bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase I trial of TRU-016, an anti-CD37 small modular immunopharmaceutical (SMIP) in relapsed and refractory CLL
Authors: Andritsos L. , Furman R. , Flinn I. W. , Foreno-Torres A. , Flynn J. M. , Stromatt S. C. , Byrd J. C. 
Published: August 2020

3017 Background: CD37 is a tetraspan family member expressed predominantly on normal and transformed B-cells across a wide range of maturational stages. TRU-016 is a novel humanized anti-CD37 SMIP. Pre-clinical studies have demonstrated CD37 SMIP mediates significantly greater direct and NK-cell mediated killing of CLL cells as compared to other therapeutic antibodies used in CLL. A phase I study with TRU-016 was initiated based upon these data. Methods: Patients with relapsed/refractory CLL or SLL who had adequate organ function, platelets > 30,000/mm3 were eligible. Six doses and two different schedules (cohorts 1–8) have/or will be studied. The planned doses range from 0.03 mg/kg to 10 mg/kg IV once a week for 4 doses (cohort 1–6). The second schedule (cohort 7–8) will test 3.0 or 10.0 mg/kg on days 1, 3, and 5 the first week followed by 3 weekly doses. Dose escalation and de-escalation is based on CTC AE toxicity grades. Results: To date, 10 patients have been enrolled (cohort 1–5) and completed treatment; 1 patient (cohort 1–3: 0.03, 0.1, and 0.3 mg/kg); 3 patients at 1.0 mg/kg, and 4 patients at 3.0 mg/kg. Eight of the 10 have high risk genomic features [del(17p13.1), n=5 and del(11q22.3), n=3]. No dose limiting toxicities or serious adverse events have occurred. Mild (grade 1–2) infusion toxicity has been observed in 3 patients. Beginning with the 0.3 mg/kg dose, all eight patients demonstrated evidence of biological activity including patients with del(17p13.1). Two patients had partial clearing of leukemia cutis, and the other six had 27–94% reduction in peripheral lymphocyte count. One pt. had an increase in Hgb of 40% and a reduction in lymph nodes of 36%. Two patients had a significant increase in platelet count. Enrollment to cohort 6 is complete and further up-to-date data will be presented. Conclusions: To date, TRU-016 is a well tolerated treatment with minimal infusional toxicity and no observed dose limiting toxicity. Encouraging reduction in tumor lymphocyte blood counts, lymph node/spleen size and improvement in normal hematopoeitic function in patients with high risk genomic CLL have already been observed at low, non-saturating doses of CD37. Future single agent and combination studies of Tru16 in CLL are warranted. [Table: see text]
Association of peripheral blood absolute lymphocyte count (ALC) and clinical activity in patients (pts) with advanced melanoma treated with ipilimumab
Authors: Berman D. M. , Wolchok J. , Weber J. , Hamid O. , O'Day S. , Chasalow S. D. 
Published: August 2020

3020 Background: Ipilimumab, an anti-CTLA-4 monoclonal antibody, induces durable survival benefits in advanced melanoma pts. Peripheral ALC from routine safety labs were collected from 533 pts with unresectable stage III/IV malignant melanoma treated with ipilimumab 0.3, 3, or 10 mg/kg (recommended dose) in 4 Phase II studies. Methods: Ipilimumab was given every 3 weeks (Q3W) x 4; eligible pts could then continue to receive ipilimumab Q12W starting at Week 24. ALC was analyzed first in studies CA184007, 008, and 022 combined (ipilimumab 0.3, 3, or 10 mg/kg), and then prospectively analyzed for confirmation in study CA184004 (ipilimumab 3 or 10 mg/kg). Using the modified World Health Organization criteria, Response-evaluable pts (n = 444) were classified by clinical activity (complete or partial response, or stable disease ≥ 24 wks) or without clinical activity. Results: Across studies 007, 008, and 022, pts with clinical activity had a greater mean rate of ALC change (slope) than did pts without clinical activity (P = 0.0013); no pt with a negative ALC slope over the induction period had clinical activity (P = 0.0013) (Table). These associations were confirmed in 004; pts with benefit had a greater mean slope (P = 0.00042), and only 1 pt with a (slightly) negative ALC slope had clinical activity (Table). Over all pts (n = 533), the rate of ALC change was significantly associated with dose (007, 008, 022: P < 0.0001; 004: P = 0.0015). Conclusions: A higher rate of ALC change was associated with clinical activity in a pooled analysis of studies 007, 008, and 022 (n = 379). This was confirmed in study 004 (n = 65). A negative ALC slope was associated with a lack of clinical activity. In both analyses, the rate of change in ALC was dose-dependent, favoring 10 mg/kg. [Table: see text] [Table: see text]
Effect of clinical status and previous treatment of melanoma patients on expansion of TIL for adoptive T-cell therapy
Authors: Peddareddigari V. R. , Miller P. W. , Nebiyou B. B. , Overwijk W. W. , Ross M. I. , Lee J. E. , Gershenwald J. E. , Prieto V. G. , Hwu P. , Radvanyi L. 
