bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract CT054: Clinical and pharmacokinetic study with a lipidic prodrug of mitomycin-c entrapped in liposomes in metastatic colorectal cancer patients
Authors: Gabizon Alberto A. , Tahover Esther , Perets Ruth , Golan Talia , Geva Ravit , Amitay Yasmine , Shmeeda Hilary , Ohana Patricia 
Published: August 2019

Abstract
Background: A phase 1A/1B study was conducted to investigate the safety of Promitil, a liposomal formulation of a lipidic prodrug of mitomycin-c (MLP) within an open, dose-escalating, phase (1A, n=27) followed by an expanded phase (1B, n=61) restricted to metastatic colorectal cancer (mCRC) patients after failure to two or more lines of therapy. We report here on the correlation between pharmacokinetic (PK) parameters and clinical observations in patients with mCRC.
Methods: PK analysis of plasma MLP levels was obtained in 53 mCRC patients (F=26, M=27), who received Promitil every 4 weeks either as single agent (n=28), in combination with capecitabine (Cap) (n=12), or in combination with Cap and bevacizumab (Bev) (n=13). The MLP dose range was 0.5-3.5 mg/kg with most patients (N=29) receiving 2.0-2.5 mg/kg. Out of 53 patients analyzed, 39 patients completed the 3rd cycle (study week 12) and were efficacy-evaluable by CT scan and Recist criteria. PK of plasma MLP levels was analyzed by noncompartmental methods. For statistical analysis and correlations of T½ and Clearance (CL) with age, sex, BMI, baseline neutrophil/lymphocyte ratio (NLR), CEA, and survival, we used t test and Pearson or Spearman coefficients.
Results: The PK of MLP was stealth-like with long T½ (~1 day), slow CL, and small Volume of distribution. Stable Disease (SD) was reported in 14 patients (36%), and Progressive Disease (PD) in 25 patients. Median survival of all 39 patients (SD+PD) was 8.3 months. SD patients had significantly longer median survival than PD patients (14.3 vs 6.5 months, p=0.0002). SD patients had significantly longer T½ and slower CL than non-SD patients. A longer T½ and slower CL were significantly correlated with longer survival. A high NLR and high CEA were correlated with shorter T½ and/or faster CL. Dose of MLP, addition of Cap and/or Bev, age and BMI did not have any apparent effect on response or survival.
Conclusions: SD was indicative of extended survival. The longer circulation time of the liposomal prodrug in SD patients and its correlation with longer survival are consistent with the well-known correlation between liposome circulation time and localization in tumors. A high NLR may signal inflammatory macrophage activation resulting in shorter liposomal circulation half-life and reducing the chances of disease control.
Citation Format: Alberto A. Gabizon, Esther Tahover, Ruth Perets, Talia Golan, Ravit Geva, Yasmine Amitay, Hilary Shmeeda, Patricia Ohana. Clinical and pharmacokinetic study with a lipidic prodrug of mitomycin-c entrapped in liposomes in metastatic colorectal cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT054.
Abstract CT055: Microdose induced oxaliplatin-DNA adducts as a predictive biomarker of response in colorectal cancer
Authors: Chen Justin , Cho May , Zimmermann Maike , Semrad Thomas , Wu Chun-Yi , Yu Aiming , Pan Chong-Xian , Henderson Paul T. , Kim Edward J. 
Published: August 2019

Abstract
Background
Combination 5-FU and oxaliplatin (FOLFOX) is standard therapy for colorectal cancer (CRC) in neoadjuvant, adjuvant, and metastatic settings. However, oxaliplatin neuropathy is the main dose-limiting toxicity that often necessitates dose reduction or discontinuation before progression. Prediction of oxaliplatin sensitivity in tumor cells would be valuable for dose optimization to maximize anti-tumorigenic effect and limit sensory neuropathy. Oxaliplatin functions via the formation of covalent drug-DNA adducts which ultimately inhibit cell replication and promote apoptosis. Detection of these drug-DNA adducts could serve as a biomarker of oxaliplatin efficacy. We therefore hypothesized that drug-DNA adduct levels induced by sub-therapeutic "diagnostic microdoses" are proportional to those induced by therapeutic doses and are predictive of tumor responses.
Methods
The feasibility of this predictive diagnostic microdosing approach was assessed in CRC cell culture and a pilot clinical trial of six CRC patients. Four CRC cell lines were cultured with therapeutically relevant (100 µM) or diagnostic microdose (1 µM) concentrations of [14C]oxaliplatin. The C-14 label enabled quantification of oxaliplatin-DNA adduct levels with accelerator mass spectrometry, an ultrasensitive isotope analysis technique. Adduct formation was correlated with oxaliplatin cytotoxicity as measured by the MTT viability assay. In a pilot clinical trial (NCT02569723), six CRC patients received an intravenous diagnostic microdose containing [14C]oxaliplatin prior to treatment and a second [14C]oxaliplatin dose during FOLFOX chemotherapy. Adduct levels from peripheral blood mononuclear cells (PBMC), used as surrogates for tumor cells, were correlated to mean tumor volume change of evaluable target lesions.
Results
Drug-DNA adduct levels were linearly proportional between microdoses and therapeutically relevant concentrations in cell culture (R2 = 0.91, p &lt; 0.0001) and patient samples (R2 = 0.63, p &lt; 0.0001). Plasma pharmacokinetics of microdoses were consistent with those of therapeutic dosing. No microdose-associated toxicity was observed in this patient population. PBMC adduct levels significantly correlated with tumor shrinkage (microdose: R2 = 0.82, p = 0.033; therapeutic dose: R2=0.65, p = 0.099).
Conclusion
Diagnostic microdosing with oxaliplatin is feasible and is predictive of oxaliplatin sensitivity in CRC patients.
Citation Format: Justin Chen, May Cho, Maike Zimmermann, Thomas Semrad, Chun-Yi Wu, Aiming Yu, Chong-Xian Pan, Paul T. Henderson, Edward J. Kim. Microdose induced oxaliplatin-DNA adducts as a predictive biomarker of response in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT055.
Abstract CT062: A Phase I study of the safety and immunogenicity of personalized mutation-derived tumor vaccine and treatment fields in patients with newly diagnosed glioblastoma
Authors: Hormigo Adilia , Rubinsteyn Alex , Kodysh Julia , Blazquez Ana , Bhardwaj Nina 
Published: August 2019

