bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of a functional polymorphism in the IL12B promoter region on survival in patients with malignant melanoma
Authors: Schadendorf D. , Ugurel S. , Paschen A. , Kern K. , Hill B. , Morahan G. , Müller-Berghaus J. 
Published: April 2020

8001 Background: Interleukin-12 (IL-12), a heterodimeric cytokine, is important in the generation of a Th1-biased immune response. Several polymorphisms have been described in IL12B, the gene encoding the p40 subunit of IL-12. A bi-allelic polymorphism within the IL12B promoter region has been reported to show association with diseases as diverse as severe childhood asthma and fatal cerebral malaria. Methods: In order to define the molecular basis for these disease associations we investigated the secretion of IL-12 by human monocyte-derived dendritic cells. The amount of IL-12p40 and p70 produced by DCs from normal blood donors was determined following CD40L activation. Subsequently, we therefore sought to investigate the frequency of IL12B genotypes and their impact on the outcome of patients with malignant melanoma. Genomic DNA was isolated from 75 normal blood donors and 80 melanoma cell lines and used for genotyping the IL12B polymorphism. Corresponding clinical data were retrieved from the in-house melanoma database. Results: Allele frequency for IL12Bpro-1 is 0.45 and for IL12Bpro-2 0.55. Homozygotes for the IL12B promoter polymorphism showed a 10-fold difference in median p70 secretion in response to CD40 ligation. Remarkably, this difference resulted from the inability of most allele 1 homozygotes to secrete heterodimeric IL-12. In contrast, most of the donors homozygous for allele 2 had detectable secretion. Distribution of genotypes in melanoma patients was not significantly different from normal blood donors. Kaplan-Meier survival analysis showed significantly decreased survival of patients homozygous for the longer allele, previously defined as being associated with decreased IL-12 secretion (log-rank p=0.015). Subgroup analysis indicated that this survival advantage was seen exclusively in female patients. Conclusions: The recently described IL12B promoter polymorphism is highly correlated with secretion of bioactive IL-12 and has a significant impact on the clinical course of disease in patients with melanoma and may therefore be useful for prognostic stratification. No significant financial relationships to disclose.
Phase II study of volociximab (M200), an α5β1 anti-integrin antibody in metastatic melanoma
Authors: Cranmer L. D. , Bedikian A. Y. , Ribas A. , O’Day S. , Forero-Torres A. , Yazji S. , Kirkwood J. M. 
Published: April 2020

8011 Background: Integrin α5β1 has been reported to be unregulated in metastatic melanoma and in tumor angiogenesis. A critical survival step in angiogenesis is the ligation of fibronectin in the extracellular matrix to α5β1 on endothelial cells. M200 is an IgG4 chimeric monoclonal antibody targeting α5β1, inducing apoptosis of proliferating endothelial cells. M200 activity is independent of growth factor stimulus, suggesting that binding of fibronectin to α5β1 occurs downstream of growth factor signalling, and is possibly a final common pathway for the development of neovasculature. Methods: This is a multicenter, open label, single cohort, pilot phase II study of 40 patients (pts) in metastatic melanoma. Pts received M200 10 mg/kg IV every 2 weeks with DTIC 1g/m2 monthly until disease progression. Pts were evaluated for efficacy every 8 weeks by objective response using RECIST criteria. Additional evaluations included pharmacokinetics and immunogenicity profile. An independent data safety monitoring board was utilized to review safety data. Results: A total of 40 pts have been enrolled to date. All pts were evaluable for safety and 30 pts for objective response using ITT population. Median age was 58.8 years, with 26 (65%) male. ECOG score was 0–1 in 37 (92%) pts. Up to 14 doses of M200 (median 4 doses) and 7 doses of DTIC (median 2) have currently been administered, with dosing continuing. Thirty-one (77.5%) pts have had at least 1 AE with 8 (20%) pts at least 1 SAE. The most frequent adverse events for M200 were nausea 17.5%, constipation 10% and vomiting 10% and for DTIC were nausea 35%, vomiting 20% and pyrexia 15%. Fifteen SAE’s with 2 possibly related to M200 including hypertension and deep vein thrombosis. Four pts died in the study, all with progressive disease (PD). Best overall response at 8 weeks was stable disease (SD) in 16/30 pts and PD in 14/30 pts. Median time to progression was 72 days. Conclusions: M200 appears to be well tolerated at 10 mg/kg Q2W in combination with DTIC. [Table: see text]
Phase I trial of lomeguatrib (PN) combined with dacarbazine (DTIC) for treatment of patients with melanoma and other solid tumors: Initial results
Authors: Tawbi H. , Tarhini A. , Moschos S. , Sulecki M. , Viverette F. , Radkowski R. , Shipe-Spotloe J. , Kunkel C. , Rae M. , Kirkwood J. 
