VEGF serum levels during bevacizumab plus paclitaxel combination in metastatic melanoma

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 8534-8534 ◽  
Author(s):  
S. Viteri ◽  
A. Diaz-Lagares ◽  
A. González ◽  
S. Martin Algarra ◽  
P. Redondo ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Serum Levels ◽  
Median Number ◽  
Hematological Toxicity ◽  
The Novel ◽  
Response Evaluation ◽  
Previously Treated ◽  
Melanoma Patients ◽  
Pre Treatment ◽  
One Year

8534 Background: Angiogenesis has an important role in melanoma progression. A prognostic value has been suggested for serum VEGF in melanoma. The novel agent bevacizumab (Bev) has demonstrated in combination with chemotherapy high activity in other tumors. We studied the combination of weekly paclitaxel (TXL) and bevacizumab (Bev) in previously treated metastatic melanoma patients (pts) and analyzed serum VEGF levels before and during treatment. Methods: TXL 70 mg/m2 weekly and Bev 10 mg/kg biweekly during 5 consecutive weeks every six weeks. VEGF levels pre-treatment and at response evaluation were analyzed with enzyme-linked immunoassays. Results: 13 pts have been treated: male/female: 4/9, median age: 45 (29–71), median PS ECOG: 2 (0–3), stage distribution M1b/ M1c: 2/11, high LDH levels: 8 pts. Median number of previous lines: 3 (1–6). Hematological toxicity: G III lymphopenia in 6 pts, G III leucopenia in 2 pts, G III thrombocytopenia in 1 pt and G I anemia in 3 pts. Non-hematological toxicities: alopecia in 7 pts, diarrhea G I in 4 pts, epistaxis G I in 8 pts. Response (and time to progression, months [m]): 2/12 PR (6 m and 4 m), 1/12 MR (6 m), 7/12 SD (7+ m, 7 m, 4 m, 4+ m, 3 m, 3 m, 3+ m), 2/12 PD. Responses were seen in soft tissue, lung and brain metastases. Overall survival at 12 months was 43.3%. Pre-treatment serum levels were high in five patients and they became negative at response evaluation (1 pt achieved MR, 3 pts SD and 1 pt PD). Unexpectedly patients with high pre-treatment VEGF levels had long survival: 4/5 patients remain alive and 2 pts have survived over one year: 12+ m, 12+ m, 5 m, 3+ m, 3.5+ m.VEGF was undetectable pre-treatment and at response evaluation in 7 pts, only 2/7 pts remained alive: 15+ m, 8 m, 7.5 m, 7 m, 6.8+ m, 3 m, 2.6 m. Conclusions: The combination of Bev and weekly TXL is active in melanoma and it has a good tolerance profile. Serum VEGF could be a good marker in this setting. Further research is needed to confirm these results. No significant financial relationships to disclose.

Vitiligo-Specific Soluble Biomarkers as Early Indicators of Response to Immune Checkpoint Inhibitors in Metastatic Melanoma Patients

2021 ◽  
Author(s):  
Maria Luigia Carbone ◽  
Gabriele Madonna ◽  
Marianna Bove ◽  
Simona Mastroeni ◽  
Lauretta Levati ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Checkpoint Inhibitors ◽  
Serum Levels ◽  
Response To Treatment ◽  
Number Of Patients ◽  
Treatment Characteristic ◽  
Favorable Prognostic Factor ◽  
Melanoma Patients ◽  
Pre Treatment ◽  
Early Indicators

