bluuebunny/crossref_metadata_2025 huggingface dataset:
Gene expression profiling (GEP) of cd 138-purified plasma cells (pc) in previously treated multiple myeloma (PTMM): Validating prognostic models developed in newly diagnosed MM (NDMM)
Authors: Alsayed Y. , Haessler J. , Barlogie B. , Crowley J. , Shaughnessy J.
Published: August 2020

8598

Background: We have previously reported on the strong discriminatory power in NDMM of GEP-derived 70-gene risk in CD138-purified plasma-cells developed in 351 patients enrolled in TT2 and validated in 441 patients enrolled in two TT3 trials and in PTMM treated with single agent high-dose dexamethasone or bortezomib. Here we report on the overall survival outcomes in 137 patients with PTMM. Methods: Treatment regimens included further autotransplantation and novel agent combinations. The purpose of the investigation was to determine whether PTMM OS was also governed by GEP features, such as high-risk (HR) score, proliferation score (PS), proliferation (PR) molecular subgroup, gain/amplification of chromosome 1q (amp1q) and deletion of the short arm (del1p) and TP53 deletion. Results: Compared with NDMM, PTMM was characterized by greater proportions with HR (32% v 16%, p<0.001), PS (20% v 10%, p=0.002) and PR (24% v 11%, p < 0.001); no difference was observed for TP53 deletion (21% v 30%, p=0.11); amp1q/del1p was more common in PTMM (17% v 9%, p=0.01). OS was 60% at 8yr in NDMM compared to a median of only 2.4yr in PTMM. According to HR, 4-yr OS estimates were 80% for LR v 37% for HR in NDMM (p<0.0001) and 52% for LR v 24% for HR in PTMM (p<0.01). On multivariate analysis of both standard prognostic factors and GEP HR, OS in PTMM was adversely affected by HR status (HR=2.00, p=0.047) and albumin <3.5g/dL (HR=2.66, P=0.013), accounting for a cumulative R2 value of 20%. Conclusions: GEP-derived high-risk features are more prevalent in PTMM relative to NDMM in terms of HR, PS, PR and amp1q/del1p status. As in NDMM, HR status confers poor OS in PTMM. Consistent with serial sampling where LR to HR transformation routinely occurs, these data support the concept that HR in PTMM is derived from clonal evolution. Treatment strategies that presume the existence of underlying HR cells even in LR disease, should be pursued.

[Table: see text]
Effect of the specific P53 stabilizer CBS9106 on multiple myeloma (MM)
Authors: Ikeda H. , Hideshima T. , Perrone G. , Okawa Y. , Raje N. , Kawabe T. , Sakakibara K. , Saito N. , Richardson P. , Anderson K.
Published: August 2020

8601

Background: The mutations of P53 tumor suppressor protein are associated with progressive in Multiple Myeloma (MM), conversely, stabilization of P53 leads to cell cycle arrest and apoptosis. In this study, we examined p53 protein expression and demonstrated the effect of P53 stabilization using a novel specific P53 stabilizer CBS9106 in MM. Method: We examined P53 protein expression using Immunoblot analysis, as well as the growth inhibitory effect of CBS9106 in MM cell lines and primary tumor cells from MM patients. We also defined whether CBS9106 can overcome the growth promoting effect of exogenous cytokines and bone marrow stroma cells (BMSCs) using [3H]-thymidine uptake assay. Results: Expression of P53 protein was observed in 3/3 primary tumor cells from MM patients and 6/6 MM cell lines. CBS9106 at low nM levels triggered cytotoxicity against p53 wild type MM cell lines and primary tumor cells from MM patients, associated with phosphorylation of P53 (serine15 and 20). In contrast, CBS9106 did not affect the survival of normal peripheral blood mononuclear cells from healthy volunteers at concentrations as high as 10 μM. This agent also induced G1 cell cycle arrest, followed by apoptosis associated with cleavage of caspase-3, -8, -9 and PARP. Neither growth stimulating cytokines (IL-6 and IGF-1) nor BMSCs protected against apoptotic effect of CBS9106. Moreover, we demonstrate that combination of CBS9106 with MDM2 inhibitor Nutrin3 or proteasome inhibitor bortezomib induces synergistic anti-MM activity in both P53 wild type MM cell lines and primary tumor cells from MM patients. Conclusions: Stabilizing P53 by CBS9106 represents a novel promising p53-based therapy in MM. These results provide the preclinical framework supporting evaluation of CBS9106 in clinical trials to improve patient outcome in MM.

No significant financial relationships to disclose.
Impact of dexamethasone responsiveness on long-term outcome in patients with newly diagnosed myeloma
Authors: Sinha S. , Rajkumar S. V. , Lacy M. , Hayman S. , Baudi F. , Dispenzieri A. , Lust J. , Greipp P. , Gertz M. , Kumar S.
Published: August 2020

8603

Background: Steroids, primarily dexamethasone (Dex), remains an integral part of the therapy for myeloma. Prior to the advent of novel agents, Dex as a single agent was demonstrated to produce overall response rates of around 50%. The toxicity associated with pulsed high dose Dex has led to this approach being abandoned. This study investigates whether responsiveness to Dex correlates with biological qualities of the plasma cell clone that predicts outcome. Methods: We identified from our prospectively maintained database, patients with newly diagnosed myeloma, who were seen at Mayo Clinic within 30 days of diagnosis and were treated with single agent Dex. The M-protein measurements and responses were assessed using the IMWG criteria. Results: 182 patients seen between March 1998 and June 2007, initially treated with single agent Dex for at least 4 weeks, were included in the analysis. The median age at diagnosis was 63 (range; 39–81) and 59% were male. The actuarial median survival for the entire group was 55 months. The median duration of Dex therapy was 15 weeks (range; 4–193). Ninety one (50%) had a partial response or better and 11 (6%) were not evaluable, with the remaining patients (44%) having less than PR or progression. 10 patients (5%) achieved a VGPR or CR. The median overall survival from diagnosis for the 91 responders was 75 months compared to 71 months for the remaining patients; p = 0.6. There was no correlation between baseline disease characteristics and Dex responsiveness. One hundred thirty (70%) patients proceeded to an autologous SCT after a median of 15 weeks (range 1–46 months) of Dex. While the median overall survival was longer among the group of patients who underwent SCT, among either group, there were no survival benefit between those with a PR or better to Dex compared to the rest. Conclusions: Among this group of patients with newly diagnosed myeloma treated with single agent Dex, failure to respond to Dex induction therapy did not impact overall survival. Failure to respond to single agent steroid does not have an adverse impact on outcome in newly diagnosed myeloma.