Published: April 2020

8016 Background: TheDNA repair enzyme O6-Alkylguanine Alkyltransferase (AGT) directly reverses the O6-methylguanine (O6-MeG) base lesion induced by treatment with DTIC. Depletion of AGT using O6-MeG analogs enhances the cytotoxicity of DTIC in preclinical models and in early phase trials of O6-Benzylguanine. Lomeguatrib (Patrin, PN) is an orally bioavailable highly potent O6-MeG analog that is well tolerated as a single agent. We report the first phase I experience of PN combined with DTIC in patients who have failed prior systemic therapy. Methods: This open-label phase I study was performed to determine the toxicity profile and maximum tolerated dose (MTD) of PN given orally for 5 or 10 days (d) combined with a single dose of DTIC administered IV on d 2, repeated on a 21 d schedule. Of 30 pts enrolled 25 (83%) had metastatic melanoma, and all had ECOG PS ≤2. Dose escalation started at 40 mg of PN once daily for 5 d and 500 mg/m2 of DTIC. 6 pts failed prior chemotherapy, 16 failed prior immunotherapy, and 3 failed both. 5 pts had no prior systemic therapy. Results: Adverse events observed in more than 50% of pts included gr 1–2 nausea and vomiting and gr 1–2 fatigue. Hematologic toxicity was prominent with gr 3–4 neutropenia (13/30, 43%) and gr 3–4 thrombocytopenia (4/30, 13%) even at doses of DTIC 50% of usual clinical doses. Prolonged neutropenia accounted for all dose-limiting toxicities (DLT) observed so far. The MTD has not been reached, however hematologic toxicities requiring dose modifications of DTIC have been frequent (42% of all cycles administered). 16 pts (53%) had stable disease as their best response with a median time to progression of 53 days (95% C.I. 40–86 days). Conclusions: Oral administration of PN substantially alters the toxicity and tolerance of DTIC inducing prolonged hematologic toxicity at doses <50% of doses in routine usage. The study is ongoing to determine the MTD of PN combined with DTIC after which a phase II trial will be completed in pts who have not had prior chemotherapy. Pending completion of accrual (total of 40 pts by May 2006) the recommended phase II dosage appears to be PN 40 mg orally BID for 10 days combined with 400 mg/m2 of DTIC. [Table: see text]
Prognostic significance of children with cutaneous melanoma: Implications for treatment
Authors: Kavanagh M. A. , Essner R. , Chen S. L. , Wanek L. A. , Scheri R. P. , Morton D. L. 
