Ipilimumab, nivolumab and tocilizumab as first-line therapy for advanced melanoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS9589-TPS9589
Author(s):  
Inderjit Mehmi ◽  
Omid Hamid ◽  
F. Stephen Hodi ◽  
Melinda Vassalo ◽  
Saundra Malatyali ◽  
...  
Keyword(s):  
Interleukin 6 ◽  
Response Rate ◽  
Acute Phase Proteins ◽  
Adaptive Immune System ◽  
Advanced Melanoma ◽  
Current Phase ◽  
Second Stage ◽  
First Line Therapy ◽  
Flat Dose ◽  
Dosing Regimens

TPS9589 Background: Interleukin 6 (IL-6) functions in the maintenance of hepatocytes, haemotopoietic progenitor cells, a variety of other tissues, and regulates the innate and adaptive immune system. IL-6 may play a role as a chronic inflammatory mediator in altering levels of acute phase proteins synthesized by the liver and circulating myeloid cells which have been shown to be associated with short survival with checkpoint inhibition and which are immune suppressive. The immunomodulatory properties of interleukin-6 may in part also be responsible for immune related adverse events, given the reversal of those toxicities observed with IL-6 receptor blockade in clinical practice. To assess if blockade of IL-6 binding is associated with a decrease in irAEs and/or an increase in efficacy defined as overall response rate (ORR) at week 24 in patients receiving ICB, we added tocilizumab to ipilimumab and nivolumab therapy. Methods: The current phase II trial is a two-stage design to assess the safety, tolerability, and grades 3-5 immune related toxicities of tocilizumab administered every 6 weeks up to week 24 in combination with ipilimumab at 1 mg/kg and nivolumab at 3 mg/kg every 3 weeks for 4 doses each during a 12 week induction period, then administered every 6 weeks with nivolumab at 240 mg flat dose every 2 weeks in maintenance for up to 24 weeks, and nivolumab alone will be given at 480 mg flat dose every 4 weeks thereafter for up to 2 years. Eligible patients include those age 18 or older with measurable and unresectable stages III/IV melanoma (cutaneous, acral, mucosal), without prior systemic treatment for metastatic disease. Adjuvant therapy (IFN-alpha, ipilimumab and/or nivolumab, or pembrolizumab) is allowed. Patients with metastatic melanoma of brain are allowed, if neurologically stable and off immunosuppressive steroids. A total of 18 patients will be treated in the first stage, and 49 additional patients in the second stage for a total of 67. The comparator data are from the N3I1 arm of Checkmate-511 trial, in which treatment-related grades 3-5 irAEs were 33.9% with a 45.6% response rate (1). Prespecified activity goal for the first stage of accrual has been met; second stage accrual began in January 2021. References: (1) Lebbé C, Meyer N, Mortier L, Marquez-Rodas I, et al. Evaluation of Two Dosing Regimens for Nivolumab in Combination With Ipilimumab in Patients With Advanced Melanoma: Results From the Phase IIIb/IV CheckMate 511 Trial. Journal of Clinical Oncology 2019 37:11, 867-875. Clinical trial information: NCT03999749.

scholarly journals Efficacy and Safety of Apatinib in Patients with Recurrent or Refractory Melanoma

2020 ◽  
Author(s):  
Shumin Yuan ◽  
Qiang Fu ◽  
Yingkun Ren ◽  
Zhimeng Li ◽  
Huijuan Wang ◽  
...  
Keyword(s):  
Malignant Melanoma ◽  
Response Rate ◽  
Objective Response ◽  
Angiogenesis Inhibitor ◽  
Progression Free Survival ◽  
Metastatic Malignant Melanoma ◽  
Advanced Melanoma ◽  
First Line ◽  
First Line Therapy ◽  
Line Therapy

