bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dose-escalation trial of milatuzumab (humanized anti-CD74 monoclonal antibody) in multiple myeloma
Authors: Kaufman J. L. , Niesvizky R. , Stadtmauer E. A. , Chanan-Khan A. , Siegel D. , Horne H. , Teoh N. , Wegener W. A. , Goldenberg D. M. 
Published: August 2020

8593 Background: CD74 (HLA-DR-associated invariant chain) is highly expressed in multiple myeloma (MM), rapidly internalized, and a promising target for immunotherapy. Methods: A multicenter dose-escalation study was initiated in patients (pts) with relapsed/refractory MM who had failed at least 2 standard therapies. Pts received milatuzumab IV twice-weekly for 4 wks, with doses escalated by a 3+3 cohort design. Pts were evaluated over 12 wks, with responding pts continuing follow-up. AEs and safety laboratories were evaluated by NCI CTC v3 grades, with any treatment-related Grade 3–4 events considered dose-limiting toxicity (DLT). Responses were classified by EBMT criteria, with PK and immunogenicity evaluated by serum milatuzumab levels and human anti-milatuzumab antibody (HAHA) titers, respectively. Results: Twenty-one pts (12M/9F, median age 63) have now received 1.5 (n=8), 4.0 (n=9) or 8.0 mg/kg (n=4) doses twice weekly. They had MM for 0.9–16.8 years (median 5.4), predominantly IgG subtype, were heavily pretreated (4 median prior treatments), and were Durie-Salmon stage II (n=13) or III (n=8). After increasing premedications and slowing administration, infusions were well tolerated (Grade 1–2). There was 1 DLT (infusion reaction) and 3 SAEs (bact. meningitis, confusion/hypercalcemia, fever post demerol) at 1.5 mg/kg, 1 DLT (unexplained anemia) and 2 SAEs (cord compression, epistaxis/thrombocytopenia), at 4.0 mg/kg, but no DLTs or SAEs at 8.0 mg/kg. There has been no pattern of other AEs nor effects on routine laboratories, including serum chemistries, CBC, serum immunoglobulins, B- or T-cells, and no cases of HAHA. At current doses, milatuzumab is rapidly cleared from serum, with little accumulation and low trough levels across infusions. There have been no objective responses so far, but 4 pts have had stable disease by EBMT criteria for at least 3 months post-treatment, occurring with a possible trend towards higher milatuzumab serum levels than pts with earlier disease progression. Conclusions: Milatuzumab doses up to 8.0 mg/kg may be given safely twice-weekly for 4 weeks. In spite of rapid clearance, several patients have had disease stabilization at 4.0 and 8.0 mg/kg doses, which is encouraging. Accrual of the next cohort receiving 16.0 mg/kg is ongoing. [Table: see text]
Role of autologous stem cell transplant after induction therapy with bortezomib-lenolidomide or bortezomib-thalidomide in newly diagnosed multiple myeloma patients
Authors: Shah N. , Weber D. , Orlowski R. , Wang M. , Thomas S. K. , Richards T. , Giralt S. , Qazilbash M. , Alexanian R. , Shah J. J. 
Published: August 2020