Published: April 2020

8021 Background: The incidence of melanoma in pediatric patients, particularly teenagers, is increasing. Treatment strategies employed for adult patients with melanoma have been applied to pediatric populations with minimal data to support similar efficacy. We performed a matched-paired analysis to compare the prognosis of pediatric (≤19 yrs old) and adult melanoma patients. Methods: Single institution, prospectively obtained melanoma database containing >14,000 records was queried for children ages 1–19 years treated for cutaneous melanoma. We identified 197 pediatric patients seen at our institute over the last 35 years. After excluding patients not seen within 4 months of initial diagnosis, 115 pediatric patients were matched to adults (age 20–70 years) chosen from the database by gender, stage, primary site and tumor characteristics (Clark level, Breslow thickness, and ulceration). Overall survival was compared between cohorts by the Kaplan-Meier method. Results: For the pediatric patients, median age at diagnosis was 17.7 years (range 7–19 years). Patients were almost equally distributed between girls (47%) and boys. AJCC stage I and II disease at presentation was most common (73%), with stage III and IV occurring much less frequently (25% and 2%). Most pediatric patients had Clark level IV (37%) lesions; Clark level II (25%), III (25%), V (4%), and I (2%) lesions were less common. Breslow thickness ranged between <1.0mm (38%), 1.1–2.0mm (20%), 2.1–4.0mm (17%), and >4.1mm (12%). The two predominant histologic types were superficial spreading (52%) and nodular (22%) melanoma. 14% of the primary lesions were ulcerated. Rates of disease-free and overall survival were 75%± 4% and 84%± 4% at 5 years and 74%± 4% and 77%± 5% at 10 years, respectively, with a median follow up of 5.1 years (range 1–30 years). Matched pediatric and adult patients showed no difference in survival from time of initial diagnosis and stage of presentation (log rank p=0.24). Conclusions: Stage-specific survival in pediatric and adult melanoma patients is similar. In the absence of specific pediatric trials, standard treatment for children with melanoma should be consistent with that for adults. No significant financial relationships to disclose.
Lymphodepletion with high-dose interleukin-2 (IL-2) and granulocyte macrophage-colony stimulating factor (GM-CSF) in metastatic melanoma patients: An interim analysis
Authors: Ketchum S. L. , Cole B. , Margolin K. , McDermott D. , Crocenzi T. , Roberts J. , Crosby N. , Meehan K. , Fisher J. , Ernstoff M. S. 
Published: April 2020

8034 Background: Lymphocyte depletion followed by homeostatic recovery has been shown to break tumor-specific tolerance. We have initiated a clinical trial of chemotherapy-induced lymphodepletion followed by high-dose (HD) IL-2 + GM-CSF in metastatic melanoma (MM) patients (pts). Methods: Pts with PS 0–1, normal organ function and with measurable MM were treated with intravenous cyclophosphamide 60 mg/kg (day 1–2), fludarabine 25 mg/m2 (day 3–7) followed by two 5-day (d) courses of intravenous HD bolus IL-2 600,000 IU/kg (d 8–12 and 21–25) and daily subcutaneous administration of GM-CSF 250 mcg/m2 (d 8 until granulocyte recovery). Results: 8 pts are presently evaluable in this first stage of accrual to confirm safety and immunomodulation. A mean of 25/28 IL-2 doses were delivered. All pts experienced transient myelosuppression with ANC < 500 cells/mm3 for a median of 7d (range 5–11d) and platelets <50,000/mm3 for a median of 5.5 days (range 0–7d). Pts exhibited reversible capillary leak associated with high-dose IL-2. With the exception of myelosuppression, no grade 4 toxicities occurred. All pts experienced neutropenic fever and 2 developed line infections. CD4+/CD25high/CD62L+ T cells rebounded by d 14, peaked around d 28 and returned to baseline by d 85. CD8+/CD28- T cells recovered to levels lower than baseline for the first 28d but then showed persistent elevation through d 113. Skewing of T-cell populations based on TCR Î² chain expression was observed. One pt achieved complete response, 2 achieved partial responses, and 5 progressed. Conclusions: Lymphodepletion followed by high-dose IL-2 can be safely administered, affects immune reconstitution, and has activity in MM that may be useful as a platform for enhancing immunotherapeutic strategies. The trial continues to accrue in order to better estimate antitumor activity and immunomodulation. No significant financial relationships to disclose.
