المؤلفون: Coyne, Geraldine O'Sullivan, Kummar, Shivaani, Hu, James, Ganjoo, Kristen, Chow, Warren A, T., Khanh, Zlott, Jennifer, Bruns, Ashley, Rubinstein, Lawrence, Foster, Jared C, Juwara, Lamin, Meehan, Robert, Piekarz, Richard, Streicher, Howard, Sharon, Elad, Takebe, Naoko, Voth, Andrea Regier, Bottaro, Donald, Costello, Rene, Wright, John J, Doroshow, James H, Chen, Alice P

المصدر: Clinical Cancer Research. 28(2)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Rare Diseases, Cancer, Clinical Research, Clinical Trials and Supportive Activities, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Anilides, Humans, Protein Kinase Inhibitors, Pyridines, Sarcoma, Vascular Endothelial Growth Factor A, Oncology & Carcinogenesis, Clinical sciences, Oncology and carcinogenesis

الوصف: PurposeSoft-tissue sarcomas (STS) are a rare, heterogeneous group of mesenchymal tumors. For decades the mainstay of treatment for advanced, unresectable STS has been palliative chemotherapy. High levels of activated MET receptor have been reported in various sarcoma cell lines, together with elevated vascular endothelial growth factor (VEGF) levels in patients with STS, suggesting that dual targeting of the VEGF and MET pathways with the multi-receptor tyrosine kinase inhibitor cabozantinib would result in clinical benefit in this population.Patients and methodsWe performed an open-label, multi-institution, single-arm phase II trial of single-agent cabozantinib in adult patients with advanced STS and progressive disease after at least 1 standard line of systemic therapy. Patients received 60 mg oral cabozantinib once daily in 28-day cycles, and dual primary endpoints of overall response rate and 6-month progression-free survival (PFS) were assessed. Changes in several circulating biomarkers were assessed as secondary endpoints.ResultsSix (11.1%; 95% CI, 4.2%-22.6%) of the 54 evaluable patients enrolled experienced objective responses (all partial responses). Six-month PFS was 49.3% (95% CI, 36.2%-67.3%), with a median time on study of 4 cycles (range, 1-99). The most common grade 3/4 adverse events were hypertension (7.4%) and neutropenia (16.7%). Patients' levels of circulating hepatocyte growth factor (HGF), soluble MET, and VEGF-A generally increased after a cycle of therapy, while soluble VEGFR2 levels decreased, regardless of clinical outcome.ConclusionsCabozantinib single-agent antitumor activity was observed in patients with selected STS histologic subtypes (alveolar soft-part sarcoma, undifferentiated pleomorphic sarcoma, extraskeletal myxoid chondrosarcoma, and leiomyosarcoma) highlighting the biomolecular diversity of STS.

وصف الملف: application/pdf

URL الوصول: https://escholarship.org/uc/item/12s070vk

المؤلفون: Chen, Huanwen, Kuhn, John, Lamborn, Kathleen R, Abrey, Lauren E, DeAngelis, Lisa M, Lieberman, Frank, Robins, H Ian, Chang, Susan M, Yung, WK Alfred, Drappatz, Jan, Mehta, Minesh P, Levin, Victor A, Aldape, Kenneth, Dancey, Janet E, Wright, John J, Prados, Michael D, Cloughesy, Timothy F, Wen, Patrick Y, Gilbert, Mark R

المصدر: Neuro-Oncology Advances. 2(1)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Cancer, Clinical Trials and Supportive Activities, Brain Disorders, Rare Diseases, Clinical Research, Brain Cancer, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, 6.2 Cellular and gene therapies, erlotinib, glioblastoma, molecular therapy, novel trial design, sorafenib

الوصف: BackgroundReceptor tyrosine kinases such as epidermal growth factor receptors (EGFRs) and their downstream signaling pathways such as the Ras-Raf-mitogen-activated protein kinase (MAPK) pathway play important roles in glioblastoma (GBM). This study investigated the safety, pharmacokinetics, and efficacy of sorafenib (Ras/Raf/MAPK inhibitor) in combination with erlotinib (EGFR inhibitor) for treatment of recurrent GBMs.MethodsPatients with recurrent GBM were eligible. A novel sequential accrual trial design was used, where patients were sequentially accrued into separate treatment arms in phase I and phase II investigations to optimize recruitment efficiency. In phase I, a standard 3 + 3 format was used to identify dose-limiting toxicities (DLTs), determine maximum tolerated dose (MTD), and investigate pharmacokinetics. Phase II followed a 2-stage design with the primary endpoint being 6-month progression-free survival (PFS6).ResultsSixteen patients were recruited for phase I, and the MTD was determined to be sorafenib 200 mg twice daily and erlotinib 100 mg once daily. DLTs include Grade 3 hypertension, Grade 3 elevated liver transaminases, and Grade 4 elevated lipase. While erlotinib did not affect sorafenib levels, sorafenib reduced erlotinib levels. In phase II, 3 of 19 stage 1 participants were progression free at 6 months. This did not meet the predetermined efficacy endpoint, and the trial was terminated.ConclusionThis study identified the MTD and DLTs for sorafenib and erlotinib combination therapy for recurrent GBMs; however, efficacy data did not meet the primary endpoint. This study also demonstrates the feasibility of a novel sequential accrual clinical trial design that optimizes patient recruitment for multiarm studies, which is particularly effective for multicenter clinical trials.