8596 Background: The introduction of novel therapeutic options with bortezomib and immunomodulatory agents in the up-front management of multiple myeloma (MM) has significantly improved induction response rates. However, the role of high dose chemotherapy and autologous stem cell transplant (ASCT) after induction with these highly active agents is not known, especially in patients with only a partial response to induction therapy. Methods: We conducted a retrospective review of 95 newly diagnosed MM patients treated with induction bortezomib-lenolidomide-dexamethasone (BLD) or bortezomib-thalidomide-dexamethasone (BTD) prior to ASCT. Responses were graded according to IMWG criteria. Results: 19 patients received BLD and 76 patients received BTD. All patients were conditioned with a melphalan-based regimen. Of the 19 patients who underwent induction with BLD, complete response (CR), very good partial response (VGPR) and partial response (PR) were achieved in 2 (11%), 8 (42%) and 9 (47%) respectively for an overall response rate (ORR) of 19/19 (100%). After ASCT, CR, VGPR and PR were achieved in 9 (47%), 5 (26%) and 5 (26%) respectively for a continued ORR of 21/21 (100%). Notably, 4/8 (50%) of patients with a VGPR after induction therapy with BLD improved to a CR after ASCT. 3/9 (33%) of patients with an initial PR to BLD improved to a CR and 1/9 (11%) with a PR improved to VGPR after ASCT. Of the 76 patients who underwent induction with BTD, CR, VGPR and PR were achieved in 6 (8%), 37 (49%) and 31(41%) respectively for an ORR of 74/76 (97%). 1 patient had stable disease and 1 patient had progressive disease. After ASCT, 27/76 (36%) achieved a CR, 30/76 (39%) a VGPR and 18/76 (24%) a PR for an ORR of 75/76 (99%). Of the patients who initially had a VGPR to BTD 16/37 (43%) improved to a CR while 5/32(16%)of PR patients improved to a CR and 9/32 (28%) of PR patients improved to a VGPR. Conclusions: Of the 40 patients who only achieved a PR after induction therapy with BLD or BTD, 16 (40%) had further improvement to a CR or VGPR after ASCT. Thus there is a significant benefit of ASCT in these patients who initially demonstrate relative resistance to induction therapy with highly active regimens. [Table: see text]
A phase I MMRC clinical trial testing the combination of bortezomib and tipifarnib in relapsed/refractory multiple myeloma
Authors: Lonial S. , Francis D. , Karanes C. , Trudel S. , Dollard A. , Harvey D. , Kaufman J. 
Published: August 2020

8597 Background: Preclinical work from our group has demonstrated that the combination of a farnesyl transferase inhibitor and bortezomib results in enhanced plasma cell apoptosis, and more recently, we have suggested that the mechanism for this synergy is due to inhibition of HDAC6, and inhibition of the proteasome and aggresome pathway. Methods: Patients with relapsed or refractory myeloma were treated with bortezomib at 1.0 or 1.3 mg/m2 on a standard schedule in conjunction with escalating doses of tipifarnib (100–400mg/BID) given on days 2–15 every 21 days. Dose escalation was accomplished using an adaptive phase I design (Escalation With Overdose Control). Results: 22 patients have been enrolled, of which 18 are evaluable, into respective tipifarnib dose levels 100 mg (n=6), 200mg (n=5) and 300mg (n=5) and 400mg (n=2). Median age for the enrolled patients is 59 and median time from myeloma diagnosis was 4.7 years. The average number of prior therapies was 4.5. Among these patients with advanced myeloma and refractory disease, stabilization of disease or better was seen among 8/10 patients with 2 of the 8 achieving an MR. Among the patients achieving clinical benefit, 1 patient had a stable M-protein, but experienced an 80% reduction in circulating plasma cells while on therapy, and another has had a 75% reduction in the free light chain assay. The most common drug related side effect was was Gr2 diarrhea (23.5%). Hematologic toxicities were difficult to ascertain as patients had advanced myeloma and many were entered onto study with platelet counts between 25 and 50. Additional grade 3 toxicities included renal insufficiency (related to PD), pneumonia and altered mental status which were all considered not related to study drug but to progression of disease. There were no Grade 3-5 drug related toxicities. One patient experienced grade 2 peripheral neuropathy who did not have pre existing PN at baseline. Conclusions: The combination of bortezomib and tipifarnib is supported by preclinical rationale and has produced stable disease or better among 10 of 18 patients with refractory myeloma. Optimal dose of tipifarnib and bortezomib have yet to be defined, and additional patients are being enrolled with 1.3mg/m2 of bortezomib, and escalating doses of tipifarnib. [Table: see text]
Prognostic factor analyses of myeloma (MM) survival outcomes on intergroup trial S9321 (int 0141): Examining whether different variables govern different time segments of survival
Authors: Crowley J. , Bolejack V. , Robert K. , Anderson K. , Barlogie B. 
Published: August 2020