Phase I clinical trials of ticilimumab: Tumor responses are sufficient but not necessary for prolonged survival
Authors: Bulanhagui C. A. , Ribas A. , Pavlov D. , Bozon V. , Sharma A. , Gomez-Navarro J. , Camacho L. 
Published: April 2020

8036 Background: Clinical studies examining anti-CTLA4 monoclonal antibodies (mAb) provide evidence of the biologic and clinical activity of this class of agents. Two Phase 1 studies with ticilimumab, a fully human anti-CTLA4 mAb, have been reported previously. In both studies, objective responses (OR) were seen in some patients (pts) with melanoma. In addition, we observed highly favorable outcomes among several pts who did not experience objective responses. This may indicate a positive impact of ticilimumab on melanoma in these pts, not well reflected by traditional response criteria. Long-term follow-up data on survival for pts enrolled in these Phase 1 studies is now reported. Methods: We studied the safety, pharmacokinetics, immunostimulatory activity, and clinical activity of ticilimumab in 53 pts with solid malignancies. Ticilimumab was administered, as a single agent, at single dose levels ranging from 0.01 to 15 mg/kg and at multiple dose levels ranging from 3 to 15 mg/kg. The dosing regimens included either a single dose, multiple doses given q3 months, or multiple doses given q1 month. Results: The two studies included 43 pts with measurable melanoma. Ticilimumab proved safe and overall was well tolerated (Ribas et al. ProcASCO 2005, and JCO Dec2005). Of the 43 pts with measurable melanoma, 18 were alive at >12 months (range: 13 - 42+) after initial treatment with ticilimumab. This includes 5 pts with an OR who continue on ticilimumab, either on-study or as part of a single IND, and 13 pts without an objective response. Among the pts who did not experience an OR, 5 had surgical resection of metastatic lesions and remain relapse free, and 8 are alive with disease. Conclusions: In pts with melanoma treated with ticilimumab, long-term survival has been achieved by all 5 pts who experienced an OR and in 13 pts who did not experience an OR. These findings suggest that lack of objective response is a poor predictor of long-term survival following ticilimumab therapy. [Table: see text]
Long-term clinical results of the combination of cisplatin (C), vinblastine (V), DTIC (D) and interferon-alfa (I) with or without tamoxifen (T) for metastatic melanoma
Authors: Sanguino A. M. , Bedikian A. Y. , Legha S. S. , Detry M. A. , Papadopoulos N. E. , Hwu P. , Hwu W. , Kim K. B. 
Published: April 2020

8039 Background: According to 2001 AJCC data, 1-yr, 2-yr, 5-yr, and 10-yr survival of melanoma patients (pts) with stage M1c were 40.6%, 23.6%, 9.5% and 6.0%, respectively. Previously, we reported the interim results of a randomized phase II trial comparing the response rates (RR) of CVDI vs. CVDI +T. Here we report long-term survival results of these pts. Methods: Chemo-naïve pts between 16 and 75 yrs of age, with histologically documented diagnosis of advanced melanoma and without symptomatic brain metastasis, were randomized to receive either CVDI (group A) or CVDI+T (group B). The dose of each drug is as follows: C 15 mg/m2 IV (d 2–5), V 1.2 mg/m2 IV (d 1–5), D 600 mg/m2 IV (d 1), I 5 MU/m2 SQ 3 times a wk and T 20 mg twice a day. The treatment was administered every 3–4 wks. After the interim analysis, the arm with a higher RR was selected for an expansion cohort (group C). The primary endpoint was the RR of CVDI regimen with or without T. The secondary endpoint was overall survival (OS) evaluation. Results: A total of 104 pts were enrolled, among which 36 and 34 were randomized to group A and B, respectively. After interim analysis of 70 pts, the CVDI regimen was selected for group C. There were no significant differences in both RR (p= 0.126) and OS (p= 0.095) between group A and B. When all 104 pt data were combined, the overall response rate (ORR) was 37.5% with a complete response rate (CRR) of 8.7% and the median survival of 10.4 months. One-yr, 2-yr, 5-yr, and 10-yr OS were 43%, 20%, 7% and 4%, respectively. Conclusions: Although the combination of CVDI with or without T is an active regimen for treatment for metastatic melanoma, long-term survival of pts receiving this regimen is similar to historical controls. [Table: see text] No significant financial relationships to disclose.
