Losartan blocks osteosarcoma-elicited monocyte recruitment, and combined with the kinase inhibitor toceranib, exerts significant clinical benefit in canine metastatic osteosarcoma

2021 ◽  
pp. clincanres.2105.2021
Author(s):  
Daniel P Regan ◽  
Lyndah Chow ◽  
Sunetra Das ◽  
Laurel Haines ◽  
Eric Palmer ◽  
...  
Keyword(s):  
Clinical Benefit ◽  
Kinase Inhibitor ◽  
Significant Clinical Benefit ◽  
Metastatic Osteosarcoma ◽  
Monocyte Recruitment

scholarly journals Pazopanib in Patients with Osteosarcoma Metastatic to the Lung: Phase 2 Study Results and the Lessons for Tumor Measurement

2022 ◽  
Vol 2022 ◽  
pp. 1-9
Author(s):  
Paul Frankel ◽  
Chris Ruel ◽  
An Uche ◽  
Edwin Choy ◽  
Scott Okuno ◽  
...  
Keyword(s):  
Doubling Time ◽  
Kinase Inhibitor ◽  
Common Adverse Event ◽  
Phase 2 ◽  
Primary Analysis ◽  
Tumor Doubling Time ◽  
Metastatic Osteosarcoma ◽  
Phase 2 Study ◽  
Study Results ◽  
Slow Growing

Background. This single-arm, multicenter, phase 2 study evaluated the safety and antitumor activity of pazopanib in patients with unresectable, pulmonary metastatic osteosarcoma. Patients and Methods. Patients with pulmonary metastatic osteosarcoma unresponsive to chemotherapy were eligible. Patients who received prior tyrosine kinase inhibitor therapy were excluded. Pazopanib at 800 mg once daily was administered for 28-day cycles. Tumor responses were evaluated by local radiology assessment 1 month prior to and after initiation of treatment to calculate tumor doubling time and after every even numbered cycle. The primary endpoints were progression-free survival at 4 months, concomitant with a demonstrated 30% increase in tumor doubling time relative to the pretreatment growth rate. Results. 12 patients (7 female) were enrolled. The study was terminated prematurely due to withdrawal of financial support by the sponsor. 8 subjects were eligible for the primary analysis, whereas 4 patients were in a predefined exploratory “slow-growing” cohort. In the “fast-growing” cohort, 3 of the 8 patients (37.5%) eligible for first-stage analysis were deemed “success” by the preplanned criteria, adequate to proceed to second-stage accrual. In addition, 1 of the 4 patients in the “slow-growing” cohort experienced a partial remission. Grade 1-2 diarrhea was the most common adverse event, and grade 3 events were infrequent. Conclusion. This study illustrates a novel method of demonstrating positive drug activity in osteosarcoma by increasing tumor doubling time, and this is further supported by a partial response in a patient with “slow-growing” disease. This trial is registered with NCT01759303.

scholarly journals Exploring Predictors of Response to Dacomitinib in EGFR-Amplified Recurrent Glioblastoma

2020 ◽  
pp. 593-613
Author(s):  
Andrew S. Chi ◽  
Daniel P. Cahill ◽  
David A. Reardon ◽  
Patrick Y. Wen ◽  
Tom Mikkelsen ◽  
...  
Keyword(s):  
Gene Amplification ◽  
Clinical Benefit ◽  
Kinase Inhibitor ◽  
Growth Factor Receptor ◽  
Genetic Alterations ◽  
Recurrent Glioblastoma ◽  
Rapid Progression ◽  
Duration Of Treatment ◽  
Egfr Gene ◽  
Predictors Of Response

PURPOSE Despite the high frequency of EGFR genetic alterations in glioblastoma (GBM), EGFR-targeted therapies have not had success in this disease. To improve the likelihood of efficacy, we targeted adult patients with recurrent GBM enriched for EGFR gene amplification, which occurs in approximately half of GBM, with dacomitinib, a second-generation, irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that penetrates the blood-brain barrier, in a multicenter phase II trial. PATIENTS AND METHODS We retrospectively explored whether previously described EGFR extracellular domain (ECD)–sensitizing mutations in the context of EGFR gene amplification could predict response to dacomitinib, and in a predefined subset of patients, we measured post-treatment intratumoral dacomitinib levels to verify tumor penetration. RESULTS We found that dacomitinib effectively penetrates contrast-enhancing GBM tumors. Among all 56 treated patients, 8 (14.3%) had a clinical benefit as defined by a duration of treatment of at least 6 months, of whom 5 (8.9%) remained progression free for at least 1 year. Presence of EGFRvIII or EGFR ECD missense mutation was not associated with clinical benefit. We evaluated the pretreatment transcriptome in circulating extracellular vesicles (EVs) by RNA sequencing in a subset of patients and identified a signature that distinguished patients who had durable benefit versus those with rapid progression. CONCLUSION While dacomitinib was not effective in most patients with EGFR-amplified GBM, a subset experienced a durable, clinically meaningful benefit. Moreover, EGFRvIII and EGFR ECD mutation status in archival tumors did not predict clinical benefit. RNA signatures in circulating EVs may warrant investigation as biomarkers of dacomitinib efficacy in GBM.