Published: August 2020

3021 Background: Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TIL) is a promising therapy for the treatment of metastatic melanoma. Trials at the NCI have shown a 50% response rate. However, outside of the NCI, ACT has been quite limited and little is known about how patient characteristics and prior treatment affect large-scale TIL expansion needed for treatment. Methods: As part of a phase II melanoma ACT clinical trial at M. D. Anderson Cancer Center, we evaluated how clinical characteristics such as age, gender, biopsy site, melanoma type, primary tumor location, and prior treatment of patients (N=134) affected TIL expansion rates. 159 isolated metastatic melanomas (19 patients having >1 tumor harvest) were analyzed for the ability to expand a minimum of 40 million TIL, considered a minimum number for the subsequent rapid expansion protocol (REP) needed for TIL infusion. Effects of these parameters on TIL anti-tumor reactivity and TIL/tumor fragment were also analyzed. Statistical analysis was done by either Fisher's Exact test, Wilcoxon Rank Sum test, or Kruskal-Wallis Test. Results: 54.7% of the samples evaluated generated ≥ 40 million TIL, and 70% of 70 samples tested had anti-tumor reactive TIL. There was a significant relationship between age categories (p=0.0216) and gender (p=0.0164) on TIL expansion success. Younger patients did the best and females did better than males (odds 2.19, p=0.044). The site of the primary melanoma affected success of TIL expansion (p=0.0059), while no effect of tumor biopsy site and histological type was found. Prior chemotherapy (or biochemotherapy) greatly reduced TIL growth (odds 0.32, p=0.010) when compared to no prior therapy. Multivariate linear regression analyses showed that prior chemotherapy decreased TIL/tumor fragment yield by 6.19 million (p=0.0004) while immunotherapy increased it by 3.51 million (p=0.16) compared to no prior therapy. Total TIL yield or TIL/tumor fragment did not correlate with patient overall survival. Conclusions: Parameters such as age, sex, primary melanoma site, and prior therapy significantly affect TIL expansion and should be considered in selecting patients for melanoma ACT. No significant financial relationships to disclose.
Association of primary melanoma ulceration and clinical benefit of adjuvant vaccination with tumor-specific antigenic peptides
Authors: Baurain J. , Stas M. , Hammouch F. , Gillain A. , Feyens A. , Van Baren N. , Tromme I. , Van Wijck R. , Garmyn M. , Coulie P. G. 
