood ◽  
Sohail Mirza ◽  
...  
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinase ◽  
Imatinib Mesylate ◽  
Kinase Inhibitor ◽  
Dermatofibrosarcoma Protuberans ◽  
Response To Therapy ◽  
Platelet Derived Growth Factor ◽  
Response To Treatment ◽  
Resected Specimen ◽  
Factor B

PURPOSE: Dermatofibrosarcoma protuberans is caused by activation of the platelet-derived growth factor B (PDGFB) receptor, a transmembrane tyrosine kinase. We investigated the response of dermatofibrosarcoma protuberans to the tyrosine kinase inhibitor imatinib mesylate. PATIENTS AND METHODS: A patient with unresectable, metastatic dermatofibrosarcoma protuberans received imatinib mesylate (400 mg bid). Response to therapy was assessed by [18F]fluorodeoxyglucose (FDG) positron emission tomography, magnetic resonance imaging, and histopathologic and immunohistochemical evaluation. RESULTS: The patient was treated for 4 months with imatinib mesylate. The hypermetabolic uptake of FDG fell to background levels within 2 weeks of treatment, and the tumor volume shrank by over 75% during the 4 months of therapy, allowing for resection of the mass. There was no residual viable tumor in the resected specimen, indicating a complete histologic response to treatment with imatinib mesylate. CONCLUSION: Imatinib mesylate is highly active in dermatofibrosarcoma protuberans. The dramatic response seen in this patient demonstrates that inhibition of PDGFB receptor tyrosine kinase activity can significantly impact viability of at least one type of solid tumor.

scholarly journals Systems Approaches to Treatment Response to Imatinib in Severe Asthma: A Pilot Study

2021 ◽  
Vol 11 (4) ◽  
pp. 240
Author(s):  
Seung Han Baek ◽  
Dinah Foer ◽  
Katherine N. Cahill ◽  
Elliot Israel ◽  
Enrico Maiorino ◽  
...  
Keyword(s):  
Gene Expression ◽  
Clinical Trial ◽  
Systems Biology ◽  
Pilot Study ◽  
Severe Asthma ◽  
Treated Patient ◽  
Expression Patterns ◽  
Airflow Limitation ◽  
Response To Treatment ◽  
Imatinib Treatment

There is an acute need for advances in pharmacologic therapies and a better understanding of novel drug targets for severe asthma. Imatinib, a tyrosine kinase inhibitor, has been shown to improve forced expiratory volume in 1 s (FEV1) in a clinical trial of patients with severe asthma. In a pilot study, we applied systems biology approaches to epithelium gene expression from these clinical trial patients treated with imatinib to better understand lung function response with imatinib treatment. Bronchial brushings from ten imatinib-treated patient samples and 14 placebo-treated patient samples were analyzed. We used personalized perturbation profiles (PEEPs) to characterize gene expression patterns at the individual patient level. We found that strong responders—patients with greater than 20% increase in FEV1—uniquely shared multiple downregulated mitochondrial-related pathways. In comparison, weak responders (5–10% FEV1 increase), and non-responders to imatinib shared none of these pathways. The use of PEEP highlights its potential for application as a systems biology tool to develop individual-level approaches to predicting disease phenotypes and response to treatment in populations needing innovative therapies. These results support a role for mitochondrial pathways in airflow limitation in severe asthma and as potential therapeutic targets in larger clinical trials.

scholarly journals Pre-exposure prophylaxis adherence with real-time adherence feedback and partner HIV self-testing: A pilot trial among postpartum women

2021 ◽  
Author(s):  
Dvora L Joseph Davey ◽  
Kathryn Dovel ◽  
Rufaro Mvududu ◽  
Dorothy Nyemba ◽  
Nyiko Mashele ◽  
...  
Keyword(s):  
Pilot Study ◽  
Real Time ◽  
Pilot Trial ◽  
Intervention Group ◽  
Standard Of Care ◽  
Postpartum Women ◽  
Care Clinic ◽  
The Past ◽  
Self Testing ◽  
Exposure Prophylaxis