scholarly journals Clinical Benefit to an Aurora A Kinase Inhibitor in a Patient with Metastatic Integrase Interactor 1‐Deficient Carcinoma

2018 ◽  
Vol 24 (2) ◽  
pp. 146-150 ◽  
Author(s):  
Theodoros Karantanos ◽  
Lisa Rooper ◽  
Youme Kang ◽  
Cheng Ting Lin ◽  
Pawla Wenga ◽  
...  
Keyword(s):  
Clinical Benefit ◽  
Kinase Inhibitor ◽  
Aurora A Kinase ◽  
Aurora A ◽  
Integrase Interactor 1

Premedication with Ipratropium Bromide for Bronchoscopy Produces Subjective Discomfort without Significant Clinical Benefit

1998 ◽  
Vol 5 (3) ◽  
pp. 200-203
Author(s):  
Jeffrey B. Rubins ◽  
Carol Bofenkamp ◽  
Melynne Youngblood ◽  
JoAnne Billings ◽  
Alain Broccard
Keyword(s):  
Clinical Benefit ◽  
Ipratropium Bromide ◽  
Significant Clinical Benefit ◽  
Subjective Discomfort

Phase II study of sunitinib administered in a continuous daily dosing regimen in patients (pts) with advanced GIST

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 9532-9532 ◽  
Author(s):  
S. George ◽  
P. G. Casali ◽  
J. Blay ◽  
A. Le Cesne ◽  
A. R. Tyler ◽  
...  
Keyword(s):  
Phase Ii ◽  
Clinical Benefit ◽  
Kinase Inhibitor ◽  
Continuous Treatment ◽  
Study Endpoint ◽  
Primary Study ◽  
Open Label ◽  
Early Results ◽  
Imatinib Resistant ◽  
Grade 3

9532 Background: Sunitinib malate (SU11248) is an oral multitargeted tyrosine kinase inhibitor with antitumor and antiangiogenic activities due to inhibition of KIT, VEGFRs, PDGFRs, RET, and FLT3. In previous phase I/II and III trials in pts with imatinib-resistant GIST, sunitinib demonstrated efficacy and favorable clinical tolerability when administered in 6-week treatment cycles consisting of 4 weeks sunitinib (50 mg QD), followed by 2 weeks off treatment. The current study examined continuous sunitinib dosing as a way to avoid potential reactivation of tumor cells during the off-treatment period. Methods: This open-label, multicenter, phase II trial was designed to evaluate the efficacy, safety, and tolerability of sunitinib administered once daily using a continuous-treatment regimen in pts with imatinib-resistant GIST. Treatment is initiated with 37.5 mg sunitinib daily, with the option to titrate dosing on an individual basis depending on tolerability. The primary study endpoint is clinical benefit rate, defined as percent of evaluable pts with confirmed CR, PR, or SD ≥24 weeks using RECIST. Secondary endpoints included ORR, TTP, PFS, OS, and safety/tolerability measures. Results: Of 28 pts who had started treatment at the time of this analysis, early results were available for 17 pts from two centers. The most commonly occurring treatment-related adverse events were stomatitis, hand-foot syndrome, gastroesophageal reflex, and fatigue, which were generally grade 1. Two pts experienced treatment-related grade 3 hypertension, and another exhibited grade 3 asymptomatic neutropenia. Five pts have been evaluated for benefit after 8 weeks of treatment. Stable disease (which is the clinical benefit typically observed in GIST pts treated with sunitinib) was demonstrated in all five pts. Expanded safety/tolerability and efficacy results will be available for presentation. Conclusions: Continuous dosing of sunitinib is feasible and appears to be associated with acceptable tolerability in pts with imatinib-refractory GIST, similar to the extensive experience documented with intermittent sunitinib dosing. It is possible that continuous daily dosing of sunitinib may further improve the outcomes of pts with GIST. [Table: see text]

scholarly journals Photochemical Rearrangement of a 6-Azasteroid Oxaziridine to a Novel 17β-Carbomethoxy-A-homo-B-seco-6-aza-3, 5-androstanedione