Published: August 2020

3022 Background: Therapeutic vaccination of metastatic melanoma patients with detectable disease is followed by tumor regression in ±10% of the patients, mostly with locoregional disease. Considering the absence of an effective treatment to prevent relapses of cutaneous melanoma, we have applied a multipeptide vaccine in the adjuvant setting. Methods and Results: We treated 45 HLA-A2-positive melanoma patients with no evidence of disease but at high risk of relapse. They received 5 vaccines every 3 weeks, then one every 3 months over 2 years. A first group (n=14) received 4 antigenic peptides derived from MAGE-A3, NA17, gp100 and Tyrosinase, emulsified independently in 4x1ml of Montanide ISA51. A second group (n=16) received the 4 peptides emulsified together in 1x1ml of Montanide. A third group (n= 15) received the 4 peptides alone. Forty-one patients were eligible for immune response analysis after 5 injections. A T-cell response to at least one peptide was detected in 21/27 patients vaccinated with Montanide, but in none of 14 vaccinated with peptides alone. Median follow-up time was 24 months ±10 months (SD). Relapse free survival (RFS) at 18 months was 37% for all the patients and no significant difference was observed between patients vaccinated with or without Montanide: 41% and 27%, respectively. Median distant metastasis-free survival time (DMFS) was doubled for patients vaccinated with vs without Montanide (p=0.132). Multivariate analysis for various prognostic factors including sex, age, PS, vaccine type, or immune response suggested that the ulceration of the primary tumor was associated with a better clinical course following vaccination (HR=0.295 with IC95%: 0.09–0.97). Conclusions: Vaccination with mutiple peptides in Montanide is well tolerated and elicits specific immune responses. Patients vaccinated with peptides in Montanide have a prolonged RFS and DMFS compared to whose vaccinated with peptides alone. Patients who had an ulcerated primary tumor seem to benefit more from this adjuvant vaccine. These results warrant further evaluation of such vaccines in a randomized trial with the ulceration of the primary tumor as a stratification factor. No significant financial relationships to disclose.
Multicenter phase II study of sequential chemotherapy, radiotherapy, and immunotherapy in locally advanced pancreatic (Pa) and biliary tree (Bt) adenocarcinoma (ADK)
Authors: Recchia F. , Sica G. , Candeloro G. , Bisegna R. , Necozione S. , Bonfili P. , Tombolini V. , Rea S. 
Published: August 2020

3047 Background: The aim of this study was to evaluate the activity and toxicity of a multistep, sequential treatment including induction chemotherapy (ICT), consolidation chemoradiotherapy (CXRT), and maintenance immunotherapy (MI) in untreated patients with locally advanced (LA), inoperable, or incompletely resected Pa and Bt ADK. MI with low-dose interleukin-2 (IL-2) and 13-cis-retinoic acid (RA) was given in order to enhance the immune function, which could eradicate minimal residual disease, as previously shown (Clin Cancer Res 2001). Methods: From September 2003 to September 2007, 54 patients, 32 men, 22 women, 63% with Pa and 37% with Bt ADK, mean age of 63 years (range 36–75), were treated with an ICT consisting of 3 courses of cisplatin, 70 mg/m2 day 1, gemcitabine 1000 mg/m2 day 1 and 8 every 3 weeks. Patients who were progression-free (PF) after ICT received CXRT, 45 Gy in 25 fractions, using coplanar four-field technique, with concurrent capecitabine 850 mg/m2/day. Six weeks after completion of CXRT, patients were restaged: In the absence of disease progression, they received, as an MI, IL-2, 1.8 x 106 I.U. and RA, 5 mg/kg, 5 days/week, 3 weeks/month for 1 year and thereafter until progression. Results: After a median follow-up of 27.5 months, all patients were evaluable. A response rate of 26% (95% c.i. 15–40%), was observed, with 44.5% of patients achieving stable disease. Thirty-eight patients, 27 with Pa and 11 with Bt ADK, had a clinical benefit from ICT, and were treated with CXRT. Fourteen PF patients, 7 Pa and 7 Bt ADK, received an MI with IL-2 and RA. Median progression-free survival (PFS) and overall survival (OS) for all 54 patients were 6.8 and 12.1 months, respectively, while the 14 patients treated with MI had a 5-year PFS and OS rate of 36% and 58%, respectively. Grade 3–4 hematological and gastrointestinal toxicity were observed in 30% and 37% of patients, respectively, while 28% of patients had grade 1–2 autoimmune reactions. Conclusions: These results support the efficacy and safety of a multistep sequential treatment with ICT, followed by CXRT, and an MI with IL-2 and RA, in patients with LA, inoperable or incompletely resected Pa and Bt ADK. Further studies are necessary to validate this strategy. No significant financial relationships to disclose.