وصف الملف: application/pdf

URL الوصول: https://escholarship.org/uc/item/37w0v4mw

المؤلفون: Reynolds-Wright, John J, Woldetsadik, Mulat A, Morroni, Chelsea, Cameron, Sharon T

المصدر: In Contraception December 2022 116:4-13

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المؤلفون: Chung, Injae, Wright, John J., Bridges, Hannah R., Ivanov, Bozhidar S., Biner, Olivier^{Aff1, Aff3}, Pereira, Caroline S., Arantes, Guilherme M., Hirst, Judy^{Aff1, IDs41467022305061_cor8}

المصدر: Nature Communications. 13(1)

المؤلفون: Kummar, Shivaani^{Aff1, Aff6}, Srivastava, Apurva K., Navas, Tony^{Aff2, Aff7}, Cecchi, Fabiola^{Aff3, Aff8}, Lee, Young H.^{Aff3, Aff9}, Bottaro, Donald P., Park, Sook Ryun^{Aff1, Aff10}, Do, Khanh T.^{Aff1, Aff11}, Jeong, Woondong^{Aff1, Aff12}, Johnson, Barry C., Voth, Andrea R., Rubinstein, Larry, Wright, John J., Parchment, Ralph E., Doroshow, James H.^{Aff1, Aff5}, Chen, Alice P.^Aff1

المصدر: Investigational New Drugs: Novel Anti-Cancer Therapeutics and Therapies. 39(6):1577-1586

المؤلفون: Grba, Daniel N., Wright, John J., Zhan Yin, Fisher, William, Hirst, Judy

المصدر: Science; 6/14/2024, Vol. 384 Issue 6701, p1247-1253, 7p, 4 Diagrams

المؤلفون: Quinn, David I.^Aff1, Tsao-Wei, Denice D., Twardowski, Przemyslaw^{Aff3, Aff4}, Aparicio, Ana M.^{Aff1, Aff5}, Frankel, Paul, Chatta, Gurkamal^{Aff6, Aff7}, Wright, John J., Groshen, Susan G., Khoo, Stella, Lenz, Heinz-Josef, Lara, Primo N., Gandara, David R., Newman, Edward

المصدر: Investigational New Drugs: Novel Anti-Cancer Therapeutics and Therapies. 39(3):812-820

المؤلفون: Apolo, Andrea B ^*, Nadal, Rosa, Tomita, Yusuke, Davarpanah, Nicole N, Cordes, Lisa M, Steinberg, Seth M, Cao, Liang, Parnes, Howard L, Costello, Rene, Merino, Maria J, Folio, Les R, Lindenberg, Liza, Raffeld, Mark, Lin, Jeffrey, Lee, Min-Jung, Lee, Sunmin, Alarcon, Sylvia V, Yuno, Akira, Dawson, Nancy A, Allette, Kimaada, Roy, Arpita, De Silva, Dinuka, Lee, Molly M, Sissung, Tristan M, Figg, William D, Agarwal, Piyush K, Wright, John J, Ning, Yangmin M, Gulley, James L, Dahut, William L, Bottaro, Donald P, Trepel, Jane B

المصدر: In The Lancet Oncology August 2020 21(8):1099-1109

المؤلفون: Gong, Jun, Mita, Alain C., Wei, Zihan, Cheng, Heather H., Mitchell, Edith P., Wright, John J., Ivy, S. Percy, Wang, Victoria, Gray, Robert C., McShane, Lisa M., Rubinstein, Larry V., Patton, David R., Williams, P. Mickey, Hamilton, Stanley R., Tricoli, James V., Conley, Barbara A., Arteaga, Carlos L., Harris, Lyndsay N., O'Dwyer, Peter J., Chen, Alice P.

المصدر: JCO Precision Oncology; 4/11/2024, Vol. 8, p1-19, 19p

مصطلحات موضوعية: FIBROBLAST growth factor receptors, TRANSFORMING growth factors, FIBROBLAST growth factors, BRAF genes

مصطلحات جغرافية: K2 (Pakistan : Mountain)

مستخلص: PURPOSE: Subprotocol K2 (EAY131-K2) of the NCI-MATCH platform trial was an open-label, single-arm, phase II study designed to evaluate the antitumor efficacy of the oral FGFR1-4 inhibitor, erdafitinib, in patients with tumors harboring FGFR1-4 mutations or fusions. METHODS: Central confirmation of tumor FGFR1-4 mutations or fusions was required for outcome analysis. Patients with urothelial carcinoma were excluded. Enrolled subjects received oral erdafitinib at a starting dose of 8 mg daily continuously until intolerable toxicity or disease progression. The primary end point was objective response rate (ORR) with key secondary end points of safety, progression-free survival (PFS), and overall survival (OS). RESULTS: Thirty-five patients were enrolled, and 25 patients were included in the primary efficacy analysis as prespecified in the protocol. The median age was 61 years, and 52% of subjects had received ≥3 previous lines of therapy. The confirmed ORR was 16% (4 of 25 [90% CI, 5.7 to 33.0], P =.034 against the null rate of 5%). An additional seven patients experienced stable disease as best-confirmed response. Four patients had a prolonged PFS including two with recurrent WHO grade IV, IDH1-/2-wildtype glioblastoma. The median PFS and OS were 3.6 months and 11.0 months, respectively. Erdafitinib was manageable with no new safety signals. CONCLUSION: This study met its primary end point in patients with several pretreated solid tumor types harboring FGFR1-3 mutations or fusions. These findings support advancement of erdafitinib for patients with fibroblast growth factor receptor–altered tumors outside of currently approved indications in a potentially tumor-agnostic manner. Activity of FGFR inhibition in solid tumors with FGFR fusions/mutations in this NCI-MATCH phase II trial. [ABSTRACT FROM AUTHOR]

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