Abstract Background: Prognosis of patients with metastatic malignant melanoma is very poor and partly due to high resistance to conventional chemotherapies. The study’s objectives were to assess the activity and tolerability of apatinib, an oral small molecule anti-angiogenesis inhibitor, in patients with recurrent advanced melanoma.Methods: This was a single-arm, single-center phase II trial. The primary endpoint was progression-free survival (PFS) and the secondary endpoints were objective response rate (ORR), disease control rate (DCR), and overall survival (OS). Eligible patients received at least one first-line therapy for advanced melanoma and experienced recurrence. Apatinib (500 mg) was orally administered daily. Trail registration: Clinical Trials, ID: NCT03383237. Registered on 24 December 2017. URL of trail registry record: https://register.clinicaltrials.gov. Results: Fifteen patients were included in the analysis. The median PFS was 4.0 months. There were two major objective responses, for a 13.33% response rate. Eleven patients had stable disease, with a DCR of 86.67%.The median OS was 12.0 months. The most common clinically significant grade 3 or 4 toxicities included hypertension and canker sore. No treatment-related deaths occurred.Conclusions: Apatinib showed antitumor activity as a second or first-line therapy in patients with malignant melanoma. The toxicity was manageable.

scholarly journals Efficacy and safety of apatinib in patients with recurrent or refractory melanoma

2020 ◽  
Author(s):  
Shumin Yuan ◽  
Qiang Fu ◽  
Yingkun Ren ◽  
Zhimeng Li ◽  
Huijuan Wang ◽  
...  
Keyword(s):  
Malignant Melanoma ◽  
Response Rate ◽  
Objective Response ◽  
Angiogenesis Inhibitor ◽  
Progression Free Survival ◽  
Metastatic Malignant Melanoma ◽  
Advanced Melanoma ◽  
First Line ◽  
First Line Therapy ◽  
Line Therapy

Abstract Background Prognosis of patients with metastatic malignant melanoma is very poor and partly due to high resistance to conventional chemotherapies. The study’s objectives were to assess the activity and tolerability of apatinib, an oral small molecule anti-angiogenesis inhibitor, in patients with recurrent advanced melanoma. Methods This was a single-arm, single-center phase II trial. The primary endpoint was progression-free survival (PFS) and the secondary endpoints were objective response rate (ORR), disease control rate (DCR), and overall survival (OS). Eligible patients received at least one first-line therapy for advanced melanoma and experienced recurrence. Apatinib (500 mg) was orally administered daily. Trail registration: Clinical Trials, ID: NCT03383237. Registered on 24 December 2017. URL of trail registry record: https://register.clinicaltrials.gov. Results Fifteen patients were included in the analysis. The median PFS was 4.0 months. There were two major objective responses, for a 13.33% response rate. Eleven patients had stable disease, with a DCR of 86.67%.The median OS was 12.0 months. The most common clinically significant grade 3 or 4 toxicities included hypertension and canker sore. No treatment-related deaths occurred. Conclusions Apatinib showed antitumor activity as a second or first-line therapy in patients with malignant melanoma. The toxicity was manageable.

Acute Phase Proteins and Interleukin?6 Serum Levels in Patients with Chronic Arterial Occlusion

2006 ◽  
Vol 762 (1) ◽  
pp. 493-495 ◽  
Author(s):  
WACLAW MAJEWSKI ◽  
RYSZARD STANISZEWSKI ◽  
ARTUR SLUPIANEK ◽  
ALEKSANDER GORNY ◽  
ANDRZEJ MACKIEWICZ
Keyword(s):  
Acute Phase ◽  
Interleukin 6 ◽  
Acute Phase Proteins ◽  
Arterial Occlusion ◽  
Serum Levels ◽  
Chronic Arterial Occlusion

Synergistic action of interleukin-6 and glucocorticoids is mediated by the interleukin-6 response element of the rat alpha 2 macroglobulin gene

1992 ◽  
Vol 12 (5) ◽  
pp. 2282-2294
Author(s):  
G M Hocke ◽  
D Barry ◽  
G H Fey
Keyword(s):  
Dna Binding ◽  
Acute Phase ◽  
Interleukin 6 ◽  
Binding Proteins ◽  
Nuclear Dna ◽  
Acute Phase Proteins ◽  
Dna Binding Proteins ◽  
Human Hepatoma Cells ◽  
Response Element ◽  
Multiple Copies