[Table: see text]
Prognostic impact of cancer-testis antigen expression in primary cutaneous melanoma
Authors: Cebon J. S. , Svobodova S. , Browning J. , Davis I. D. , Scolyer R. , Murali R. , Thompson J. F. , Deb S. , Azad A. , MacGregor D.
Published: August 2020

9004

Background: Cancer-testis antigens (CTAg) are epigenetically regulated molecules expressed in many cancers including melanoma. Although functional studies are limited, they are often immunogenic making them attractive targets for immunotherapy. In normal tissues expression is restricted to germ cells and a small range of other tissues such as trophoblast. Previous studies have shown that CTAg expression increases with disease progression. We investigated whether the expression of three CTAgs, against which vaccines have been developed, may have prognostic significance in early stage melanoma. Methods: 233 AJCC Stage II melanomas were analyzed for expression of MAGE-A1, MAGE-A4 and NY-ESO-1 by immunohistochemistry. The relationship between CTAg expression, clinico-pathological features and relapse free survival (RFS) from initial diagnosis were correlated. Mutivariate analysis using known prognostic factors and CT Ag expression in the model were used to calculate hazard ratios. Results: All three CTAg were significantly co-expressed with each other (P=0.0001). RFS was reduced if tumors expressed any of these CTAgs (CTAg+ve). Median RFS for patients with CTAg+ve tumors was 45m versus 72m for those with CTAg-ve tumors (P=0.008, logrank test). Univariate analysis demonstrated that the impact of CTAg expression on RFS was comparable in magnitude to ulceration, Breslow thickness and mitotic rate, currently accepted prognostic factors. Multivariate analysis demonstrated CTAg expression, ulceration and thickness but not mitotic rate were independently associated with poorer RFS ( Table ). Conclusions: CTAg expression in cutaneous primary melanoma has impact on prognosis comparable to Breslow thickness ulceration and mitotic rate. Further study into their function and the impact of clinical targeting is warranted.

[Table: see text]

No significant financial relationships to disclose.
Long-term follow-up of patients with minimal sentinel node tumor burden (< 0.1mm) according to Rotterdam criteria: A study of the EORTC Melanoma Group
Authors: van Akkooi A. C. , Rutkowski P. , van der Ploeg I. M. , Voit C. A. , Hoekstra H. J. , Nieweg O. E. , Schäfer-Hesterberg G. , Nowecki Z. I. , de Wilt J. H. , Eggermont A. M.
Published: August 2020

9005

Background: Many studies have identified Sentinel Node (SN) tumor burden as a prognostic factor for additional non- SN (NSN) positivity and / or disease-free (DFS) and melanoma specific survival (MSS). It remains unclear if pts with minimal SN tumor burden can safely be managed without Completion Lymph Node Dissection (CLND). Pts with minimal SN tumor burden might be at risk for late recurrences (> 5 years). Methods: Slides of 595 SN positive patients were reviewed for this pan-European study collaboration in 5 major centers. Slides were reviewed for the microanatomic location and SN tumor burden according to the Rotterdam Criteria (< 0.1mm, 0.1 - 1.0mm and > 1.0 mm) for the maximum diameter of the largest metastasis. MSS, DFS and distant metastasis-free survival (DMFS) rates were calculated, as was NSN positivity. Results: In 595 SN positive pts, the mean and median Breslow thickness was 4.73 and 3.5 mm. Ulceration was present in 51% of melanomas. 67 pts had metastases < 0.1 mm (11%), 226 pts (38%) had 0.1 - 1.0 mm metastases and 302 pts had metastases > 1.0 mm (51%). Mean and median follow-up was 48 and 40 months for all patients (range 1 - 172). Patients with metastases < 0.1 mm had mean and median follow-up of 61 and 57 months, 46% (31pts) had follow up > 5 years and 25% (17 pts) had follow-up longer than 80 months (range 3 - 132). 5-year MSS rates were 94% for metastases < 0.1 mm, 70% for 0.1 - 1.0 mm and 57% for > 1.0 mm (p<0.001). 5-year DMFS rate was 91% for metastases < 0.1 mm. NSN positivity occurred in 5% of < 0.1mm, 17% of 0.1 - 1.0 and 29% of metastases > 1.0 mm (p<0.001). Conclusions: This large multicenter experience (n=595) has demonstrated that long-term follow-up of melanoma patients with minimal SN tumor burden (< 0.1 mm) indicates very low relapse rates and excellent MSS, seemingly identical to SN negative patients. With prolonged follow-up, an increase in the occurrence of relapses of any kind between 5 and 10 years follow up has not been identified, and excellent 10-year survival rates are expected.