Phase II trial of the mTOR inhibitor everolimus (RAD-001) in metastatic melanoma
Authors: Rao R. D. , Windschitl H. E. , Allred J. B. , Lowe V. J. , Maples W. J. , Gornet M. K. , Suman V. J. , Creagan E. T. , Pitot H. C. , Markovic S. N. 
Published: April 2020

8043 Background: Mammalian target of rapamycin (mTOR) is a serine-threonine kinase that regulates the production vascular endothelial growth factor (VEGF) and cell growth and proliferation. Inhibitors of mTOR have anti-mitotic and anti-angiogenic effects in various cancers (including melanoma). Everolimus (RAD-001), an orally administered inhibitor of mTOR, is well tolerated at a dose of 30 mg/week. We conducted a phase II study to evaluate the role of RAD-001 in treating patients with metastatic melanoma (MM). Methods: A 2 stage, phase II multi-institutional trial was conducted in patients with MM to assess progression free survival (PFS) rate at 16 weeks was at least 50% against the alternative it was at most 30%. Data about expected baseline PFS were derived from historical controls. Each cycle was 8 weeks in duration. Inclusion criteria: measurable disease, ECOG performance score (PS) of 0–2. Exclusion criteria: presence of intracranial metastases, concurrent use of inducers of cytochrome 3A4 and abnormal hepatic, renal or bone marrow function. Correlative studies included changes pharmacodynamic endpoints to evaluate effect of therapy on signaling pathways. Results: 24 patients with MM were enrolled. Median age was 56 years (33–79), 21 (88%) had at 2 or more sites of metastatic disease. Most (75%) had stage M1c, with 13% each having 1a and 1b disease. PS was 0, 1 and 2 in 58, 38% and 4%, resp. All but 9 had received previous therapy for MM. Planned interim analysis was done after 20 patients were enrolled. Of these, 7 (i.e., 35%) were PF at 16 weeks, which exceeded the decision rule for restarting accrual. No patient had an objective response; all 7 had stable disease. There were no grade 3 toxicities. Grade 2 toxic events (at least possibly related to therapy) were: fatigue (17%), diarrhea (8%) and anemia (8%). Patients had a clinically relevant benefit, with the median PFS for all 24 patients of 3 months. Median overall survival was not reached. Three patients continue on therapy. RAD-001 treatment resulted in changes in serum VEGF levels. Conclusion: Interim analysis after enrollment of 20 patients suggests that RAD-001 is well tolerated and has sufficient anti-tumor activity in MM to warrant the opening of enrollment to the second stage of this trial. Further accrual is planned. No significant financial relationships to disclose.
A phase II multicenter study on the histone deacetylase (HDAC) inhibitor MS-275, comparing two dosage schedules in metastatic melanoma
Authors: Hauschild A. , Trefzer U. , Garbe C. , Kaehler K. , Ugurel S. , Kiecker F. , Eigentler T. , Krissel H. , Schadendorf D. 