Background: Pre-exposure prophylaxis (PrEP) is safe and effective in postpartum women. HIV self-testing (HIVST) for partners combined with biofeedback counselling through real-time adherence measures may improve daily PrEP use among postpartum women. Methods: Between August 2020 and April 2021 we conducted a pilot study in one primary care clinic in Cape Town, South Africa. We randomized postpartum women who initiated PrEP in pregnancy 1:1 to the intervention group (HIVST + biofeedback counselling following urine tenofovir test) or to standard of care (facility-based HIV tests and routine counselling without biofeedback). The outcomes of interest were PrEP adherence in the past 48-72hours via urine tenofovir tests and partner HIV testing, measured 1-month after randomisation. Secondary outcomes included proportion of partners who tested for HIV and discrepancy between self-reported PrEP adherence and urine tenofovir result. Results: We enrolled 106 women (median age=26 years; median months postpartum=2). Almost half of women reported having sex since giving birth (48%); 76% of those reported condomless sex at last sex. At enrolment most women (72%) reported missing <2 doses in the past 7-days; 36% of women had tenofovir present in her urine (no significant differences by arm). One month after enrolment, 62% (n=33) of women in the intervention arm had tenofovir present in their urine compared to 34% (n=18) in the standard of care arm (RR=1.83; 95% CI=1.19, 2.82). Two-thirds of women in the intervention arm reported that her partner tested for HIV (66%; n=35); compared to 17% (n=9) in the standard of care arm (RR=3.89; 95% CI=2.08, 7.27). The proportion of women with a discrepant adherence result (self-reported good recent adherence with no tenofovir in urine test) was significantly lower in the intervention group (n=8; 17%) compared to the standard of care group (n=24; 46%) (RR=0.33; 95% CI=0.17, 0.67). No social or clinical adverse events were reported in the intervention arm. Conclusions: In this pilot study, HIVST for partners and biofeedback counseling increased levels of recent PrEP adherence, pointing to the importance of these interventions to support PrEP use in this population.

scholarly journals Genotoxic and Cytotoxic Damage by Cyclophosphamide and Adriamycin as a Response to Treatment in Breast Cancer Patients: Pilot Study

2015 ◽  
Vol 06 (02) ◽  
pp. 163-168 ◽  
Author(s):  
Jimena Garibay-Garcia ◽  
Fernando Mejia-Sanchez ◽  
Eduardo Ramírez-San-Juan ◽  
Miriam V. Flores-Merino ◽  
Julieta Castillo-Cadena
Keyword(s):  
Breast Cancer ◽  
Pilot Study ◽  
Cancer Patients ◽  
Response To Treatment ◽  
Breast Cancer Patients

scholarly journals Sequential intra-arterial infusion of 90Y-resin microspheres and mitomycin C in chemo refractory liver metastatic breast cancer patients: a single centre pilot study

2020 ◽  
Vol 54 (1) ◽  
pp. 33-39
Author(s):  
Brigitte Maximiliana Aarts ◽  
Elisabeth Geneviève Klompenhouwer ◽  
Raphaëla Carmen Dresen ◽  
Christophe Michel Albert Louis Omer Deroose ◽  
Regina Gien Hoa Beets-Tan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Pilot Study ◽  
Mitomycin C ◽  
Progressive Disease ◽  
Metastatic Breast ◽  
Response To Treatment ◽  
Breast Cancer Patients ◽  
Arterial Infusion ◽  
Resin Microspheres

AbstractBackgroundThe aim of the study was to evaluate the safety and feasibility of intra-arterial mitomycin C (MMC) infusion after selective internal radiation therapy (SIRT) using Yttrium-90 (90Y) resin microspheres in liver metastatic breast cancer (LMBC) patients.Patients and methodsThe prospective pilot study included LMBC patients from 2012–2018. Patients first received infusion of 90Y resin microspheres, after 6–8 weeks response to treatment was assessed by MRI, 18F-FDG PET/CT and laboratory tests. After exclusion of progressive disease, MMC infusion was administrated 8 weeks later in different dose cohorts; A: 6 mg in 1 cycle, B: 12 mg in 2 cycles, C: 24 mg in 2 cycles and D: maximum of 72 mg in 6 cycles. In cohort D the response was evaluated after every 2 cycles and continued after exclusion of progressive disease. Adverse events (AE) were reported according to CTCAE version 5.0.ResultsSixteen patients received 90Y treatment. Four patients were excluded for MMC infusion, because of extra hepatic disease progression (n = 3) and clinical and biochemical instability (n = 1). That resulted in the following number of patient per cohort; A: 2, B: 1, C: 3 and D: 6. In 4 of the 12 patients (all cohort D) the maximum dose of MMC was adjusted due biochemical toxicities (n = 2) and progressive disease (n = 2). One grade 3 AE occurred after 90Y treatment consisting of a gastrointestinal ulcer whereby prolonged hospitalization was needed.ConclusionsSequential treatment of intra-arterial infusion of MMC after 90Y SIRT was feasible in 75% of the patients when MMC was administrated in different escalating dose cohorts. However, caution is needed to prevent reflux after 90Y SIRT in LMBC patients.