No significant financial relationships to disclose.
Ulceration of primary melanoma and responsiveness to adjuvant interferon therapy: Analysis of the adjuvant trials EORTC18952 and EORTC18991 in 2,644 patients
Authors: Eggermont A. M. , Suciu S. , Testori A. , Patel P. , Spatz A.
Published: August 2020

9007

Background: Ulcerated (Ulc) melanomas have a worse prognosis than non-ulcerated (N-Ulc) melanomas. Ulc and N-Ulc primaries have different stromal characteristics and gene profiles reflecting differences in biology. We analyzed outcome after adjuvant interferon (IFN) therapy in the 2 largest phase III trials (EORTC18952 and 18991) ever conducted in stage IIB-III melanoma patients (pts). Methods: EORTC18952 compared IFNα-2b (10 MIU, sc, qd, 5 days/wk, for 4 wks) followed by either 10MIU,sc, tiw for 12 mts, or 5MIU for 24 mts) with observation in 1,388 stage IIB-III pts (Lancet 2005;366). EORTC18991 evaluated pegylated IFNα-2b (6 μg/Kg, 1×/wk, for 8 wks followed by 3μg/Kg, 1×/wk for up to 5 yrs) versus observation in 1,256 stage III pts (Lancet 2008;372). Using meta-analytical methods, predictive value for Ulc on the value of IFN on relapse-free survival (RFS), distant metastasis-free survival (DMFS), and overall survival (OS) was assessed, overall, and according to stage (IIB, III-N1 or N2=microscopic or macroscopic-nodal disease). Results: Overall, the comparison (PEG-)IFNα-2b versus observation regarding RFS, DMFS, and OS led to a reduction in the hazard ratio (HR) of -16% (SE=5%), -13%(5%), and -8%(5%). Among 2,644 pts randomized, 849 had Ulc primaries, 1,336 N-Ulc primaries, and 459 Ulc unknown. In Ulc group the impact was much greater than in N-Ulc group for RFS (Test For Interaction: p=0.02), DMFS (p<0.001), and OS (p<0.001). The greatest reductions occurred in pts with Ulc and stages IIB/III-N1 In N-Ulc pts reduction was absent. Consistency in the treatment impact was seen in both trials. Conclusions: The post hoc analyses of EORTC1892 and EORTC18991 indicate strongly that pts with an Ulc primary are far more sensitive to IFN than pts with N-Ulc primaries. This hypothesis will now be tested in the EORTC18081 trial, which compares PEG-IFNα-2b versus observation in pts with Ulc primaries ≥ 1mm.

[Table: see text]

[Table: see text]
Correlation of ultrasound criteria for detection of melanoma metastases in the sentinel lymph node (SN) with tumor burden and survival
Authors: Voit C. A. , van Akkooi A. C. , Schaefer-Hesterberg G. , Schoengen A. , Sterry W. , Eggermont A. M.
Published: August 2020

9015

Background: We demonstrated that US guided FNAC (fine needle aspiration cytology) prior to SN biopsy can identify up to 65% of SN-positive patients (EJC, 2007; 5(6):11: abstr 3BA). We presented US patterns of SN-involvement at ASCO 2008 (JCO 26: 2008(suppl; abstr 9014). Here we show how these patterns correlate with tumor burden, progression of disease and survival. Methods: Prior to SN-biopsy patients (pts) underwent lymphoscintigraphy followed by US-exam. US images were prospectively scored for 6 morphologic criteria. FNAC was performed in suspicious US. All pts underwent a SN biopsy. Final SN pathology was the gold standard. Sensitivity, specificity and negative/positive predictive value (NPV and PPV) of combinations of US patterns were calculated and correlated with tumor burden and survival. Hazard ratios (HR) were calculated for the patterns by multivariate analysis. Results: Since 2001 850 consecutive pts have been included into a prospective database. Median Breslow thickness of the first 400 stage I/II melanoma pts was 1.8 mm, median follow-up 42 months. Balloon Shape (BS) & Loss of Central Echoes (LCE) are often linked (up to 83%) and are late signs correlating with high tumor load. In contrast the presence of Peripheral Perfusion (PP) is an early sign, correlating with small tumor load. PP and/or BS and/or LCE together raise the sensitivity of US alone to > 80%, spec.80%, PPV 52%, NPV of 94% (p<0.001). Overall Survival of neither vs. Peripheral Perfusion (PP) only vs. BS/LCE (with or without PP) was 93% vs. 87 % vs. 56 % and Distant Metastasis-Free Survival was 74% vs. 60% vs. 26%. BS/LCE was a late sign correlating with high tumor load, fast progression and a high HR (5.50). PP alone was an early sign correlating with small tumor load, slow progression, and a low HR (2.19). Conclusions: BS and/or LCE indicate high tumor load, PP alone indicates small tumor load in the SN. These US-criteria identify the SN tumor burden correctly prior to SN biopsy in 75% - 90% of pts. They are independent prognostic factors for survival.

No significant financial relationships to disclose.
Serum vitamin D levels, VDR, and survival from melanoma
Authors: Newton Bishop J. A. , Beswick S. , Randerson-Moor J. , Chang Y. , Affleck P. , Elliott F. , Elder D. , Barrett J. , Bishop T.
Published: August 2020

9016

Background: Vitamin D has pleiotropic effects, which may moderate the interaction between patients and their tumors. Two studies were carried out to test the hypothesis that higher vitamin D levels reduce the risk of relapse from melanoma. Methods: A pilot retrospective case-control study in 271 melanoma patients suggested that vitamin D may protect against recurrence of melanoma. We then tested these findings in a survival analysis in a cohort of 872 cases recruited to the Leeds Melanoma Cohort (median follow up of 4.7 years). Results: Pilot study Results suggested that taking vitamin D reduced the risk of relapse from melanoma (OR 0.6, 95% CI: 0.4, 1.1). Non-relapsers had higher mean 25-dihydroxyvitamin D3 levels than relapsers (49 nmol/L compared with 46, p=0.3). Cohort study Higher 25-dihydroxyvitamin D3 levels were associated with lower Breslow thickness at diagnosis and were independently protective of relapse and death: hazard ratio (HR) for relapse free survival (RFS) 0.76, 95% CI: (0.64, 0.96), for a 20nmol/L increase in serum level. There was evidence of interaction between the vitamin D receptor (VDR) BsmI genotype and serum 25-dihydroxyvitamin D3 levels on RFS. Conclusions: The pilot study provided preliminary evidence for a role for vitamin D in outcome from melanoma. The cohort study provided further evidence that higher 25-dihydroxyvitamin D3 levels, at diagnosis, were associated both with thinner tumors and better survival, independent of Breslow thickness, from melanoma. Melanoma patients should avoid vitamin D deficiency. Further studies are needed to establish optimal serum levels for melanoma patients.