One class of genes coding for the acute-phase proteins (acute-phase genes) is induced by interleukin 6 (IL-6) through the human transcription factor NF-IL-6 and its rat homolog IL-6-DBP/LAP. A second class, represented by the rat alpha 2 macroglobulin gene, utilizes a different IL-6 response element (IL-6-RE) and different DNA-binding proteins interacting with this element, the so-called IL-6-RE binding proteins (IL-6 RE-BPs). Human Hep3B and HepG2 hepatoma, U266 myeloma, and CESS lymphoblastoid cells contain IL-6 RE-BPs that form complexes, with the IL-6-RE, with gel mobilities indistinguishable from those of the corresponding complexes of rat liver cells. The ability to form these complexes was induced by IL-6 in human hepatoma cells with a maximum reached after 4 h and required ongoing protein synthesis. Multiple copies of an 18-bp element containing the IL-6-RE core were sufficient to confer both induction by IL-6 and a synergistic induction by IL-6 plus glucocorticoids to minimal promoters. The synergism was blocked by the receptor antagonist RU486 and thus was dependent on the glucocorticoid receptor (GR). However, the 18-bp element contained no consensus GR-binding site, and recombinant GR did not bind at this sequence. Therefore, the synergism was probably achieved by an indirect effect of a glucocorticoid-activated intermediate gene on the IL-6 RE-BPs. The rat IL-6 RE-BP had a molecular weight of 102 +/- 10 kDa and was thus distinct from NF-IL-6 and IL-6-DBP/LAP. Therefore, IL-6 must activate two different classes of liver acute-phase genes through at least two different nuclear DNA-binding proteins: NF-IL-6/IL-6-DBP/LAP and the IL-6 RE-BP.

scholarly journals Bacterial enteric pathogens and serum interleukin-6 levels in children with acute diarrhea

2016 ◽  
Vol 56 (3) ◽  
pp. 144
Author(s):  
Herlina Herlina ◽  
Jeanette Irene Manoppo ◽  
Adrian Umboh
Keyword(s):  
Acute Diarrhea ◽  
Interleukin 6 ◽  
Acute Phase Proteins ◽  
Cross Sectional Study ◽  
Enteric Pathogens ◽  
Cross Sectional ◽  
Wide Range ◽  
Bacterial Gastroenteritis ◽  
Stool Samples ◽  
Blood Specimens

Background Acute diarrhea is currently one of the major causes of morbidity and mortality in developing countries. A wide range of enteric pathogens, including bacteria, is responsible for the pathogenesis of acute infectious diarrhea. Recent studies have shown an increase in acute phase proteins, such as serum interleukin-6 (IL-6) levels, in patients with acute bacterial gastroenteritis. Thus, IL-6 may be a useful marker to differentiate bacterial from non-bacterial enteric pathogens.Objective To assess for a correlation between bacterial enteric pathogens and serum IL-6 levels in children with acute diarrhea.Methods We conducted a cross-sectional study from November 2013 to March 2014 in two hospitals in Manado. Subjects were children aged 1-5 years with acute diarrhea and good nutritional status. Subjects’ provided stool samples for bacterial culture and microscopic examination, as well as blood specimens for serum IL-6 measurements. Data was analyzed by linear regression and Pearson’s correlation tests for a correlation between bacterial enteric pathogens and serum IL-6 levels.Results In children with acute diarrhea, those with bacterial enteric pathogens had significantly higher mean serum IL-6 than those with non-bacterial enteric pathogens (r = 0.938; P < 0.001).Conclusion Serum IL-6 levels are significantly more elevated in children with acute diarrhea and bacterial enteric pathogens. Therefore, serum IL-6 may be a useful marker for early identification of bacterial gastroenteritis in children aged 1-5 years. [Paediatr Indones. 2016;56:144-8.].

scholarly journals 548 Phase 2 study of FLX475 in combination with ipilimumab in advanced melanoma

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A578-A578
Author(s):  
Rakesh Goyal ◽  
Nicole Nasrah ◽  
Dan Johnson ◽  
William Ho
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
Antitumor Activity ◽  
Regulatory T Cells ◽  
Response Rate ◽  
Advanced Melanoma ◽  
Phase 2 ◽  
Car T Cells ◽  
Phase 2 Study ◽  
Car T