scholarly journals An integrated behavioural intervention combined with varenicline for heavy-drinking smokers: a randomized pilot study

2020 ◽  
Vol 15 (3) ◽  
pp. 119-127
Author(s):  
Lisa M. Fucito ◽  
Ran Wu ◽  
Stephanie S. O'Malley ◽  
Tess H. Hanrahan ◽  
Jolomi T. Ikomi ◽  
...  
Keyword(s):  
Pilot Study ◽  
Pilot Trial ◽  
Heavy Drinking ◽  
Medium Effect ◽  
Behavioural Intervention ◽  
Open Label ◽  
Academic Medical Centre ◽  
Academic Medical ◽  
Medium Effect Size ◽  
Promote Smoking Cessation

AbstractObjectivesCombined smoking and heavy drinking is a significant health burden. Varenicline, an efficacious tobacco pharmacotherapy that also shows promise for drinking, has yielded mixed results among heavy-drinking smokers. This pilot study investigated integrated tobacco and alcohol counselling plus varenicline for this vulnerable group.DesignTwelve-week parallel, randomized controlled pilot trial of two behavioural interventions in combination with open-label varenicline. Participants were randomized using computer-generated tables, stratified by sex.SettingOutpatient academic medical centre research clinic.ParticipantsVolunteers who reported smoking and heavy drinking and sought tobacco or alcohol treatment (N = 26).Intervention(1) Integrated tobacco + alcohol counselling (INT; n = 13) or (2) counselling focused on their presenting concern (i.e., tobacco or alcohol) (SINGLE; n = 13), plus varenicline (2 mg) for 12 weeks.Main outcomesFeasibility/acceptability, smoking quit rates and heavy drinking.ResultsINT feasibility/acceptability was high among men but not women. More participants quit smoking in INT than SINGLE. This outcome was only in men, not significant, but had a medium effect size. Both conditions yielded significant drinking reductions.ConclusionIntegrated tobacco and alcohol behavioural counselling plus varenicline may be feasible and promote smoking cessation among men who smoke and drink heavily, but a larger sample is needed to replicate this finding.

scholarly journals ACTR-19. REPORT ON THE COMBINATION OF AXITINIB AND TUMOR TREATING FIELDS (TTFIELDS) IN THREE PATIENTS WITH RECURRENT GLIOBLASTOMA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi16-vi16
Author(s):  
Ellina Schulz ◽  
Almuth F Kessler ◽  
Judith Weiland ◽  
Thomas Linsenmann ◽  
Ralf-Ingo Ernestus ◽  
...  
Keyword(s):  
Treatment Regimen ◽  
Male Patient ◽  
Kinase Inhibitor ◽  
Combined Therapy ◽  
Pilot Trial ◽  
Neurological Status ◽  
Recurrent Glioblastoma ◽  
Tumor Treating Fields ◽  
Initial Surgery ◽  
Newly Diagnosed Glioblastoma