No significant financial relationships to disclose.
Selective activity of dasatinib for the most common KIT mutation in melanoma (L576P)
Authors: Woodman S. E. , Trent J. C. , Stemke-Hale K. , Lazar A. , Pricl S. , Pavan G. M. , Papadopoulos N. , Hwu P. , Mills G. B. , Davies M. A.
Published: August 2020

9019

Background: Point mutations in the KIT receptor tyrosine kinase gene have recently been identified in melanomas from mucosal, acral lentiginous (AL), and chronically sun-damaged (CSD) sites. An improved understanding of the molecular characteristics of melanoma-prevalent KIT mutations may lead to more effective therapeutic approaches. Methods: Human melanoma cell lines were screened by mass-spectroscopy based genotyping for KIT mutations, and a cell line with an endogenous L576P KIT mutation was identified. The cell line was treated in vitro with a panel of small molecule KIT inhibitors and the effects on cell viability were quantified. Molecular modeling of the interaction of the inhibitors with the KIT L576P mutant protein was determined to estimate binding affinity. PET/CT studies were performed on patients with mucosal melanoma harboring the L576P mutation pre- and post-dasatinib treatment. Results: We have identified the first human melanoma cell line with an endogenous L576P mutation, the most common KIT mutation in melanoma. In vitro testing demonstrated that this cell line is resistant to imatinib, nilotinib and sorafenib (0 - 1 uM), KIT inhibitors shown to be effective in non-melanoma cells with other KIT mutations. However, the mutant cell line was inhibited by dasatinib at concentrations as low as 10 nM, and was significantly more sensitive than melanoma cell lines with wild-type KIT (p = 0.02). No difference in sensitivity to Src inhibitors was observed, supporting that this sensitivity was due to KIT inhibition. Molecular modeling demonstrated that the L576P mutation induces structural changes in KIT that reduce the affinity for imatinib but not for dasatinib. Two metastatic melanoma patients with the L576P KIT mutation were treated with dasatinib, including one patient previously treated with imatinib. Both patients had marked reduction and elimination of tumor FDG- avidity by PET imaging after dasatinib treatment. Conclusions: This data supports that dasatinib has a selective inhibitory effect against the most common KITmutation in melanoma and has implications for the development of AL, CSD, and mucosal melanoma treatment.

[Table: see text]
Quantitative assessment of AKT activation in melanoma
Authors: Davies M. A. , Stemke-Hale K. , Calderone T. , Deng W. , Lazar A. , Prieto V. G. , Aldape K. , Mills G. B. , Gershenwald J. E.
Published: August 2020

9022

Background: Activating mutations of BRAF are highly prevalent in melanoma. However, multiple lines of evidence suggest that other pathways must also contribute to this disease. Activation of the PI3K-AKT pathway has been implicated in melanoma by mutations of NRAS and PTEN. Little direct information is known about the activation of the PI3K-AKT signaling pathway in melanoma, particularly in metastases. Methods: Proteins isolated from 99 frozen melanoma tumors were measured by reverse phase protein arrays (RRPA). A total of 53 proteins were assessed using validated antibodies. Activating mutations were assessed by mass spectroscopy-based genotyping. Activation of AKT (phospho-AKT) was compared to mutations and anatomic sites. Results: Samples from 75 regional metastases (LN or in-transit) and 24 distant metastases were analyzed. Technical replicates (same lysate) and biological replicates (same tumor, different lysates) demonstrated average Pearson correlation coefficients (r) of > 0.90, supporting the high technical quality of the analysis. A positive correlation was observed between levels of p-AKT and known AKT substrates p-GSK3 and p-TSC2 (p< 0.001 for both), and a negative correlation with PTEN (p < 0.01), supporting the maintenance of phosphorylation events during sample processing. Relative differences in p-AKT by RPPA were also confirmed by immunohistochemistry of representative tumors. Tumors with BRAF mutations had higher levels of p-AKT than tumors with NRAS mutations (p = 0.03). Indeed, tumors with NRAS mutations had p-AKT levels similar to tumors wild-type for BRAF and NRAS (p =0.73). Detailed analysis demonstrated that all tumors with elevated p-AKT had low PTEN expression. Similar results were seen in human melanoma cell lines. Analysis of distant metastases demonstrated that brain metastases had higher levels of p-AKT, p-GSK3, and p-TSC2, and lower levels of PTEN, compared to metastases to the lung or liver. Conclusions: AKT activation in melanoma correlates with PTEN expression, and does not correlate with NRAS mutation. Activation of the PI3K-AKT pathway may contribute to the aggressiveness of brain metastases. These findings have clinical implications for targeting this pathway, and demonstrate the feasibility and potential of RPPA analysis of signaling pathways in melanoma.

No significant financial relationships to disclose.
Therapeutic vaccination with an autologous TriMix-Dendritic cell vaccine combined with sequential interferon alfa-2b in patients with advanced melanoma
Authors: Wilgenhof S. , Van Nuffel A. M. , Benteyn D. , Pierret L. , Heirman C. , De Coninck A. , Van Riet I. , Bonehill A. , Thielemans K. , Neyns B.
Published: August 2020