Abstract Background: Immunotherapy with checkpoint inhibitors strongly improved the outcome of metastatic melanoma patients. However, not all the patients respond to treatment and identification of prognostic biomarkers able to select patients who would respond to this therapy is of outmost importance. Considering that development of vitiligo-like depigmentation in melanoma patients represents both an adverse event of immunotherapy and a favorable prognostic factor for overall survival, we analyzed known soluble biomarkers of vitiligo to validate them as early indicators of response to checkpoint inhibitors in metastatic melanoma.Methods: Fifty-seven patients with metastatic melanoma receiving anti-PD-1 checkpoint inhibitor immunotherapy were enrolled. Patient sera and plasma were evaluated for vitiligo biomarkers at pre-treatment and after 1 and 3 months of therapy. Patients were divided and analyzed according to the best overall response to treatment. Characteristic vitiligo proteins were analyzed by ELISA, while expression of circulating microRNAs, distinctive of vitiligo, was determined using real-time RT-PCR.Results: Basal serum CD25 levels were higher in stable and responder melanoma patients and remained higher during the first 3 months of anti-PD-1 therapy compared to non-responder patients. The chemokine CXCL9 was absent in non-responder patients before therapy beginning. Moreover, an increase of CXCL9 levels was observed at 1 and 3 months of therapy for all patients, although higher CXCL9 amounts were present in stable and responder compared to non-responder patients. Finally, higher levels of miR-19b, miR-25 and miR-16 were observed after 1 month of therapy in plasma of stable and responder compared to non-responder patients.Conclusions: Serum levels of CD25 and CXCL9 before and during the first months of treatment could represent biomarkers of response to anti-PD-1 immunotherapy in metastatic melanoma patients. Plasmatic miR-19b, miR-25 and miR-16 could also represent possible early biomarkers of response to anti-PD-1 treatment, but they must be validated in a higher number of patients.

scholarly journals Updated efficacy and toxicity of treatment with the anti-CTLA-4 antibody ipilimumab in metastatic melanoma patients previously treated with anti-PD-1 therapy

2015 ◽  
Vol 3 (Suppl 2) ◽  
pp. P126 ◽  
Author(s):  
Prashanth Prithviraj ◽  
Grant McArthur ◽  
Victoria Atkinson ◽  
Phillip Parente ◽  
Miles Andrews ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Previously Treated ◽  
Melanoma Patients

Phase III study of gemcitabine plus vinorelbine (VG) versus vinorelbine (V) in patients (pts) with metastatic breast cancer (MBC) previously treated with anthracyclines (A) and taxanes (T). Final results of GEICAM 2000–04 study

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 575-575
Author(s):  
M. Muñoz ◽  
M. Martín ◽  
A. Ruiz ◽  
A. Balil ◽  
J. García-Mata ◽  
...  
Keyword(s):  
Objective Response ◽  
Metastatic Breast ◽  
Progression Free Survival ◽  
Median Number ◽  
Primary Objective ◽  
Phase Iii ◽  
Hematological Toxicity ◽  
Hematologic Toxicity ◽  
Previously Treated ◽  
Visceral Disease

575 Background: VG has shown to be efficacious and safe in MBC in pts previously treated with AT. This study compared treatment (TT) V with the combination of VG. Primary objective was progression free survival (PFS). Methods: pts previously treated with AT, aged ≥18, ECOG ≤ 2, were randomized to V: 30 mg/m2 day (d) 1, d8, or VG 30/1200 mg/m2 d1, d8, both every 21 days until disease progression. Stratification criteria were previous lines of TT for MBC (0 vs.1 vs.2) and visceral disease (yes vs. no). 126 pts per arm were needed to demonstrate a prolongation in PFS of 2 months (m) (from 3 to 5; HR = 1.67; α and β errors 0.05 and 10). Results: 252 pts (127 V and 125 VG) were recruited between 2001 and 2005. Arms were well balanced: median age was 57 years; median number of metastatic sites 2; visceral disease was present in 75% of pts; 17%, 53% and 29% of pts received study TT as first, second and third line respectively. Median number of cycles were 4 (1–21) in V and 6 (1–26) in VG. Median PFS was 6.3 m (95% CI, 5.3–7.3) for VG and 4.1 m (95% CI, 3.3–4.9) for V (p=0.0011). Objective response rate was 37% (CI 95% 29–46) for VG and 25% (CI 95%: 17–33) for V (p= 0.035). CTC grade 3–4 hematologic toxicity was significantly higher with VG vs. V (65% vs. 43% neutropenia, 33% vs. 17% leucopenia, and 11% vs. 2% thrombocytopenia); febrile neutropenia was present in 10.5% of pts on VG and 6% of pts in V (p=ns). Non-hematological toxicity was low and manageable in both arms. Conclusions: VG demonstrated significant efficacy advantages over V in pts with MBC previously treated with AT, with manageable toxicity. This favorable risk-benefit profile supports the use of this combination in this patient population. [Table: see text]