8599 Background: MM survival varies enormously from few months to more than a decade. Baseline prognostic factors (PF) have been identified that are linked to survival outcomes, especially B2M and albumin. MM survival plots are typically characterized by 3 segments of slopes with decreasing steepness, suggesting that different PF may govern these time segments. Methods: We therefore examined, in S9321, PF that were associated with overall survival (OS) from baseline (BL) and from 3 subsequent landmarks 3, 5, and 7 years later (LM3, LM5, LM7). With a median follow-up of 9 years, OS and EFS were virtually identical in transplant and standard therapy arms so that the data were pooled. Results: Median OS and EFS for 817 eligible patients are 48 and 22 months. The BL model identified age (>60yr), hemoglobin (<10g/gL), platelet count (<130,000/uL), albumin (<3.5g/dL), B2M (>3.5g/dL), calcium (>10mg/dL), creatinine (>2mg/dL), LDH (>190U/L), performance status (PS, >1), IL-6 level (>140mg/L) and plasma cell labeling index (PCLI, >1%) as being univariately associated with short OS, while age (p=0.002), platelet count (p=0.04), calcium (p<0.001), B2M (p=0.002), LDH (p=0.010) and PCLI (p<0.001) retained significance in multivariate analysis. For the LM3 analyses, age (p=0.006) and B2M (p=0.009) were independently associated with poor OS, whereas PCLI was the only PF associated with LM5 (p=0.026) and age with LM7 (p<0.001). While associated univariately with OS from BL, CRP, platelet count, hemoglobin, albumin, calcium, creatinine, LDH, IL6 and PS all failed to affect OS from later LM times. Conclusions: Whereas the initial 3 years of OS are governed by a combination of features related to disease aggressiveness (LDH, calcium, albumin, CRP), tumor burden (hemoglobin, platelet count) and host tolerance (PS, creatinine), B2M and PCLI as reflectors of tumor burden and proliferation have sustained long-term OS implications. The age factor figures in partly due to death from other causes. In an era of ever-improving survival outcomes, such LM-based PF analysis may reveal trial-specific differences and thus provide guidance toward individualizing therapy. [Table: see text]
A phase II study of imatinib mesylate (IM) for patients with advanced melanoma harboring somatic alterations of KIT
Authors: Carvajal R. D. , Chapman P. B. , Wolchok J. D. , Cane L. , Teitcher J. B. , Lutzky J. , Pavlick A. C. , Bastian B. C. , Antonescu C. R. , Schwartz G. K. 
Published: August 2020

9001 Background: Three prior phase II studies of Imatinib mesylate (IM) in 62 pts with advanced melanoma reported only 1 response in a pt with acral melanoma. A proportion of melanomas arising from acral, mucosal, and chronic sun damaged (CSD) sites are characterized by KIT mutations (mut) or amplifications (amp) and we hypothesized that this subset of tumors would be sensitive to IM. We thus designed this phase II study of IM restricted to pts with melanoma harboring such alterations in KIT. Methods: Pts with unresectable melanoma arising from acral, mucosal, and CSD sites whose tumor harbored a 4q12 amp by FISH or mut in KIT and who had measureable disease by RECIST were eligible. Pts received IM 400 mg BID continually. Response was assessed every cycle (6 wks). A Simon 2-stage design was employed where initially 16 pts would be treated; if ≥ 2 responses were observed, a total of 25 pts would be enrolled. If ≥5 responses were seen in 25 pts, the study was to be considered positive. Results: Of 81 pt tumors screened, 17 (21%) had a KITmut or amp: 5/22 (23%) acral, 12/45 (27%) mucosal, 0/13 (0%) CSD, 0/1 (0%) unknown primary. 12 (15%) had a mut only; 4 (5%) had an amplification only; 1 (2%) had both. Thus far, 7 have been treated, with 5 currently evaluable for response. Median age: 64 yrs (range, 61–86); 2 male/5 female; median KPS: 90 (range, 80- 90); median # of prior therapies: 1 (range, 0–4). 3 pts (43%) achieved a PR (18 wks - exon 13 mut; 21 wks, ongoing - exon 11 mut; 18 wks, ongoing - exon 11 mut & amp); 2 pts (28%) achieved SD (12 wks - exon 11 mut; 11 wks - amp). 3 pts required a dose reduction to 400 mg QD for rash, GI toxicity and fatigue. 1 pt required a second dose reduction to 300 mg QD for visual changes. Conclusions: In this pt population, 21% of tumors are characterized by mut or amp of KIT. The 3 responses observed have allowed expansion to the second stage of enrollment which is currently on-going. While IM has limited activity in a non-selected melanoma pt population, a substantial proportion of melanomas harboring KIT mut or amp appear to respond. It may be possible to identify appropriate pts prospectively for treatment with IM. (Supported by R01FD003445–01, ASCO YIA, N01CM62206, and the Live4Life Foundation.) No significant financial relationships to disclose.
Association of gene expression profile in metastatic melanoma and survival to a dendritic cell-based vaccine
Authors: Gajewski T. , Zha Y. , Thurner B. , Schuler G. 
Published: August 2020