9024

Background: Electroporation of dendritic cells (DC) with mRNA encoding fusion-proteins of a HLA-class II targeting signal and a melanoma associated antigen (MAA) together with mRNA encoding CD40 ligand, a constitutively active TLR4 and CD70 (TriMix) improves the immunostimulatory capacity of autologous DC. Methods: Following leukapheresis, immature DCs (derived from adherent PBMC cultured for 6 days in IL-4 / GM-CSF supplemented medium) are electroporated with mRNA encoding MAGE-A3, MAGE-C2, Tyrosinase and gp100 linked to DC-LAMP, and TriMix mRNA. TriMix-DC (12.5 106/antigen) are cryopreserved and administered by 4 ID-injections q2w, and q8w thereafter. After the 4th vaccination, interferon alfa-2b (IFN- a2b, 5 MIU TIW) is initiated. Immune monitoring is performed by skin biopsy of a vaccine injection site. Biopsies are investigated by IHC and by analyzing the activation (CD137+), cytolytic capacity (CD107a+), and cytokine release (IFN-γ and TNF-α) of DTH infiltrating T-cells in response to autologous EBV-B cells expressing MAA. Results: 29 pts (17M/12F; med age 49, range 28–75) with stage III/IV melanoma, nl LDH, and no CNS metastases were recruited. Vaccine related AE's (first 24 pts): gr2 local injection site reactions (all pts); fever & lethargy (gr2, 1 pt). Pts (20) who initiated IFN-a2b experienced constitutional side effects (gr3, 1 pt). Vaccine-specific DTH infiltrating T cells were documented post-vaccination in 13/17 pts (10/13 pts had a CD137+CD8+ and 2/13 pts a CD4+ response). Out of the 11 pts without evaluable disease, 2 had a local recurrence (salvaged by surgery). After a mFU of 7.8 mths (range 4.3–13.7) all pts remain disease-free. Out of the 13 pts with measurable disease, BOR (RECIST) was 8 SD and 5 PD; 1 pt with initial PD subsequently obtained a PR. Regression of metastases occurred in lung- (2 pts), orbita- (1 pt) and lymph node metastases (3 pts). After a mFU of 7 mths (range 1–14), the mPFS is 3,1 mths (95% CI 2,29–4,08); 4 pts remain progression-free after respectively 5, 8, 10 and 11 mths of follow-up. Conclusions: Therapeutic vaccination with TriMix-DC combined with sequential IFN-a2b is feasible, safe, immunogenic and associated with anti-tumor activity in patients with advanced melanoma.

[Table: see text]
Phase II trial of sagopilone (ZK-EPO), a novel synthetic epothilone, with significant activity in metastatic melanoma
Authors: Daud A. , Weber J. , Urbas P. , Andrews S. , Maker N. , Sondak V. K. , DeConti R. C.
Published: August 2020

9031

Background: Sagopilone (ZK-Epothilone) is a novel, fully synthetic epothilone with promising preclinical activity in several cancer models. This phase II study aims to define the efficacy and safety of sagopilone in patients with metastatic melanoma, as well as perform pharmacokinetic evaluation of this dose and schedule. Methods: Patients with unresectable stage III or IV malignant melanoma, with up to 2 prior chemotherapy and any prior immunotherapy regimens with measurable disease were eligible. Sagopilone was administered at 16 mg/m2 as a 3-hour IV infusion every 21 days. The primary end point of the trial was response rate, and secondary endpoints included time to progression, overall survival, and tolerability. Pharmacokinetic analysis was done on the first 10 patients. A total of 37 patients were to be accrued to have 33 evaluable patients. The trial had a 0.90 power and assumed α of 0.03. Results: Thirty four patients have been enrolled to date. Sagopilone appears to be well tolerated: The most common side effects seen have been sensory neuropathy, (55%, 19/34, 5 Grade 2, 14Grade 1) motor neuropathy (23%, 8/34, All Grade 1); anemia (26 %, 9/34) neutropenia (14%, 5/34 1 Grade 2, 4 Grade 1) thrombocytopenia (14%, 5/34) and fatigue (38%, 13/34). Two patients have shown grade 3 events (syncope and mental status changes, respectively, possibly related to therapy), both of which resolved and an additional patient had a pulmonary embolism which was considered unlikely to be related to therapy. Responses have been seen in 4 patients (3 RECIST confirmed PR, 1 unconfirmed PR). Stable disease was seen for at least 12 weeks in an additional 10 patients for a clinical benefit rate (CR+PR+SD) of 44%. No grade 4 events have been reported. Conclusions: Unlike the epothilone analogs patupilone or ixabepilone, sagopilone appears to be an active drug in advanced melanoma. The side effect profile seen to date at 16 mg/m2 given over 3 hours repeated every 3 weeks appears to be notably free of myelosuppression indicating that it could be combined with other drugs active in melanoma. Pharmacokinetic studies show a prolonged terminal half life, probably due to release from deep tissue compartments.

[Table: see text]
Phase II clinical trial with a second generation, GM-CSF encoding, oncolytic herpesvirus in unresectable metastatic melanoma
Authors: Senzer N. N. , Kaufman H. , Amatruda T. , Nemunaitis M. , Daniels G. , Glaspy J. , Goldsweig H. , Coffin R. S. , Nemunaitis J.
Published: August 2020

9035

Background: OncoVEXGM-CSF is a an oncolytic HSV, encoding GM-CSF . We recently completed a phase II trial involving 50 advanced melanoma patients (stage IIIc and IV) with at least one injection accessible lesion, including by ultrasound. Methods: Patients received a single IT injection of 106 pfu/ml apportioned between 10 or less injectable tumors, followed 3 wks later by 24 or less sequential injections of 108 pfu/ml every 2 wks until clinically significant disease progression, or overall or injectable lesion complete response. Response (RECIST modified to allow progression before response and biopsy of residual masses) and survival were monitored. Results: All 50 pts have been enrolled and are evaluable (Stage IIIc, n=10; IV M1a, n=16; IV M1b, n=4; IV M1c, n=20). A median of 6 injections were administered. Adverse effects were limited and generally involved transient flu-like symptoms. Both injected and uninjected regional and distant disease demonstrated response including clearly documented responses at uninjected visceral sites. The overall response rate was 26% (8 CR, 5 PR); 10 responses have been maintained for >6 months and 2 are ongoing at <6months, the longest currently being at 35 months from first dose. 93% of patients (14 of 15) with PR, CR or surgical CR remain alive. Ten additional patients had SD for >3 months. Kaplan Meier one year survival is 61% overall, 58% stage IV only, 48% for Stage IV M1c. The median OS is 16+ months. Conclusions: The 1-year survival and durable objective response rate are encouraging. Responses of distant and visceral disease provide further compelling evidence of systemic effectiveness. This, combined with a limited toxicity profile, suggests OncoVEXGM-CSF is a promising treatment for metastatic melanoma. A phase III clinical trial is planned.