A novel recombinant tandem repeat DNA vaccine targeting at MUC1
Authors: Wu W. , Jin D. , Lou W. , Fan J. , Wang D. , Qin X. 
Published: August 2020

3066 Background: Tandem repeat (TR) is the key epitope of mucin 1 (MUC1) for inducing cytotoxic T lymphocytes (CTL) to kill the tumor cells specifically. A novel recombinant TR DNA vaccine was constructed to study its induced immune responses. Methods: A recombinant human TR (rhTR) gene encoding a single TR polypeptide of MUC1 was synthesized and cloned into the multiple cloning sites of plasmid pcDNA3.1/Myc-his (+) A to construct the recombinant plasmid pcDNA3.1-TR/Myc-his (+) A (pTR plasmid). Expression of pTR plasmid was confirmed by transfection assay and Western blot analysis. C57BL/6 (H-2b) mice were immunized with pTR plasmid (n=15) by tibial muscle injection. Mice inoculated with the empty vector (EV group, n=15) and 0.9% NaCl solution (NS group, n=15) were used as vector and blank control respectively. Four weeks later, all mice were immunized again. Specific antibody detection and cytotoxic assay were used to evaluate the vaccine-induced TR specific immune responses. Results: DNA sequencing confirmed that the pTR plasmid was exactly constructed. Transfection assay and Western blot analysis found that the transfected COS7 cells expressed TR polypeptide of MUC1 48 hours after transfection. Cytotoxic assay showed that immunization with pTR plasmid into C57BL/6 mice resulted in more efficient induction of CTL specific cytolysis against TR polypeptide than that of EV group and NS group (p<0.01). Vaccine immunized mice had a higher equivalent concentration of anti-TR specific antibodies (2324μg/ml±238μg/ml) than that of EV group (1896μg/ml±533μg/ml, p<0.01) and NS group (1736μg/ml±142μg/ml, p<0.01). Conclusions: The novel recombinant TR DNA vaccine targeting at MUC1 was exactly constructed, immunization with which could induce TR specific CTL response and antibodies response in mice. No significant financial relationships to disclose.
A phase I study of XL281, a selective oral RAF kinase inhibitor, in patients (Pts) with advanced solid tumors
Authors: Schwartz G. K. , Robertson S. , Shen A. , Wang E. , Pace L. , Dials H. , Mendelson D. , Shannon P. , Gordon M. 
Published: August 2020

3513 Background: XL281 is a potent and selective inhibitor of wild type and mutant RAF kinases showing anti-tumor activity in multiple xenograft models. Mutations in KRAS or BRAF can activate the RAF/MEK/ERK pathway in human tumors and may promote sensitivity to RAF kinase inhibitors. Methods: Pts were enrolled in successive cohorts of XL281 orally once daily on a 28-day cycle. Tumor response was assessed per RECIST every 8 wks. Plasma pharmacokinetic and pharmacodynamic samples were collected. The maximum tolerated dose (MTD) was expanded to 10 pts each with colorectal (CRC), melanoma, papillary thyroid (PTC) and NSCLC. Pre- and post-dose tumor and surrogate tissues were obtained. Biomarker and genotype analyses of pathway genes were performed. Results: The dose escalation phase is complete; 30 pts were treated with XL281. DLTs of fatigue, nausea, vomiting, and diarrhea were observed at the MAD (225 mg). The MTD is 150 mg. The most common related AEs included Grade 1/2, fatigue (48%), diarrhea (35%), nausea (35%), vomiting (35%) and anorexia (30%). Three pts had related AEs ≥G3: hypokalemia, nausea, and vomiting. One pt with an ocular melanoma demonstrated a cPR of 4 mos duration. Twelve pts had SD (3 -17+ mos), including 2 with I131-refractory PTC harboring BRAF V600E mutations (15+ and 17+ mos). Nine of these pts had decreases in target lesions (5–29%), including a pt with KRAS mutant CRC on study for 20 wks with marked symptomatic improvement. At the MTD, paired biopsies from 4 pts (3 melanoma, 1 NSCLC) show an average 72 % decrease in pMEK, 68 % decrease in pERK, 24 % decrease in Ki67 (proliferation) and 64 % increase in TUNEL (apoptosis). Three of 6 evaluable pts in the MTD cohort show SD at first assessment, including 1 melanoma pt with a NRAS Q61R mutation who showed a 20% decrease in target lesions. Conclusions: XL281 was generally well tolerated and the MTD was established at 150 mg. One cPR occurred in an ocular melanoma subject, and clinical benefit (PR or SD) occurred in 43% (13/30) of pts in the dose-escalation phase. XL281 demonstrates biological activity by modulation of the RAF pathway in tumor and surrogate tissue, with decreases in cell proliferation and increases in apoptosis. [Table: see text]
Functional imaging using DCE-US: Which parameter for the early evaluation of antiangiogenetic therapies?