Abstract OBJECTIVE Tumor Treating Fields (TTFields) significantly improved survival of newly diagnosed glioblastoma (ndGBM) patients in the EF-14 trial. Axitinib is an orally available tyrosine kinase inhibitor which is approved for the treatment of metastatic renal cell carcinoma. It has a high affinity and specificity for vascular endothelial growth factor receptors. In phase 2 trials, Axitinib improved response rate and PFS in recurrent GBM (rGBM) patients with a manageable toxicity profile. Here, three rGBM patients treated with TTFields and Axitinib (AxiTTFields) are presented. PATIENT SECTION A 53-year-old male patient (#1) presented with a progressing GBM after initial surgery, radiochemotherapy followed by 4 cycles of temozolomide (TMZ) and TTFields. In a 46-year-old male patient (#2), early progress occurred after surgery, radiochemotherapy and 3 cycles of TMZ combined with TTFields. In both patients Axitinib was added to the treatment regimen to meet the urgent need of an alternative treatment. In a 61-year-old male patient (#3) with rGBM after surgery, radiochemotherapy and 6 cycles of TMZ, TTFields therapy was initiated at recurrence and the treatment regimen was adapted to AxiTTFields. RESULTS No additional adverse events due to the combined therapy of AxiTTFields were observed. Patients #1 and #2 were on AxiTTFields therapy for more than 8 months, presenting an improved neurological status with a partial response in the MRI 3 months after initiating AxiTTFields. #3 declined in his neurological status without any change in the MRI monitoring and died 2.4 months after initiating AxiTTFields. With an average of 77%, the TTFields usage rate was above the independent prognostic threshold of 75%, underlining the feasibility of this approach. CONCLUSION AxiTTFields was feasible and safe in three rGBM patients. The addition of Axitinib to TTFields therapy is a promising approach and safety/feasibility will be further investigated in a pilot trial.

scholarly journals Minocycline augmentation in older adults with persistent depression: an open label proof of concept study

2020 ◽  
Vol 32 (7) ◽  
pp. 881-884
Author(s):  
Jimmy N. Avari ◽  
Dora Kanellopoulos ◽  
Nili Solomonov ◽  
Lauren Oberlin ◽  
George S. Alexopoulos
Keyword(s):  
Older Adults ◽  
Antidepressant Treatment ◽  
Pilot Trial ◽  
Substantial Improvement ◽  
Response To Treatment ◽  
Open Label ◽  
Adequate Treatment ◽  
Augmentation Strategies ◽  
Persistent Depression ◽  
Open Pilot

ABSTRACTLess than 40% of depressed older adults treated with an antidepressant achieve remission. Incomplete response to treatment is common. Current augmentation strategies have limited efficacy, and many have side effects that restrict their utilization in older adults. We conducted the first open pilot trial of minocycline augmentation in older adults who had failed to achieve remission after adequate psychopharmacologic treatment. Subjects older than 55 years of age with major depression and failure to achieve substantial improvement of depressive symptoms after at least 6 weeks of antidepressant treatment were given augmentation with minocycline 100 mg twice daily over an 8-week period. At the end of 8 weeks of augmentation with minocycline, 31% (4/13) patients achieved remission. Remitters had higher baseline ratings of hopelessness and apathy. Minocycline was well tolerated with no reported adverse events or discontinuation due to intolerance. Larger placebo-controlled studies are needed to evaluate the effects of minocycline augmentation in older adults who had failed to achieve remission after adequate treatment with antidepressants.

scholarly journals Targeting extracellular and juxtamembrane FGFR2 mutations in chemotherapy-refractory cholangiocarcinoma

2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Michael Bitzer ◽  
Stephan Spahn ◽  
Sepideh Babaei ◽  
Marius Horger ◽  
Stephan Singer ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Response To Treatment ◽  
Gene Fusions ◽  
Potential Treatment ◽  
Promising Candidate ◽  
Recommended Treatment ◽  
Tumor Boards ◽  
Functional Consequences ◽  
Selection For ◽  
A Current

AbstractIntrahepatic cholangiocarcinoma (iCCA) has emerged as a promising candidate for precision medicine, especially in the case of activating FGFR2 gene fusions. In addition to fusions, a considerable fraction of iCCA patients reveals FGFR2 mutations, which might lead to uncontrolled activation of the FGFR2 pathway but are mostly of unknown functional significance. A current challenge for molecular tumor boards (MTB) is to predict the functional consequences of such FGFR2 alterations to guide potential treatment decisions. We report two iCCA patients with extracellular and juxtamembrane FGFR2 mutations. After in silico investigation of the alterations and identification of activated FGFR2 downstream targets in tumor specimens by immunohistochemistry and transcriptome analysis, the MTB recommended treatment with an FGFR-inhibiting tyrosine kinase inhibitor. Both patients developed a rapidly detectable and prolonged partial response to treatment. These two cases suggest an approach to characterize further detected FGFR2 mutations in iCCA to enable patients´ selection for a successful application of the FGFR -inhibiting drugs.

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