Abstract
Glioblastoma (GBM) like other cancers generates mutation-derived tumor antigens (MTA) arising from somatic mutations such as insertions, deletions, nucleotide substitutions and gene fusions. These mutations can be recognized by the immune system, providing a specific target for antitumor therapy. The use of TTFields, a modality that utilizes low intensity electric fields that disrupt cell division, increases progression-free survival and overall survival in newly diagnosed GBM. Among several mechanisms of action, TTFields potentially induces an immunogenic cell death. Therefore, we combined this modality treatment with the standard of care of adjuvant Temozolomide chemotherapy and a personalized vaccine for newly diagnosed GBM in a single-arm, open label clinical trial. Phase Ia tests the safety and immunogenicity of MTA-vaccine and phase Ib tests the safety and immunogenicity of the vaccine in conjunction with the TTFields. RNA and DNA are extracted from tumor specimens and blood, and whole-exome sequencing and mRNASeq is performed. HLA typing is obtained for each patient. MTA are identified using a computational pipeline for prediction and ranking according to both HLA binding affinity and expression. A maximum of 10 peptides is selected for the synthesis of each patient vaccine. Patients receive 14 doses of the MTA-vaccine in combination with 14 doses of poly-ICLC, the vaccine adjuvant. We have found mutation-derived tumor antigens in all patients included in phase Ia despite a low mutational load in GBM patients. The patients that took part in phase Ia have received multiple vaccinations spanning over 6 months of treatment. The vaccine has been well tolerated without serious adverse events. Quantitative and qualitative changes in epitope-specific circulating T-cell response is currently being evaluated.
Citation Format: Adilia Hormigo, Alex Rubinsteyn, Julia Kodysh, Ana Blazquez, Nina Bhardwaj. A Phase I study of the safety and immunogenicity of personalized mutation-derived tumor vaccine and treatment fields in patients with newly diagnosed glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT062.
Abstract CT078: Cyfi: Results from a Phase Ib expansion cohort of anti-hepatocyte growth factor and cytarabine in relapsed and refractory AML
Authors: Wang Victoria E. , Andreadis Charalambos 
Published: August 2019

Abstract
Objective: Patients with AML who are refractory to induction therapy or relapse within 1 year have poor outcomes. Elevated serum hepatocyte growth factor (HGF) level is an adverse prognostic factor. Pre-clinical models have shown that myeloid blasts produce HGF in an autocrine fashion and pharmacologic blockade of the HGF/c-Met axis sensitizes blasts to cell death. We initiated a Phase Ib study with dose expansion cohort study to assess the safety and tolerability of the anti-HGF antibody ficlatuzumab with cytarabine in AML patients who are refractory to 7+3 or have relapsed within 1 year of induction.
Methodology: The 3 x 3 design was used for the Phase I with an expansion cohort of an additional 13 patients accrued and treated at the MTD. Ficlatuzumab was administered in escalated dosing of 10, 15, or 20 mg/Kg for 4 doses every 2 weeks starting on day 1. 20 mg/Kg dose was used for the expansion cohort. Cytarabine was administered at a fIxed dose of 2 g/m2 on days 2-7. PBMCs were collected at defined time points. Differential expression from multiplexed single cell RNA sequencing (scRNAseq) was used to assess biomarkers predictive of response.
Results: Of the total 18 patients accrued thus far, 16 are evaluable. 5 had progressive disease, and 11 responded, all complete responses. Most frequent grade 3/4 TEAEs were febrile neutropenia, LFT abnormalities, and electrolyte disturbance. There was 1 death from sepsis and multi-organ failure on day 23, following ANC recovery, from the disease, and 1 patient who withdrew from the study due to grade 4 gastrointestinal bleed, likely ficlatuzumab related, both prior to response assessment. scRNA sequencing identified a TNF alpha and IFN gamma inflammatory signature that correlates with response to ficlatuzumab at count recovery.
Conclusion: Cytarabine and ficlatuzumab is a safe combination with promising efficacy in high risk relapsed and refractory AML. This combination is warranted in further Phase II studies. scRNAseq may be used to identify biomarkers of response.
Citation Format: Victoria E. Wang, Charalambos Andreadis. Cyfi: Results from a Phase Ib expansion cohort of anti-hepatocyte growth factor and cytarabine in relapsed and refractory AML [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT078.
Abstract CT084: Long-term exposure (LTE) to Tislelizumab, an investigational anti-PD-1 antibody, in a first-in-human Phase I study
Authors: Desai Jayesh , Markman Benjamin , Friedlander Michael , Gan Hui , Horvath Lisa , Townsend Amanda , Millward Michael , Jameson Michael , Yen Chia-Jui , Hou Ming-Mo , Hou Jeannie , Wu John , Liang Liang , Deva Sanjeev 
Published: August 2019