[Table: see text]
Efficacy of ipilimumab 10 mg/kg in advanced melanoma patients (pts) with good and poor prognostic factors
Authors: Wolchok J. D. , de Pril V. , Linette G. , Waterfield W. , Gajewski T. , Chiarion-Sileni V. , Ibrahim R. , Chin K. , Hoos A. , Hamid O.
Published: August 2020

9036

Background: Ipilimumab is a fully human monoclonal antibody against cytotoxic T-lymphocyte antigen-4. In total, ∼50% of metastatic melanoma pts treated with 10 mg/kg ipilimumab are alive at 1 year (Wolchok et al. CRI-CVC annual meeting 2008. Oral presentation), and identifying prognostic factors may help select pts most likely to benefit from treatment. Factors predictive of poorer prognosis in melanoma include advanced stage of disease (ie, M1c), age 60+, gender (male), elevated baseline lactate dehydrogenase (LDH) levels, and lack of a prior response to therapy. In this pooled analysis, potential prognostic factors in pts with advanced melanoma treated with ipilimumab 10 mg/kg in 2 phase II studies (CA184–008, N=155 and -022, N=72) were explored. Methods: Ipilimumab 10 mg/kg was given every 3 weeks (Q3W) × 4 (induction); eligible pts could continue to receive ipilimumab Q12W starting at week (Wk) 24 (maintenance). Response was based on modified World Health Organization criteria. Each variable was analyzed separately. Results: Disease control rate (complete/partial response [CR/PR] and stable disease) seems not to be associated with age (<65 yrs: 25.2%; ≥65 yrs: 32.9%), gender (male: 22.6%; female: 34.0%), M stage (M0: 33.3%; M1a: 41.0%; M1b: 26.4%; M1c: 23.6%), response to prior systemic therapy (yes: 32.5%; no: 26.7%), prior immunotherapy (yes: 21.6%; no: 35.3%), LDH >upper normal limit (UNL) (yes: 25.9%; no: 29.7%), or LDH >2×UNL (yes: 15.9%; no: 30.6%). Best overall response rate (CR or PR) was not associated with age (<65 yrs: 7.3%; ≥65 yrs: 7.9%), gender (male: 4.0%; female: 11.7%), M stage (M0: 8.3%; M1a: 15.4%; M1b: 5.7%; M1c: 5.7%), response to prior systemic therapy (yes: 12.5%; no: 6.4%), prior immunotherapy (yes: 3.2%; no: 12.7%), LDH >UNL (yes: 8.6%; no: 6.3%), or LDH >2×UNL (yes: 4.5%; no: 8.2%). Overall survival was not associated with age (median OS: <65 yrs: 11.6 mo; ≥65 yrs: 7.59 mo), M stage (median OS: M0: 21.9 mo; M1a: 15.7 mo; M1b: 15.4 mo; M1c: 6.6 mo), or response to prior systemic therapy (median OS: yes: 11.6 mo; no: 10.7 mo). Conclusions: Ipilimumab demonstrates clinical activity independent of negative prognostic factors, and may even benefit those pts with the worst prognosis.

[Table: see text]
Long-term survival of patients (pts) with advanced melanoma treated with ipilimumab with or without dacarbazine
Authors: Hersh E. , Weber J. , Powderly J. , Pavlik A. , Nichol G. , Yellin M. , Cranmer L. , Urba W. , O'Day S.
Published: August 2020

9038

Background: Ipilimumab is a fully human monoclonal antibody targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4). Here, we report updated survival of pts with advanced melanoma treated with ipilimumab in 2 completed studies. Methods: Seventy-two chemotherapy-naïve pts were randomized to receive 3 mg/kg ipilimumab every 4 weeks (Q4W) × 4 alone or with ≤6 × 5-day courses of DTIC 250 mg/m2/day (ipilimumab, n = 37; ipilimumab + DTIC, n = 35) in the multicenter, open- label Phase II study MDX010–08 (Sep 2002-Aug 2004)(Hersh E et al. J Clin Oncol 26: 2008 (May 20 suppl; abstr 9022)). In the phase I/II dose-ranging study MDX010–15, 23 pts were treated with 10 mg/kg ipilimumab every 3 weeks (Q3W) × 4 (induction) (Jun 2004- Jul 2006) (Urba W et al. J Clin Oncol 26: 2008 (May 20 suppl; abstr 3018)). No maintenance ipilimumab was administered in either study. Long-term survival was determined under a follow-up protocol (MDX010–28) from May 2007-Jan 2008. Results: Long-term data are available for 62 pts for MDX010–08 and 22 pts for MDX010–15. For MDX010–08, the median follow-up was 4.3 years (range, 4.0–4.7 years); it was 2.2 years (range, 2.0–2.4 years) for MDX010–15. Survival rates are reported in the Table . Conclusions: Ipilimumab monotherapy, administered at 3 mg/kg and without maintenance dosing, resulted in survival rates better than those observed with historical controls (Korn EJ et al. J Clin Oncol 26:527–34; 2008). Adding DTIC to ipilimumab did not suppress the effect of ipilimumab (as might have been predicted), but enhanced it still further. Consistent with previously reported response data showing that 10 mg/kg is the recommended dose (study CA184022) (Hamid O et al. J Clin Oncol 26: 2008 (May 20 suppl; abstr 9025)), there was a trend toward better survival with the higher dose (eg, a 2-year survival rate of 36% vs. 22% for 10 mg/kg vs. 3 mg/kg).