BackgroundRegulatory T cells (Treg) can dampen antitumor immune responses in the tumor microenvironment (TME) and have been shown to correlate with poor clinical outcome. Translational studies have demonstrated an accumulation of Treg in tumors after treatment with immunotherapies including CAR-T cells and anti-CTLA-4, which could potentially reflect a mechanism of adaptive immune resistance.1–2 CCR4, the receptor for the chemokines CCL17 and CCL22, is the predominant chemokine receptor on human Treg and is responsible for the migration and accumulation of Treg in the TME. Preclinical studies with orally available CCR4 antagonists have demonstrated potent inhibition of Treg migration into tumors, an increase in the intratumoral Teff/Treg ratio, and antitumor efficacy as a single agent and in combination with checkpoint inhibitors, including anti-CTLA-4.3 In a first-in-human trial conducted in healthy volunteers, the oral CCR4 antagonist FLX475 was demonstrated to be well tolerated with outstanding pharmacokinetic and pharmacodynamic properties.4 An ongoing Phase 1/2 clinical trial of FLX475 is examining the safety and preliminary antitumor activity of FLX475 as monotherapy and in combination with pembrolizumab in subjects with several types of advanced cancer.5 Given the preclinical data demonstrating a significant enhancement of the antitumor activity of anti-CTLA-4 when combined with FLX475, a Phase 2 study investigating the combination of FLX475 and ipilimumab is now being conducted in subjects with advanced melanoma.MethodsThis clinical trial is a Phase 2, multicenter, open-label, single-arm study to determine the antitumor activity of FLX475 in combination with ipilimumab in subjects with advanced melanoma previously treated with an anti-PD-1 or anti-PD-L1 agent. The primary objectives of the study are to evaluate objective response rate, and the safety and tolerability of this combination. The study will first examine the safety of the combination of the 100 mg PO QD recommended Phase 2 dose of FLX475 and the approved 3 mg/kg IV Q3W dose of ipilimumab as part of a safety run-in phase, prior to examining the degree of antitumor activity in approximately 20 subjects. Evidence of an overall response rate (ORR) notably greater than the expected ORR of ipilimumab monotherapy alone in such subjects, which has been shown to be approximately 14%,6 would provide preliminary clinical evidence in support of the clinical hypothesis that CCR4 blockade by FLX475 can significantly enhance the antitumor activity of an anti-CTLA-4 checkpoint inhibitor.Trial RegistrationClinicalTrials.gov Identifier: NCT04894994ReferencesO’Rourke D, Nasrallah M, Desai A, Melenhorst J, Mansfield K, Morrissette J, Martinez-Lage M, Brem S, Maloney E, Shen A, Isaacs R, Mohan S, Plesa G, Lacey S, Navenot J, Zheng Z, Levine B, Okada H, June C, Brogdon J, Maus M. A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma. Sci Transl Med 2017;9:eaaa0984. doi: 10.1126/scitranslmed.aaa0984.Sharma A, Subudhi S, Blando J, Vence L, Wargo J, Allison JP, Ribas A, Sharma P. Anti-CTLA-4 immunotherapy does not deplete FOXP3+ regulatory T cells (Tregs) in human cancers-Response. Clin Cancer Res 2019;25:1233–1238.Marshall L, Marubayashi S, Jorapur A, Jacobson S, Zibinsky M, Robles O, Hu D, Jackson J, Pookot D, Sanchez J, Brovarney M, Wadsworth A, Chian D, Wustrow D, Kassner P, Cutler G, Wong B, Brockstedt D, Talay O. Tumors establish resistance to immunotherapy by regulating Treg recruitment via CCR4. J Immunother Cancer 2020;8:e000764.van Marle S, van Hoogdalem E, Johnson D, Okal A, Kassner P, Wustrow D, Ho W, Smith S. Pharmacokinetics, pharmacodynamics, and safety of FLX475, an orally-available, potent, and selective small-molecule antagonist of CCR4, in healthy volunteers. J Immunother Cancer 2018; 6(Suppl 1):P484(SITC 2018).Powderly J, Chmielowski B, Brahmer J, Piha-Paul S, Bowyer S, LoRusso P, Catenacci D, Wu C, Barve M, Chisamore M, Nasrah N, Johnson D, Ho W. Phase I/II dose-escalation and expansion study of FLX475 alone and in combination with pembrolizumab in advanced cancer. Journal of Clinical Oncology 2020;38(15_suppl): TPS3163 (ASCO 2020).Long G, Mortier L, Schachter J, Middleton M, Neyns B, Sznol M, Zhou H, Ebbinghaus S, Ibrahim N, Arance A, Ribas A, Blank C and Robert C. Society for Melanoma Research 2016 Congress. Pigment Cell & Melanoma Research 2017;30:76–156.Ethics ApprovalThis study has been approved by the Institutional Review Board at each investigational site.

scholarly journals Phase Ib/II Study of Pembrolizumab and Pegylated-Interferon Alfa-2b in Advanced Melanoma