Published: April 2020

8044 Background: The acetylation of histones is a key component of gene regulation, which plays an important role in tumor initiation and progression. MS-275, an inhibitor of the benzamide series, is a synthetic orally available inhibitor of HDACs which showed anti-tumor activity in 3 phase 1 trials. Methods: A phase II, multicenter, randomized, parallel-group study of oral MS-275 evaluated the efficacy and toxicity in patients with non-resectable metastatic melanoma. Patients should have received at least one, but not more than two previous systemic therapies (chemo- and/or immunotherapy) for stage IV melanoma. Patients were stratified to receive either 3 mg MS-275 biweekly (days 1+15 of a 4-week cycle) or 7 mg MS-275 weekly (days 1+8+15 of a 4-week cycle) until disease progression or unacceptable toxicity. Study endpoints were the assessment of tumor response and toxicity. Results: A total of 28 patients have been randomized equally to the two dosing groups. Patients were classified as belonging to AJCC stage IVa (n=0), IVb (n=9; 32%), and IVc (n=19; 68%). In general, MS-275 was very well tolerated. No treatment-related SAEs have been observed. Most frequently reported side effects were nausea (CTC Grade 1+2, 32%) hypophosphatemia (CTC Grade 1–3, 29%), and diarrhea (CTC Grade 1+2, 18%). Stable diseases lasting from 8 wks to more than 48 wks have been observed in 4 pts (29%) in the 3 mg and 3 pts (21%) in the 7 mg dose group. Stabilizations occurred in these metastatic localizations: skin, peripheral and visceral lymph nodes, lung and bone, respectively. However, objective tumor responses were not observed. Conclusions: The results suggest that MS-275 is well tolerated and shows long-lasting tumor stabilizations in patients with pre-treated metastatic melanoma. The failure of objective tumor responses in the single-agent treatment with MS-275 warrants further evaluation also in combinational settings. [Table: see text]
Results of the ESOPE (European Standard Operating Procedures on Electrochemotherapy) study: Efficient, highly tolerable and simple palliative treatment of cutaneous and subcutaneous metastases from cancers of any histology
Authors: Gehl J. , Sersa G. , Garbay J. , Soden D. , Rudolf Z. , Marty M. , O’Sullivan G. , Geertsen P. F. , Mir L. M. 
Published: April 2020

8047 Background: By applying brief, electric pulses, cell membranes can be transiently permeabilised (electroporation). This can be applied focally to tumors, enhancing the uptake of certain chemotherapeutic agents dramatically (electrochemotherapy). Methods: From 2003 to 2005, patients with cancer of any histological diagnosis and symptomatic metastases to skin or subcutis were accrued in four cancer centers. Patients had been offered standard treatment options previously. Primary endpoint was response. One treatment was performed in either general anesthesia or local anesthesia, depending on anatomical site, size and number of tumors. The Cliniporator (IGEA, Italy) was used to deliver electric pulses, with 3 different electrode types: 1) Plate electrodes, 2) Linear array needle electrodes 3) Hexagonal needle electrodes. Eight pulses of 100 μs were applied using 1) 1300 V/cm, 2 and 3) 1000 V/cm. Either intravenous bleomycin 15000 IU/M-2, or intratumoral injections of either bleomycin or cisplatinum, were administered prior to application of electric pulses to the tumors. Responses were documented through direct tumor measurement and digital photography. Results: 41 patients, with altogether 171 cutaneous metastases of malignant melanoma (98 nodules, 57 %), carcinoma or sarcoma were treated. Overall, 145 (84.8%) of the treated nodules responded (CR or PR), with CR in 126 of the nodules (73.7%). Negative response was observed in very low percentage of the treated nodules being either NC (10.5%) or PD (4.7%). Treatment of melanoma and non-melanoma nodules was equally successful. Treatment time per session (one or more nodules) was median 25 min (range 6–60). Intravenous and intratumoral administration of bleomycin, or cisplatinum yielded similar results. No significant toxicity was found, and 96% of patients reported they would agree to another treatment if indicated. Conclusions: Electrochemotherapy is an efficient, safe and simple palliative treatment of cutaneous and subcutaneous metastases of cancers of various histologies. Patient acceptance of treatment was excellent and 73.7% of nodules were in CR after one single treatment. No significant financial relationships to disclose.