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[Table: see text]
Adjuvant vaccination with melanoma antigen pulsed dendritic cells (DCs) in stage III melanoma patients
Authors: Markowicz S. , Nowecki Z. I. , Rutkowski P. , Lipkowski A. W. , Jakubowska-Mucka A. , Switaj T. , Biernacka M. , Misicka A. , Walewski J. A. , Ruka W.
Published: August 2020

9039

Background: This is a pilot study evaluating of high-risk melanoma patients (pts) treated with peptide-DC vaccine after lymphadenectomy (LND). DC vaccination was designed to induce the immune response against melanoma antigens in melanoma pts who remain at high risk of dissemination after LND. Methods: DCs were generated from the bone marrow with the use GM-CSF, SCF, FLT3-L and TNFa or from peripheral blood adherent monocytes with GM-CSF and IL-4. DCs pulsed with HLA-A2-binding TYR, MART-1 and gp100 peptides and/or HLA-A1-binding MAGE-1, MAGE-3 peptides, tumor lysate if available, or with tracer antigen keyhole limpet hemocyanin (KLH), were injected sc 9 times within 8 months (mos). Boost injections were performed after 12 and 24 mos. Vaccinated pts were matched to unvaccinated controls (22 of 587) by sex, number of metastatic lymph nodes, extracapsular involvement, completion or therapeutic LND, Breslow stage (T), and ulceration. Results: HLA-A2+, -A1+ or -A3+ melanoma pts (n=22), stage III, N1b-N3, enrolled between Sept. 2002 and Apr. 2004, received 5–16 vaccinations (median: 11) within 2 yrs. Cutaneous delayed type hypersensitivity (DTH) to melanoma peptides was induced in 12 of 22 pts. Peptide-specific IFNg producing CD8+ cells were detected in peripheral blood of 13 of 19 pts after vaccination. At least one of these responses to melanoma antigens was elicited in 17 of 22 pts. DTH to KLH was positive in 15 of 22 pts. Nine vaccinated pts are free of disease, and 1 is stable by Dec. 2008 (follow up is 58–76 mos after LND). Survival analysis for vaccinated pts and matched controls is presented in the Table . Conclusions: The DC/peptide vaccine elicited immune responses to melanoma antigens. Vaccinated pts had clinically substantially longer overall survival (OS) and disease free survival (DFS) than matched control. OS was associated with the immune responsiveness to melanoma antigens and to KLH.

[Table: see text]

No significant financial relationships to disclose.
Prognostic factors in metastatic melanoma patients treated with biochemotherapy and maintenance immunotherapy
Authors: Minor D. R. , Kashani-Sabet M. , Moore D. , Kim C. , Venna S. S. , Wang W. , Boasberg P. D. , O'Day S.
Published: August 2020

9051

Background: Patients with stage IV metastatic melanoma are usually felt to be incurable with a median survival of 6.4 months and a 5-year survival of only 2%. Biochemotherapy has shown promise with long-term survival in selected patients. We felt the study of prognostic factors would determine which patients might benefit the most from this intensive therapy. Methods: 135 consecutive patients with stage IV melanoma treated with decrescendo biochemotherapy followed by maintenance immunotherapy at one melanoma treatment center were studied to determine the most important prognostic factors; these factors were then validated by analysis of 133 patients treated in a multi-center trial at other institutions. Patients were treated using the inpatient regimen of O'Day (JCO23:710s,2005 abstract). Results: Median overall survival (OS) was 16.6 months with 1-year survival of 70% and 5-year survival of 28%. Median progression-free survival (PFS) was 7.6 months with 15% progression-free at 5 years. PFS curves showed no relapses after 30 months, so remissions were durable. For OS performance status 0, normal LDH, stage M1a, and non-visceral sites of metastases were favorable prognostic factors. For PFS performance status 0, normal LDH, female sex, age <50 and stage M1a were favorable prognostic factors Multivariate analysis demonstrated two important prognostic factors for survival: normal serum LDH and the presence of either skin or nodes as one of the sites of metastatic disease. The group with normal LDH and skin or node metastases had a relatively good prognosis with median survival of 44 months and a 5-year survival of 38%. Conversely patients with elevated LDH without any skin or nodal metastases had a poor prognosis, with no long-term survivors. Conclusions: Metastatic melanoma patients treated with biochemotherapy and maintenance immunotherapy that have either a normal LDH or skin or nodes as one of their metastatic sites may have durable remissions of their disease, and this therapy should be studied further in these groups.

[Table: see text]
Long-term survival of patients with metastatic melanoma (MM) treated with dacarbazine (DTIC) or temozolomide (TMZ)
Authors: Kim C. , Lee C. W. , Klasa R. , Shah A. , Savage K. J.
Published: August 2020

9054

Background: Patients with metastatic melanoma (MM) generally have a poor prognosis, with a median survival of 6 to 9 months. There is a small proportion of patients who achieve long term survival (LTS), however, it is unclear whether LTS reflects sensitivity to systemic therapy, indolent tumor biology or host immune factors. Dacarbazine (DTIC) is the only approved chemotherapy for the treatment of MM, although temozolomide (TMZ) has similar efficacy. There is limited information as to the frequency of complete response (CR) following DTIC or TMZ, duration of response and whether LTS occurs only in patients who achieve a CR. We sought to identify all patients with MM treated with either DTIC (alone or in combinations) or TMZ at the BC Cancer Agency (BCCA) who achieved LTS defined as survival ≥ 18 months from the time of administration of chemotherapy. Methods: All patients with MM treated with either DTIC or TMZ from January 1, 1988 to February 1, 2006 were identified in the BCCA pharmacy database. The BCCA surveillance and outcomes unit (SAO) was utilized to identify cases of LTS. CR was defined as disappearance of all disease by diagnostic imaging. Given the retrospective nature of the analysis, progressive disease (PD) was defined as any tumor growth, and partial response or stable disease (PR/SD) were combined. Results: In the 18-year period reviewed, 397 patients with MM were treated with DTIC (n= 349) or TMZ (n=48). Of these, 45 patients met the criterion of LTS and had the following characteristics: median age 53 (range 22–86); male 67 %; ocular primary 7%; non-pulmonary visceral metastases 38%; DTIC 11.7% (41/349), TMZ 8.3% (4/48). The best response to DTIC or TMZ documented was: CR 18%, PR/SD 67%, PD 13%. The 5-year overall and progression-free survival rates were 33% and 12%, respectively. Eleven patients survived > 5 years (range 5–27.5), and 6 patients remain in remission (5 CR, 1 PR). Disease progression occurred in 5 patients in < 1 year however, they remain alive for at least 5 years (range 5.2–17.9). Conclusions: LTS occurs in patients with MM treated with either DTIC or TMZ. However, a minority have a sustained response following chemotherapy, and most cases of LTS are likely the result of indolent disease or host biology.