IL-12p40 and MIP3a to predict clinical responses to anti-PD-1 therapy in patients with metastatic melanoma.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 9535-9535
Author(s):  
Jesus Vera Aguilera ◽  
Courtney L. Erskine ◽  
Vera J. Suman ◽  
Jonas Paludo ◽  
Robert R. McWilliams ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Rank Correlation ◽  
Correlation Coefficients ◽  
Serum Levels ◽  
Preclinical Model ◽  
Meso Scale Discovery ◽  
Baseline Serum ◽  
Serum Cytokines ◽  
Pre Treatment ◽  
Pretreatment Serum

9535 Background: A broad understanding of baseline immunity is needed in order to predict responses to PD-1 blockade. We previously reported in a preclinical model that elevated Th1 signature cytokines are present after successful therapy with PD-1 blockade. In this study we evaluated serum cytokines as biomarkers of response in a cohort of patients with metastatic melanoma undergoing anti-PD1 therapy. Methods: 27 pts diagnosed with metastatic melanoma (MM) received anti-PD-1 therapy and had peripheral blood collected prior to anti-PD-1 therapy start and 12 weeks after; 55 proinflammatory-related serum cytokines were analyzed at both times using the Meso Scale Discovery (MSD) assay. At week 12, we identified 15 pts who had radiographic complete or partial response (TR) and 12 had progressive disease (PD) using RECIST criteria. Spearman rank correlation coefficients (rho) were used to assess association between pre-treatment serum cytokine levels. For each cytokine, differences in pretreatment serum levels and the ratio of the 12 week to pre-treatment serum levels between TR and PD groups were assessed using Wilcoxon rank sum tests. Results: Pretreatment serum IL-12p40 and MIP3a (CCL20) were moderately correlated (rho=0.3944). Pretreatment IL-12p40 and was found to be significantly higher (p=0.0025) in the TR group (median=48.5; 25th to 75th percentile [IQR]:25.3-63.8) relative to the PD group (median=17.3; IQR: 8.6-30.3). Pretreatment MIP3a was also found to be significantly higher (p=0.0359) in the TR group (median=1.72; IQR: 1.41-2.65) relative to the PD group (median=1.33; IQR: 1.09-1.98). The 12th week pretreatment IL-12p40 ratio (median=1.98; IQR: 1.4-11.3) in the TR group was greater than that (median=0.64; IQR: 0.23-1.61) in the PD group (p=0.0029); we identified that baseline serum levels >15pg/ml of IL12p40 prior to immunotherapy were associated with significantly prolonged event free survival (p=0.001). Conclusions: Measurements of IL-12p40 and MIP-3a levels before immunotherapy may help to select patients who are likely to benefit from anti-PD1 therapy. Additionally, exploration of combination therapies that increase IL-12P40 and MIP3 prior or during immunotherapy should be undertaken.

Clinical value of noninvasive biomarkers reflecting a collagen-rich stroma in metastatic melanoma patients treated with anti-PD1 therapy.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3049-3049
Author(s):  
Christina Jensen ◽  
Daan Hurkmans ◽  
Stijn L.W. Koolen ◽  
Morten A. Karsdal ◽  
Ron H.J. Mathijssen ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Poor Response ◽  
Cross Linking ◽  
Survival Outcomes ◽  
Type Iii Collagen ◽  
Collagen Formation ◽  
Type Iii ◽  
Checkpoint Inhibitor Therapy ◽  
Melanoma Patients ◽  
Pre Treatment