2018 ◽  
Vol 36 (35) ◽  
pp. 3450-3458 ◽  
Author(s):  
Diwakar Davar ◽  
Hong Wang ◽  
Joe-Marc Chauvin ◽  
Ornella Pagliano ◽  
Julien J. Fourcade ◽  
...  
Keyword(s):  
Overall Survival ◽  
Objective Response Rate ◽  
Response Rate ◽  
Objective Response ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Pegylated Interferon ◽  
Gene Signature ◽  
Advanced Melanoma ◽  
Phase Ib

Purpose Objective responses are reported in 34% to 37% of patients with programmed death-1 (PD-1)–naïve advanced melanoma treated with PD-1 inhibitors. Pre-existing CD8+ T-cell infiltrate and interferon (IFN) gene signature correlate with response to PD-1 blockade. Here, we report a phase Ib/II study of pembrolizumab/pegylated (PEG)-IFN combination in PD-1–naïve advanced melanoma. Patients and Methods PEG-IFN (1, 2, and 3 μg/kg per week) was dose escalated using a modified toxicity probability interval design in three cohorts of four patients each, whereas pembrolizumab was dosed at 2 mg/kg every 3 weeks in the phase Ib portion. Thirty-one patients were enrolled in the phase II portion. Primary objectives were safety and incidence of dose-limiting toxicities. Secondary objectives included objective response rate, progression-free survival (PFS), and overall survival. Results Forty-three patients with stage IV melanoma were enrolled in the phase Ib and II portions of the study and included in the analysis. At the data cutoff date (December 31, 2017), median follow-up duration was 25 months (range, 1 to 38 months). All 43 patients experienced at least one adverse event; grade 3/4 treatment-related adverse events occurred in 21 of 43 patients (48.8%). Objective responses were seen at all three dose levels among 43 evaluable patients. The objective response rate was 60.5%, with 46.5% of patients exhibiting ongoing response. Median PFS was 11.0 months in all patients and unreached in responders, whereas median overall survival remained unreached in all patients. The 2-year PFS rate was 46%. Conclusion Pembrolizumab/PEG-IFN demonstrated an acceptable toxicity profile with promising evidence of clinical efficacy in PD-1–naïve metastatic melanoma. These results support the rationale to further investigate this pembrolizumab/PEG-IFN combination in this disease.

Management of refractory myeloma: a review.

1988 ◽  
Vol 6 (5) ◽  
pp. 889-905 ◽  
Author(s):  
A C Buzaid ◽  
B G Durie
Keyword(s):  
Protein Concentration ◽  
Response Rate ◽  
Clinical Problem ◽  
Initial Therapy ◽  
M Protein ◽  
Treatment Modalities ◽  
High Dose ◽  
First Line ◽  
First Line Therapy ◽  
New Treatment

Management of refractory myeloma represents a common and challenging clinical problem. Approximately 30% to 50% of patients with multiple myeloma do not respond to first-line therapy, and those who initially achieve a remission will eventually relapse. Surprisingly, there is no routinely accepted approach to patients with refractory disease. Therefore, we review the literature in an attempt to provide an overview of the published results and outline our treatment recommendations for such patients. We suggest the following: (1) for truly resistant patients (ie, those who clearly progress with initial therapy), administration of high-dose or pulsed glucocorticosteroids is the best treatment, with an expected response of 40% (defined as a greater than or equal to 50% reduction in monoclonal [M]-protein concentration); (2) for patients who relapse during therapy or relapse within 6 months of stopping the initial treatment, the VAD regimen (vincristine, doxorubicin, and dexamethasone) is one of the most effective salvage therapies, resulting in an approximately 75% response rate (greater than or equal to 50% reduction in M-protein concentration); (3) for patients who relapse within more than 6 months of stopping therapy (unmaintained remission), reinitiation of the initial therapy represents an excellent alternative, leading to recontrol in 60% to 70% of patients (greater than or equal to 50% reduction in M-protein concentration). If progression is observed or if there is response and then relapse in this setting, VAD chemotherapy can be administered again. (4) Patients who fail second-line salvage therapies should enter well-designed clinical trials to evaluate new treatment modalities. If this is not feasible, alpha-interferon or "systemic" radiotherapy are recommended in selected cases.

Sign in / Sign up

Export Citation Format

Share Document