Authors: Lassau N. , Koscielny S. , Chebil M. , Chami L. , Bendjilali R. , Roche A. , Escudier B. , LeCesne A. , Soria J. 
Published: August 2020

3524 Background: The early evaluation of anti-angiogenic treatments is a challenge in oncology. Functional imaging methods based on the measure of tumoral vascularization have been developed using different modalities (CT, MRI, US). We analyzed the response in four studies using different targeted treatments with dynamic contrast enhanced-ultrasonography (DCE-US). Seven parameters characterizing tumoral perfusion were estimated. The objective of the study was to determine which parameter is the most appropriate to confirm earlier the efficacy of treatments. Methods: A total of 823 DCE-US were performed in 117 patients included in 4 following studies (multikinase inhibitor targeting angiogenic-receptor with a cytotoxic or thyrosine-kinase inhibitor targeted angiogenic-receptor and C-kit or monoclonal antibody anti-VEGFR). Each DCE-US was performed using contrast agent (Sonovue, Bracco) with perfusion and quantification softwares (Toshiba) from raw linear data with a high temporal resolution: 4 frames per second during 3 minutes. Seven quantitative parameters of perfusion were estimated: peak intensity (PI) and area under the total curve (AUC), area under the wash-in (AUWI), area under the wash-out (AUWO), time to peak intensity, mean transit time (MTT), wash-in slope. DCE-US were performed before treatment and after D3, D 8, 15, 21 (according each study design) and every 2 months. Patients were classified in good responders and bad responders according the response (RECIST on CT-scan) after 2 cycles or 2 months. Results: Among the 7 parameters, 2 parameters related to the blood volume studies (AUC and AUWO) were always earlier significantly modified (p = 0.04 to p = 0.004). One was never modified: MTT. For the 4 others, it's depending of each study. Conclusions: DCE-US appears as a sensitive tool to evaluate tumoral response to anti-angiogenic drugs. Functional parameters related to the blood volume are more pertinent and represent a key add value to early evaluation of these therapies studies. No significant financial relationships to disclose.
Correlation of plasma levels of free insulin-like growth factor 1 and clinical benefit of the IGF-IR inhibitor figitumumab (CP- 751, 871)
Authors: Hixon M. L. , Gualberto A. , Demers L. , Paz-Ares L. G. , Novello S. , Blakely L. J. , Langer C. L. , Lipton A. , Pollak M. , Karp D. D. 
