NCCTG N0879 (Alliance): A randomized phase 2 cooperative group trial of carboplatin, paclitaxel, and bevacizumab ± everolimus for metastatic melanoma

McWilliams, Robert R.; Allred, Jacob B.; Slostad, Jessica; Katipamula, Rajini; Dronca, Roxana S.; Rumilla, Kandelaria M.; Erickson, Lori A.; Bryce, Alan H.; Joseph, Richard W.; Kottschade, Lisa A.; King, David M.; Leitch, John M.; Markovic, Svetomir N.

doi:10.1002/cncr.31072

Cited by 17 publications

(29 citation statements)

References 30 publications

(49 reference statements)

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“… 4 – 6 For example, in a clinical Phase II randomized controlled trial, combining bevacizumab with carboplatin and paclitaxel chemotherapy medicine in the control group for treatment, the ORR was 13%, the median PFS was 5.6 months, and the median OS was 14.5 months, and when erolimus was added to the experimental group, the ORR could be increased to 23%, while the median PFS and the median OS were not as good as those in the control group. 6 The above research indicated that antiangiogenic inhibitors may be effective in MM treatment. Therefore, we used Apatinib Mesylate Tablet, a novel small-molecule inhibitor of VEGFR-2 tyrosine kinase, for treating the metastatic MM.…”

Section: Discussionmentioning

confidence: 99%

“… 2 In the advanced MM, antiangiogenic therapy is still an important therapeutic method. Related studies using chemotherapy combined with recombinant human Endostar ™ (endostatin), 3 or monoclonal antibody drugs (McAb) of VEGFR, 4 – 6 have confirmed that chemotherapy combined with antiangiogenic therapy can improve the survival of patients with advanced MM. Therefore, in our study, apatinib mesylate tablet was used as the main drug to treat patients with Stage IV MM who failed conventional chemotherapy, in order to evaluate the clinical efficacy and safety of the drug.…”

Section: Introductionmentioning

confidence: 99%

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Apatinib mesylate tablet in the treatment of advanced malignant melanoma

Yang

Zhu

Luo

et al. 2018

OTT

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BackgroundObserving and studying clinical efficacy and safety of apatinib mesylate tablet in the treatment of advanced malignant melanoma (MM).MethodsRetrospectively analyzing the clinical data of 22 patients with metastatic MM who had failed conventional chemotherapy from June 2016 to January 2018. All patients took 500 mg of apatinib mesylate tablets per day. The efficacy should be evaluated according to RECIST 1.1 criteria. Adverse events (AEs) should be graded according to NCI-CTCAE 4.0.ResultsThere were two cases of partial remission (PR), 11 of stable disease (SD) and nine of progressive disease (PD) in the 22 patients with advanced MM, where the objective remission rate (ORR) was 9.1% and the disease control rate (DCR) was 59.1%. The median progression-free survival (PFS) was 7.5 months, and the 6-month progression-free survival rate (PFR) was 54.7%. Six patients died and the overall survival (OS) was not reached. AEs were controllable and all were in Grade 1–3.ConclusionApatinib mesylate tablets have a certain curative effect on patients with malignant melanomas of Stage IV who failed conventional chemotherapy. Apatinib mesylate tablets at a daily dose of 500 mg are well tolerated by most patients.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Apatinib mesylate tablet in the treatment of advanced malignant melanoma

Yang

Zhu

Luo

et al. 2018

OTT

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“…Lastly, a recent study evaluated the combination of everolimus, bevacizumab, carboplatin and paclitaxel (CPB) in a randomized phase II trial. A total of 149 patients affected by stage IV melanoma were treated with CPB or with CPB plus everolimus: no differences in terms of PFS or OS were noted among the two groups, but everolimus strongly increased toxicity (McWilliams et al, 2018).…”

Section: Mtormentioning

confidence: 99%

Non-BRAF Mutant Melanoma: Molecular Features and Therapeutical Implications

Vanni

Tanda

Dalmasso

et al. 2020

Front. Mol. Biosci.

