Across multiple preclinical choices, synergistic effects have been reported using antiendoglin and anti\VEGF agents to simultaneously block both pathways [29]

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Across multiple preclinical choices, synergistic effects have been reported using antiendoglin and anti\VEGF agents to simultaneously block both pathways [29]. In Mouse monoclonal to CD3/HLA-DR (FITC/PE) conclusion, the finding of a biomarker selected population that might benefit from the combination of Isoeugenol carotuximab and axitinib was not robust enough to merit further clinical development of this therapy. cell renal cell carcinoma (mccRCC) who had progressed following one or more Isoeugenol prior VEGF inhibitors. Methods TRAXAR was a multicenter, international randomized 1:1 (stratified by ECOG, 0 vs. 1), phase II study of carotuximab combined with axitinib versus axitinib alone in mccRCC patients who had progressed following one or more prior VEGF inhibitors. The primary endpoint was progression\free survival (PFS) assessed by independent central review (ICR) per RECIST 1.1 Results A total of 150 patients were randomized. The combination therapy resulted in shorter median PFS by RECIST 1.1 than axitinib monotherapy (6.7 vs. 11.4 months). The combination was tolerated similarly to axitinib monotherapy, and there were no treatment related deaths. Exploratory evaluation of pretreatment circulating biomarkers suggested the combination might benefit patients who have low baseline VEGF levels. Conclusion The combination of carotuximab with axitinib did not demonstrate additional efficacy over single agent axitinib in patients with mccRCC who progressed following one or more prior VEGF inhibitor treatment. ?1) and all grade 3 and above AEs by arm =?73), (%)=?74), (%)values (PIntx) for predictive analyses were not subjected to multiple testing correction. We observed that patients with low baseline VEGF levels exhibited longer median PFS in arm TRC105 + axitinib (TRAX) compared with arm axitinib monotherapy (AX) (22.4 vs. 16.9 months, PIntx = .004; Fig. ?Fig.2).2). Increased expression of VEGF and VEGFR have previously been associated with clinical responses and improved PFS on sunitinib. Lower VEGF levels might indicate an overall diminished VEGF signaling and perhaps a greater role for drugs targeting angiogenesis through non\VEGF related mechanisms, such as carotuximab. Open in a separate window Figure 2 Kaplan\Meier estimate of progression\free survival by RECIST 1.1 by independent central review according to baseline median VEGF levels stratified by treatment arm. Abbreviations: AX, axitinib monotherapy; TRAX, TRC105 + axitinib; VEGF, vascular endothelial growth factor. Lack of PFS benefit in the TRAX arm when compared with the AX arm led to termination of further development of carotuximab. It is critical to establish solid safety and efficacy signals in a phase Ib study prior to committing patients, investigators, and resources on a larger randomized clinical trial. Despite the favorable efficacy of the combination of axitinib and carotuximab found in a phase Ib study with 18 patients with mRCC [1], another randomized clinical trial in which carotuximab was added to bevacizumab in 59 patients with mRCC failed to improve PFS [2]. Much still remains to be learned in how Isoeugenol best to use antiangiogenic therapies in mRCC and whether any biomarker can guide selection of patients. Indeed, the observation of improved PFS in the subpopulation of patients with mRCC with lower than median VEGF emphasizes the value of patient preselection using predictive biomarkers to improve clinical outcomes. Trial Information Disease Renal cell carcinoma C clear cell Stage of Disease/Treatment Metastatic/advanced Prior Therapy 1 prior regimen Type of Study Phase II, randomized Primary Endpoint Progression\free survival Additional Details of Endpoints or Study Design The analysis of the primary endpoint of PFS compared arm AX and arm TRAX using a log\rank test stratified by performance status (0 or 1). A hazard ratio of 0.67 was considered to be clinically relevant. Based on 1:1 randomization and the use of a one\sided log\rank test at the = 0.10 level of significance, 115 events were required to have 80% power to detect a hazard ratio of 0.67. The expected PFS of patients treated with axitinib who had progressed following first\line treatment with a VEGF inhibitor was assumed to be 4.8 months. Based on a planned accrual period of 12 months, and a minimum follow\up period of 4.3 months, approximately 150 patients were recruited. Statistical analyses were done using R. The trial population for safety included all patients who received a dose of either study drug according to treatment actually received. An interim analysis for futility was planned following 55 events that defined the PFS endpoint but was not done.