9002 Background: Emerging data suggests that features of the melanoma tumor microenvironment may determine the clinical outcome to immunotherapies. We recently have observed a gene expression signature that correlated with a favorable clinical outcome in response to an IL-12-based melanoma vaccine. Increased expression of chemokine genes and T cell transcripts, and decreased expression of genes associated with aggressive tumor biology, were observed in the favorable group. To determine whether these patterns were reproducible, gene expression profiling was performed from an independent vaccine clinical trial. Methods: Patients with advanced melanoma were treated with autologous, mature monocyte-derived dendritic cells loaded with a combination of melanoma antigen peptides. Pretreatment biopsies were cryopreserved for RNA extraction and gene expression profiling. Patients were categorized into “long survival” (> 24 months) or “short survival” outcomes. Supervised hierarchical clustering was performed to identify genes differentially expressed in the two outcome groups. Results: RNA that passed quality control was obtained from 17 stage IV patients, 5 with a short survival and 12 with a long survival. 408 genes were differentially at least 2- fold. Consistent with previous observations, tumors from favorable outcome patients expressed higher levels of several T cell-specific genes, including Thy1 and CD28; chemokines, including CCL19, CXCL12, and CXCL14; and other immune genes, including LTβ, IL-1R, IFNαR2, IL27R, CD69, and FcRs. Conversely, tumors from unfavorable outcome patients expressed higher levels of pro- angiogeneic genes, including Flt1; anti-apoptotic genes, including SerpinH1 and Serpine1; and multiple collagens. Conclusions: Our results confirm that a subset of transcripts expressed in melanoma metastases may be useful as a predictive biomarker for response to melanoma vaccines. The categories of genes identified point toward new opportunities for overcoming resistance mechanisms. Future studies should integrate gene expression profiling of pre-treatment biopsies as a stratification or enrichment factor in immunotherapy trials. No significant financial relationships to disclose.
Clinical relevance of miRNA expression in metastatic melanoma
Authors: Segura M. F. , Zakrzewski J. , Belitskaya-Levy I. , Gaziel A. , Kushnir M. , Hoshen M. , Hanniford D. , Cohen D. , Osman I. , Hernando E. 
Published: August 2020

9006 Background: We recently reported the identification of a specific miRNA cluster frequently overexpressed in melanoma which enhances the metastatic behavior (Segura et al., 2009. PNAS. In press). In this study, we aim to define the clinical relevance of miRNA expression, in particular whether miRNAs can serve as prognostic biomarkers for melanoma patients. Methods: Total RNA was extracted from formalin-fixed paraffin embedded (FFPE) tissue samples from 61 metastatic melanoma specimens (25 lymph node, 16 soft tissue/skin, 13 brain and 7 visceral) accrued by the NYU Interdisciplinary Melanoma Cooperative Group (IMCG). RNA was hybridized into miRNA arrays (miRdicatorTM, Rosetta Genomics, Inc) containing probes for more than 600 miRNA sequences, including all the human miRNAs in the 9.0 version of miRBase. The Significance Analysis of Microarrays (SAM) was used to identify miRNAs significantly associated with survival, and the False Discovery Rate (FDR) approach was used to adjust for multiple comparisons. Results: We identified a signature of 18 miRNAs, whose up-regulation significantly associates with better prognosis (increased overall survival and post-recurrence survival) using the FDR of 0%. Quantitative RT-PCR on the same tissues has verified the array results in 15 out of 15 miRNAs analyzed. Some of these miRNAs were significantly associated with stage at recurrence, while others significantly correlated with the site of metastasis (i.e. visceral, brain, soft-tissue). Using cross-validation, we selected a miRNA signature consisting of 10 of these significant miRNAs with lowest misclassification error in predicting 1.5-year post-recurrence survival. We are currently validating these findings in a separate cohort of metastatic patients. Furthermore, we are investigating whether these ‘protective' miRNAs can be detected in the corresponding primary lesions and thus, whether they already hold prognostic value at early stages of the disease. Conclusions: Our data suggest a role for miRNAs as melanoma biomarkers, and support the development of miRNA- based monitoring assays. These analyses are also expanding our understanding of the molecular alterations underlying melanoma progression, by revealing miRNAs whose down-regulation associates with a more aggressive biological behavior. [Table: see text]
Association of baseline and on-study tumor biopsy markers with clinical activity in patients (pts) with advanced melanoma treated with ipilimumab
Authors: Hamid O. , Chasalow S. D. , Tsuchihashi Z. , Alaparthy S. , Galbraith S. , Berman D. 
Published: August 2020