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Melanoma is one of the most aggressive tumors of the skin, and its incidence is growing worldwide. Historically considered a drug resistant disease, since 2011 the therapeutic landscape of melanoma has radically changed. Indeed, the improved knowledge of the immune system and its interactions with the tumor, and the ever more thorough molecular characterization of the disease, has allowed the development of immunotherapy on the one hand, and molecular target therapies on the other. The increased availability of more performing technologies like Next-Generation Sequencing (NGS), and the availability of increasingly large genetic panels, allows the identification of several potential therapeutic targets. In light of this, numerous clinical and preclinical trials are ongoing, to identify new molecular targets. Here, we review the landscape of mutated non-BRAF skin melanoma, in light of recent data deriving from Whole-Exome Sequencing (WES) or Whole-Genome Sequencing (WGS) studies on melanoma cohorts for which information on the mutation rate of each gene was available, for a total of 10 NGS studies and 992 samples, focusing on available, or in experimentation, targeted therapies beyond those targeting mutated BRAF. Namely, we describe 33 established and candidate driver genes altered with frequency greater than 1.5%, and the current status of targeted therapy for each gene. Only 1.1% of the samples showed no coding mutations, whereas 30% showed at least one mutation in the RAS genes (mostly NRAS) and 70% showed mutations outside of the RAS genes, suggesting potential new roads for targeted therapy. Ongoing clinical trials are available for 33.3% of the most frequently altered genes.

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“…A recent study evaluated the addition of everolimus to carboplatin, paclitaxel, and bevacizumab; this combination was found to be ineffective in metastatic melanoma because of inability to give the full dose of everolimus, predominantly because of cytopenias . Although it was a negative study, the investigators reported that the everolimus combination arm performed exceptionally well, receiving >30 cycles of therapy .…”

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Phase II Study of Everolimus in Metastatic Malignant Melanoma (NCCTG-N0377, Alliance)

et al. 2018

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Lessons Learned. Everolimus does not have sufficient activity to justify its use as single agent in metastatic melanoma.Patients treated with 10 mg per day dose were most likely to require dose reductions.Everolimus appeared to reduce the numbers of regulatory T cells in approximately half of the treated patients; unfortunately, these effects were not correlated with clinical outcomes.Background.Everolimus (RAD‐001) is an orally active rapamycin analogue shown in preclinical data to produce cytostatic cell inhibition, which may be potentially beneficial in treating melanoma. We conducted a phase II study to evaluate the efficacy and safety of everolimus in patients with unresectable metastatic melanoma (MM).Methods.This study included two cohorts; cohort 1 received 30 mg of everolimus by mouth (PO) weekly, and cohort 2 was dosed with 10 mg of everolimus PO daily. The endpoints of the study were safety, 16‐week progression‐free survival (PFS), overall survival (OS), and measures of immunomodulatory/antiangiogenic properties with therapy. Tumor samples before therapy and at week 8 of treatment were analyzed. Peripheral blood plasma or mononuclear cell isolates collected prior to therapy and at weeks 8 and 16 and at time of tumor progression were analyzed for vascular endothelial growth factor and regulatory T‐cell (Treg) measurements.Results.A total of 53 patients were enrolled in cohort 1 (n = 24) and cohort 2 (n = 29). Only 2 patients of the first 20 patients enrolled in cohort 2 had treatment responses (25%; 95% confidence interval, 8.6%–49.1%); this result did not allow full accrual to cohort 2, as the study was terminated for futility. Median OS was 12.2 months for cohort 1 versus 8.1 months in cohort 2; no PFS advantage was seen in either group (2.1 months vs. 1.8 months). Dose‐limiting toxicities included grade 4 myocardial ischemia (3.4%); grade 3 fatigue, mucositis, and hyperglycemia (10.3%); and anorexia and anemia (6.9%). Everolimus significantly reduced the number of Tregs in approximately half of the treated patients; however, these effects were not correlated with clinical outcomes.Conclusion.Everolimus does not have sufficient single‐agent activity in MM; however, we have identified evidence of biological activity to provide a potential rationale for future combination studies.

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NCCTG N0879 (Alliance): A randomized phase 2 cooperative group trial of carboplatin, paclitaxel, and bevacizumab ± everolimus for metastatic melanoma

Cited by 17 publications

References 30 publications

Apatinib mesylate tablet in the treatment of advanced malignant melanoma

Apatinib mesylate tablet in the treatment of advanced malignant melanoma

Non-BRAF Mutant Melanoma: Molecular Features and Therapeutical Implications

Phase II Study of Everolimus in Metastatic Malignant Melanoma (NCCTG-N0377, Alliance)

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