2019 ◽  
Vol 53 (3) ◽  
Author(s):  
Stephen Frye
Keyword(s):  
Clinical Benefit ◽  
Structure Activity Relationship ◽  
Ring System ◽  
Activity Relationship ◽  
Reaction Sequence ◽  
Human Type ◽  
Significant Clinical Benefit ◽  
Photochemical Rearrangement ◽  
Structure Activity

4- and 6-azasteroids have been shown to be potent inhibitors of human 5α-reductase and certain azasteroids have shown significant clinical benefit in the treatment of androgen-related disorders. In an effort to expand the diversity of steroidal heterocycles synthetically accessible for structure-activity relationship exploration, a novel reaction sequence was applied to the preparation of the 6-azasteroid framework. To this end, photolysis of the oxaziridine derived from 17β-carbomethoxy-3β-triisopropylsilyloxy-6-azaandrost-5-ene (1) yielded a novel 7, 5-steroidal ring system that was evaluated for inhibition of human type 1 and 2 5α-reductase.

Oral tyrosine kinase inhibitor masitinib in combination with gemcitabine in patients with advanced pancreatic cancer: A multicenter phase II study

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 4617-4617
Author(s):  
P. Hammel ◽  
F. Mornex ◽  
G. Deplanque ◽  
E. Mitry ◽  
P. Levy ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Clinical Benefit ◽  
Kinase Inhibitor ◽  
Survival Rates ◽  
Phase Iii ◽  
Human Pancreatic Cancer ◽  
Pancreatic Cancer Cells ◽  
Multicenter Phase

4617 Background: Masitinib, a tyrosine kinase inhibitor targeting c-Kit, PDGFR, FGFR3 and affecting the FAK pathway, can enhance the antiproliferative effects of gemcitabine (GEM) in human pancreatic cancer cells. This multicenter phase 2 study aimed to determine the efficacy and safety of masitinib in combination with GEM in the first-line treatment of patients with locally advanced (LAPC) or metastatic (MPC) pancreatic cancer. Methods: Patients received oral masitinib (9 mg/kg/d) and standard weekly infusion of GEM (1,000 mg/m2). Primary endpoint was time-to-progression (TTP). Our hypothesis for efficacy was a TTP over 2.1 months. Secondary endpoints included survival rates, tumor response (RECIST) and clinical benefit. Results: 22 patients, with LAPC (n=9) or MPC (n=13), KPS[80–100]/[70] (18/4) were enrolled and treated with masitinib plus GEM. Median TTP was 6.4 months, well beyond our threshold for efficacy (LAPC: 8.3 months, MPC: 2.7 months, KPS[80–100]: 6.4 months, KPS[70]: 0.8 months). At 12 months, 17% of LAPC and 14% of KPS[80–100] were progression-free; all MPC and KPS[70] patients had progressed. The disease control rate was 73% (LAPC: 89%, MPC: 62%, KPS[80–100]: 89%; KPS[70] patients progressed immediately). Median OS was 7.1 months (LAPC: 8.4 months, MPC: 6.8 months, KPS[80–100]: 8.0 months, KPS[70]: 4.4 months). At 18 months, the survival rate was 23%. However, when considering KPS[80–100] alone, it reached 28%. The 18-months survival rates were similar for LAPC (22%) and MPC (23%). 16% of the 19 patients evaluated experienced clinical benefit (LAPC: 38%, KPS[80–100]: 18%). One patient (5%) presented suspected grade 4 neutropenia. Main suspected grade 3 toxicity were anemia, lymphopenia (23%), leucopenia, neutropenia (18%), asthenia (14%), diarrhea, cytolytic hepatitis, and skin rash (9%). Altogether, the combination masitinib plus GEM did not seem to increase the toxicity commonly reported with GEM alone. Conclusions: The antitumor activity of the combination masitinib plus GEM is very promising and does not present limiting toxicities. Based on those encouraging data, a randomized phase III trial comparing masitinib plus GEM with GEM alone is now actively recruiting patients in the US and in Europe. [Table: see text]

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