3049 Background: Poor response to anti-PD1/PD-L1 remains a clinical challenge in a subgroup of patients with metastatic melanoma. Recent evidence strongly suggests that these poor responses are associated with TGF-β signaling and CD8+ T-cell excluded tumors characterized by a collagen-rich peritumoral stroma that blocks the interaction between T cells and tumor cells. In the pursuit of identifying non-invasive biomarkers associated with a T-cell excluded phenotype and predict resistance/response to immune checkpoint inhibitor therapy, we evaluated the association between blood-based biomarkers measuring type III collagen formation and cross-linking and survival outcomes in metastatic melanoma patients treated with anti-PD1 therapy. Methods: 107 patients with metastatic melanoma who started anti-PD1 monotherapy between May 2016 – March 2019 entered in a prospective real-life study (nivolumab n = 62, pembrolizumab n = 45). Type III collagen formation (PRO-C3) and type III collagen formation and cross-linking (PC3X) were measured with ELISAs in pre-treatment serum. Biomarker levels were associated to Disease Control Rate (according to RECIST v.1.1) by Mann-Whitney test and correlated to survival outcomes by Kaplan-Meier and Cox regression analyses. Results: PRO-C3 was significantly elevated in patients with progressive disease compared to the combined group of patients with complete response, partial response and stable disease (p = 0.046). High PRO-C3 and PC3X ( > 75th percentile) prior to treatment were significantly associated with poor overall survival (PRO-C3: HR = 2.4, p = 0.008; PC3X: HR = 2.2, p = 0.019) and progression free survival (PRO-C3: HR = 1.91, p = 0.016; PC3X: HR = 1.94, p = 0.013). The median overall survival was 417 and 511 days in biomarker high patients compared to 1269 and 1269 days in biomarker low patients, for PRO-C3 and PC3X, respectively. Conclusions: Biomarkers quantified in a pre-treatment liquid biopsy reflecting excessive collagen formation and cross-linking were associated with poor response and survival outcomes in metastatic melanoma patients treated with anti-PD1 therapy. This supports an association between collagen formation and resistance to anti-PD1 therapy. Furthermore, if validated, these non-invasive collagen biomarkers may have potential for guiding patient stratification for immune checkpoint inhibitor therapy and combination therapies. Clinical trial information: NTR7015 .

Preliminary Report from an Exploratory Phase II Trial with Plitidepsin (Aplidin®) in Patients with Refractory/Relapsed Multiple Myeloma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2569-2569 ◽  
Author(s):  
M. V. Mateos ◽  
J. Blade ◽  
F. Prosper ◽  
J. J. Lahuerta ◽  
R. Garcia-Sanz ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase Ii ◽  
Proteasome Inhibitors ◽  
Median Number ◽  
Hematological Toxicity ◽  
Second Stage ◽  
Liver Transaminases ◽  
Previously Treated ◽  
Grade 3 ◽  
Number Of Cycles

Abstract Introduction and objectives : Plitidepsin is a cyclic depsipeptide originally isolated from the marine tunicate, Aplidium albicans. It appears very potent against multiple myeloma (MM) cells. Specifically, it was observed that it was active against a broad panel of 35 human MM cell lines, which included MM cells resistant to conventional anti-MM agents and novel agents (i.e. thalidomide, bortezomib). Plitidepsin also induced cell death in primary MM tumor cells freshly isolated from patients resistant to thalidomide or its analogs and/or proteasome inhibitors. Phase I has been completed exploring 4 different schedules of administration. Muscle and liver (transaminases and/or alkaline phosphatase) toxicities were the main DLTs. Hematological toxicity was not observed at the recommended dose. The aim of this trial was to explore the activity of plitidepsin in patients with previously treated refractory/relapsed MM. Material and Methods: This is a non-randomized two-stage Phase II, multicenter, clinical and pharmacokinetic trial, with Aplidin® (APLD) 5 mg/m2 as a 3 h intravenous infusion every 2 weeks, with antiemetic and antihistaminic prophylaxis. In the first stage 16 patients evaluable for efficacy were included. At least one response was requested in order to proceed with the second stage, in which a total of 37 patients will be included. Results: Between June’04 and June’05, 19 patients have been enrolled and data are available for 18 patient (7 men and 11 women, median age was 65.7y, range 48–82). Patients were previously relapsed/refractory. Prior treatments included: stem cell transplantation 64.7%, thalidomide 35.28% and bortezomib 17.64%. The median previous chemotherapy lines received were 3, range 1–6. The APLD median number of cycles received 4, range 1–16. Thirteen patients are currently evaluable for efficacy. One patient (7.7%) achieved a partial response (PR) with a 70% reduction in M-component lasting 8 months. Stable disease lasting between 3–5 months was observed in 3 patients (23.0%). In 2 patients (15.38%) a stabilization lasting 2.5 months was stated and the remaining 7 patients (53.8%) progressed. NCI-CTC grade 3–4 related toxicities were reported for n=17 patients and were mainly fatigue in 2 patients (11.8%), myalgia in 1 patient (5.9%), elevation of CPK in 1 patient (5.9%) and transient transaminases increase in 9 patients (52.9%). Significant hematological toxicity did not occurred in spite of 2 patients included and treated with thrombopenia grade 3–4 and 2 patient with neutropenia grade 3. Conclusions: First stage data shows that APLD presents hints of activity in patients with refractory/relapsed MM, with acceptable toxicity profile, thus meeting the criteria for proceeding to second stage recruitment. The absence of significant hematological toxicity is a well known feature of this drug and is being confirmed in this trial.