Published: August 2020

3539 Background: Free IGF-1 (fIGF-1) represents the biologically active fraction of IGF-1, the main circulating ligand of the Insulin-like Growth Factor type I Receptor (IGF-IR). Signaling through the IGF-IR induces tumor survival and resistance to cancer therapy. Figitumumab (F) (CP-751,871) inhibits IGF-1-induced IGF-IR autophosphorylation with an IC50 of 0.42 nmol/L. Methods: Plasma levels of fIGF-1 were measured in a phase 1b/2 multi-center study of Paclitaxel (T) and Carboplatin (C) and F in patients (pts) with treatment-naïve NSCLC. Other serum markers of the IGF-IR pathway, including circulating soluble IGF-IR (sIGF-IR), IGFBP3 and ALS (acid-labile subunit), were also investigated. The Kaplan-Meier method was used to estimate median survival times. Results: A total of 536 blood samples from 159 pts were analyzed. Baseline median and range fIGF-1 were 0.53 and 0.07–1.99 ng/mL. fIGF-1 directly correlated with IGFBP3 and ALS, and inversely with sIGF-IR (Rho=-0.430, p=0.03). Treatment with F resulted in dose-dependent accumulation of fIGF-1 with a sustained >10 fold increase in fIGF-1 plasma levels at the 20 mg/kg dose, suggesting complete systemic blockade of fIGF-1 binding to the IGF-IR. sIGF-IR decreased and IGFBP3 increased in response to F, but increases in IGBP3 were more modest than those of fIGF-1. Baseline plasma levels of fIGF-1 had a 96.6% negative predictive value for PFS status at 6 months (p=0.03). Median PFS were respectively 2.73 and 6.53 months for TC alone and TC with F (20 mg/kg) in the high fIGF-1 group (p=0.001) while no significant treatment effect of F was observed in the low (<0.54 ng/mL) fIGF-1 group. Sixty three percent of pts with high fIGF-1 had tumors of adenocarcinoma histology. Conclusions: IGF-1 is a key element in the biology of NSCLC of adenocarcinoma histology and its determination may contribute to the identification of pts who benefit from figitumumab therapy. [Table: see text]
Analysis of biomarkers during early phase clinical development of AMG 479, an investigational fully human monoclonal antibody antagonist of type 1 insulin-like growth factor receptor (IGF-1R)
Authors: McCaffery I. , Tolcher A. , Puzanov I. , Sarantopoulos J. , Rosen L. , Deng H. , Paweletz K. , Friberg G. 
Published: August 2020

3545 Background: AMG 479 showed anti-tumor activity in a phase 1 (P1) and phase 1b (P1b) trial (Tolcher, J Clin Oncol. 2007;25:3002; Sarantopoulos, J Clin Oncol. 2008;26:3583). We sought to identify predictive markers of response to AMG 479 in these trials by analyzing pharmacodynamic (PD) markers in serum, and expression and mutations of regulators of the IGF-1R pathway in tumors. Methods: Patients (pts) had advanced solid tumors and received AMG 479 (1–20 mg/kg Q2W) in the P1 trial or AMG 479 (6 or 12 mg/kg Q2W) + panitumumab (6 mg/kg Q2W) or gemcitabine (1,000 mg/m2 QW) in the P1b trial. Serum levels of IGF-1 and IGFBP-3 were measured pre dose on Day -1 and post dose at various time points. In the P1 trial, we examined relationships between tumor response (by RECIST) and: 1) levels of IGF-1 and IGFBP-3 (at baseline or PD change from baseline); 2) somatic mutations in key genes (including K-ras, and PTEN) of the IGF-1R pathway (in archival tumors); and 3) expression of PTEN (measured by immunohistochemistry in archival tumors). Results: Serum IGF-1 and IGFBP-3 increased in a concentration-dependent manner between 1 and 12 mg/kg AMG 479, with an apparent plateau between 12 and 20 mg/kg AMG 479. Baseline and PD changes in IGF-1 and IGFBP-3 were not substantially different in pts with a tumor response compared with those without a tumor response. A partial response to AMG 479 was observed in a pt with an activating K-ras mutation. No responses have been observed in tumors that lack expression of PTEN. Conclusions: The PD results suggest near complete biochemical coverage at 12-mg/kg AMG 479. Our hypothesis-generating analyses suggest that: 1) pre and postdose levels of IGF-1 and IGFBP-3 do not predict response to single-agent AMG 479; 2) activating K-ras mutations do not appear to preclude responsiveness to single-agent AMG 479 (in contrast to EGFR inhibitors); 3) expression and mutations of regulators of the PI3K/Akt pathway downstream of IGF-1R activation may be useful in predicting response to AMG 479. [Table: see text]