No significant financial relationships to disclose.
Chemoablation of melanoma with intralesional rose bengal (PV-10)
Authors: Agarwala S. S. , Thompson J. , Smithers M. , Ross M. , Coventry B. , Minor D. , Scoggins C. , Hersey P. , Wachter E.
Published: August 2020

9060

Background: Intralesional rose bengal (PV-10, a sterile 10% solution in saline) can elicit selective ablation of solid tumors and an apparent bystander response in untreated lesions. In phase 1 testing in 20 subjects with AJCC Stage III (19 subjects) or IV (1 subject) melanoma, a single injection of PV-10 into 1–20 lesions led to durable objective response (OR) at 12–24 weeks in 40% of subjects (20% CR + 20% PR by modified RECIST) and locoregional disease control (CR + PR + SD) in 75% of subjects. Untreated bystander lesions achieved an OR in 15% of subjects, and all subjects with an OR of their injected lesions achieved disease control of their bystander lesions. PV-10 was well tolerated, with only one Grade 3 adverse event (photosensitivity reaction). The most common AEs were transient pain at the treatment site (75% of subjects), followed by local inflammation or infection (25%). Methods: Expanded phase 2 testing commenced in late 2007 in up to 80 subjects with measurable Stage III or IV melanoma. After an initial treatment of 1–20 cutaneous, subcutaneous or nodal lesions, new or incompletely responsive lesions can be retreated at weeks 8, 12 or 16, with follow-up to 52 weeks. An additional 1–2 lesions, including visceral lesions, remain untreated for assessment of bystander response. Seven centers in Australia and the USA are enrolling subjects, with completion of enrolment expected by mid-2009. A modified Fleming design allows interim assessment of safety and OR at weeks 4 and 24, respectively, after treatment of the 20th and 40th subjects. The primary end-point is OR of injected lesions in the intent-to-treat population; secondary endpoints include OR of bystander lesions and PFS. Results: Interim safety data for the first 40 subjects treated is comparable to phase 1, with transient mild to moderate locoregional pain, vesicles or edema most common; Grade 3 AEs have been rare (1 case each of vesicles and skin flap necrosis), with no Grade 4 or 5 AEs attributed to PV-10. Interim efficacy for the first 20 subjects is also comparable to that of phase 1 (15% CR + 15% PR); efficacy data for the first 40 subjects will be presented at the meeting. Conclusions: The safety and efficacy profile of intralesional therapy with PV-10 compares favorably with available therapeutic options for this patient population.

No significant financial relationships to disclose.
Selective internal radiation therapy (SIRT) as salvage therapy for uveal melanoma (UM) hepatic metastases
Authors: Gonsalves C. F. , Eschelman D. J. , Sullivan K. L. , Anne P. R. , Doyle L. , Sato T.
Published: August 2020

9066

Background: The liver is the first site of metastasis in >80% of patients with UM. Transarterial chemoembolization (TACE) has been used to control hepatic metastases, however, patients eventually progress through or experience complications related to TACE. We report our results using SIRT as salvage therapy for patients with UM liver metastases who are no longer candidates for TACE. Methods: Patients with UM liver metastases previously treated with TACE were treated with SIRT. Patients were followed 1-month post-SIRT for acute toxicity then every 3 months for tumor response evaluation and for complications of delayed toxicity. Common Toxicity Criteria 3.0 (CTC) was used for toxicity assessment. Best radiographic tumor response was determined by MRI using RECIST criteria. Results: Five men and 7 women, ages 48–81 (median 65) with UM liver metastases were treated with SIRT after tumor progression post-TACE (n=9), complications of TACE (n=1) or patient preference (n=2). Pretreatment whole liver tumor burdens were as follows: <25% (n=10), 25–50% (n=1) and >50% (n=1). Patients had both hepatic lobes treated on separate occasions (n=7), one lobe (n=3) or whole liver (n=2) therapy. Treatment dose per patient was reduced by 25% due to prior TACE procedures. The mean total SIRT dose delivered was 1.0 GBq (0.62–1.47 GBq). Five patients had an increase in hepatic enzymes (Grade 1–4) at 1-month follow-up. No procedure related deaths or serious adverse events were experienced. Best tumor response was as follows: CR (n=0), PR (n=0), SD (n=8), PD (n=4), with a median follow-up of 7.8 months (1.0–16.0). The median time to liver progression was 7.0 months (1.0- 15.5). Nine of the 12 patients, including 2 patients with >25% pretreatment tumor burden, died due to progression of liver disease (n=6), extrahepatic disease (n=1) or both (n=2). Post-SIRT, median overall patient survival was 10.8 months (1.0–19.0). Three patients (ECOG 0 performance status) are still alive at 13.5–19.0 months (median 16.2 months) following SIRT. Conclusions: SIRT was safely used and showed a potential clinical benefit for patients previously treated with TACE. Further investigation is warranted to determine if SIRT should be employed as a first line therapy for patients with UM liver metastases.

No significant financial relationships to disclose.