Serial Serum Cytokine Measurement in a Patient with Systemic Scleromyxedema.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 5100-5100
Author(s):  
Timothy Devos ◽  
Wouter Meersseman ◽  
Benedicte Dubois ◽  
Jozef Goebels ◽  
Gregor Verhoef ◽  
...  
Keyword(s):  
Plasma Cells ◽  
Serum Levels ◽  
Skin Lesions ◽  
Pulse Therapy ◽  
High Dose ◽  
Serum Samples ◽  
Hematopoietic Stem ◽  
Pre Treatment ◽  
One Year ◽  
High Dose Melphalan

Abstract Systemic scleromyxedema (SSME) is a generalized and rare variant of lichen myxedematosus and is characterized by cutaneous papular mucinous deposits and extracutaneous manifestations. In 80% of the cases, SSME is associated with a monoclonal gammopathy and in approximately 10% with multiple myeloma. Pulmonary, gastrointestinal, rheumatologic and severe neurologic complications have been described. Clonal plasma cells are thought to stimulate excessive fibroblast proliferation resulting in the clinical presentation of this disorder, but little is known about the cytokine-mediated crosstalk between the monoclonal plasma cells and fibroblasts. For that purpose, we have sequentially measured the serum levels of the cytokines VEGF, FGF-b, TGF-b1 and IL-6 in a 39-year old male patient diagnosed with SSME and an IgG kappa paraprotein. The patient presented with repeated generalized epileptic insults, cognitive impairment, and progressively developed thickened skin furrows at the level of the glabella. The diagnosis of SSME was histologically proven. A transient neurologic improvement was seen after plasmapheresis and dexamethason pulse therapy and stem cells were subsequently mobilized with the CAD regimen (cyclophosphamide, adriamycin, dexamethason) and readministered after high dose melphalan. The neutropenic phase was complicated by sepsis and progressive neurological deterioration, after which the decision was taken to start with thalidomide at the dose of 200 mg/d. The patient gradually improved and one year later his cognitive function has normalized and the skin lesions have disappeared. A small M-spike remains visible on serum electrophoresis. Levels of VEGF, FGF-b, TGF-b1 and IL-6 were quantified by ELISA on platelet-poor serum and were measured at diagnosis and at six and twelve months after transplantation. Compared to the high pre-treatment levels of all four cytokines, a decrease was observed during the months after transplantation and at six months. Table 1: serum levels of VEGF, b-FGF, TGF-b1 and IL-6 in a patient with SSME before ASCT 6 months after ASCT one year after ASCT value = mean of 5 serum samples +/− SD VEGF (pg/ml) 227,87 (+/−33,3) 110,81 (+/−24,8) 189,61 (+/−13,5) b-FGF (ng/ml) 17,77 (+/−0,32) 1,93 (+/−0,29) 1,64 (+/−0,37) TGF-b1 (ng/ml) 37,94 (+/−1,21) 20,45 (+/−0,85) 18,95 (+/−0,49) IL-6 (pg/ml) 92,82 (+/−3,2) 33,2 (+/−5,3) 32,0 (+/−4,5) One year after administration of high-dose melphalan and autologous hematopoietic stem cell transplantation (ASCT), the serum levels of FGF-b, TGF-b1 and IL-6 remain low. Remarkably, since the dose of thalidomide has been tapered because of persistent ulnar neuropathy, the serum concentration of VEGF is increasing but not reaching the pre-transplant levels. We conclude from this report that serum levels of VEGF, FGF-b, TGF-b and IL-6 follow the clinical evolution in this patient with SSME, suggesting a role for these cytokines in the pathogenesis of SSME.

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