9008 Background: Ipilimumab is a fully human monoclonal antibody to cytotoxic T-lymphocyte antigen-4. Identifying predictive markers may help select advanced melanoma pts most likely to benefit from ipilimumab therapy. Biomarkers in the tumor microenvironment are thought to be more relevant for predicting response than those in the peripheral blood. Methods: We examined tumor biopsy markers in a Phase II study CA184004 (ipilimumab 3 and 10 mg/kg). Ipilimumab was administered every 3 weeks (Q3W) x 4; eligible pts could receive ipilimumab Q12W starting Wk 24. Pre- and post-treatment (Wk 4) tumor biopsies were performed for hematoxylin and eosin analysis of tumor-infiltrating lymphocytes (TILs); immunohistochemistry of FOXP3 and indoleamine 2,3-dioxygenase (IDO); and mRNA expression profile analysis. Response was assessed with modified World Health Organization criteria. Associations between tumor biomarkers and clinical activity (complete response, partial response, or stable disease ≥ 24 wks) were assessed. Results: Ipilimumab 3 or 10 mg/kg was administered to 40 and 42 pts, respectively. In tumor biopsies, clinical activity was associated with high expression of FOXP3 (P = 0.014) and IDO (P = 0.012) at baseline and an increase from baseline in TILs (Wk 4) (P = 0.005) ( Table ). Tumor mRNA profiling identified genes with significant changes from baseline in expression, or with baseline expression levels that may be associated with clinical activity. These included various immune response genes and known melanoma antigens. Conclusions: Biomarkers in the tumor microenvironment have been demonstrated to be associated with clinical activity in pts treated with ipilimumab. [Table: see text] [Table: see text]
Prediction of response to alkylator-based chemotherapy in metastatic melanoma (MM) using gene expression and promoter methylation signatures
Authors: Tawbi H. A. , Buch S. , Pancoska P. , Lin Y. , Saul M. , Romkes M. , Sobol R. , Kirkwood J. M. 
Published: August 2020

9009 Background: Temozolomide and dacarbazine (TMZ and DTIC) remain the mainstay of alkylator-based chemotherapy for MM, despite response rates of 10–15% and the absence of any impact on survival. Classification of patients according to responsiveness can guide the individualization of therapy and inform approaches to abrogate mechanisms of chemotherapy resistance. Epigenetic mechanisms play an important role in regulation of genes associated with resistance and were evaluated in tandem with gene expression profiling in biological samples from MM patients (pts) to refine our understanding of the epigenomic-genomic-phenotypic interplay. Methods: We examined promoter methylation and gene expression in tumor tissues of 21 pts with MM treated with TMZ or DTIC, using high throughput technologies (Illumina Inc). The cases were divided into responder (R) and non-responder (NR) groups based on clinical response. The data were analyzed using Prediction Analysis of Microarrays (PAM) from BRB array tools. Results: Differential promoter methylation analysis revealed that 63.6% of promoter sites were hypomethylated in tumors obtained from R pts (p<0.0001). PAM analysis of gene expression data revealed that a classifier set consisting of 82 genes was able to predict NRs from Rs with 83% sensitivity and 89% specificity. Promoter methylation profiling did not independently correlate with R status. A simultaneous analysis of the promoter methylation and gene expression values first stratified into 3 data-driven categories and then combined into a 3 by 3 matrix allowed us to identify a common gene expression/methylation signature of 15 genes that classified both NR and R groups accurately 100% of the time. Conclusions: Gene expression signatures independently predict response to chemotherapy in MM, however promoter methylation profiling alone does not. Analysis of combined gene expression and promoter methylation in a well- annotated clinical data set dichotomized according to response identified a highly predictive signature. The findings from this study are qualified by the relatively small sample size and are currently being validated in an expanded sample set. Supported in part by the ECOG Paul Carbone, MD, Fellowship Award. No significant financial relationships to disclose.