Abstract
Background Tislelizumab (BGB-A317), an investigational monoclonal antibody with high affinity and specificity for PD-1, was engineered to minimize binding to FcγR on macrophages in order to abrogate antibody-dependent phagocytosis, a potential mechanism of resistance to anti-PD-1 therapy. Previous reports from early phase studies suggest tislelizumab was generally well tolerated and had antitumor activity in patients (pts) with advanced solid tumors. Clinical effects of tislelizumab LTE (&gt;12 mo) in pts enrolled in the first-in-human study (NCT02407990) are presented here.
Methods Patients with advanced solid tumors received IV tislelizumab 0.5, 2, 5, or 10 mg/kg Q2W, 2 or 5 mg/kg administered Q2W or Q3W, or 200 mg IV Q3W. Antitumor activity was assessed by RECIST v1.1 criteria; PD-L1 expression was retrospectively assessed with the VENTANA PD-L1 (SP263) assay.
Results As of 31 Aug 2018, 63 of the 451 pts received tislelizumab for &gt;12 mo. In these 63 pts, median age was 64 yr and 70% had received ≥1 prior systemic therapy. Tislelizumab LTE was most common in NSCLC (n=9), HCC (n=7), and bladder and ovarian (n=5 each) cancers. Four of the 5 pts who achieved CR during this study had LTE to tislelizumab (Table); all 4 pts were PD-L1+ (≥1% expression on tumor cells). Across the LTE cohort, ORR was 66.7%; PR and SD were observed in both PD-L1+ and PD-L1- tumors. The median time to CR/PR (3.7 mo) and duration of CR/PR (21.1 mo) were longer in pts with LTE than pts who responded but did not remain on treatment for &gt;12 mo (2.1 and 6.3 mo, respectively). Rash was the only treatment-related AE (TRAE) reported in ≥15% of pts. Most TRAEs were of mild or moderate severity; arthritis, diarrhea, fatigue, granuloma, hyperglycemia, and lichenoid keratosis (n=1 each) were the only grade ≥3 TRAEs reported with tislelizumab LTE.
Conclusion Tislelizumab remained well tolerated for &gt;12 mo and elicited durable responses in pts with a variety of tumor types regardless of PD-L1 status.
PD-L1+ (n=35)PD-L1- (n=22)Missing (n=6)Total (N=63)CR4004 (6.3%)PR2113438 (60.3%)SD99220 (31.7%)PD1001 (1.6%)Abbreviations: CR, complete response; PD, progressive disease; PR, partial response; SD stable disease.
Citation Format: Jayesh Desai, Benjamin Markman, Michael Friedlander, Hui Gan, Lisa Horvath, Amanda Townsend, Michael Millward, Michael Jameson, Chia-Jui Yen, Ming-Mo Hou, Jeannie Hou, John Wu, Liang Liang, Sanjeev Deva. Long-term exposure (LTE) to Tislelizumab, an investigational anti-PD-1 antibody, in a first-in-human Phase I study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT084.
Abstract CT111: Preclinical justification for the Phase II clinical trial ADI-PEG 20 in combination with gemcitabine and docetaxel for the treatment of soft tissue sarcoma
Authors: Prudner Bethany C. , Rathore Richa , Godec Abigail , Chang Samuel F. , Hirbe Angela , Tine Brian A. Van 
Published: August 2019

Abstract
The response to acute and long-term arginine starvation results in an adaptive metabolic reprogramming that can be harnessed for therapeutic opportunities in ASS1-negative tumors. In examining modulations within the pyrimidine pathway, we identified that the addition of docetaxel (DTX) to cells treated with arginine deiminase (ADI-PEG20) results in a stabilized and translocation c-Myc to the nucleus. This effect drives increased hENT1 cell surface, allowing for the uptake of gemcitabine (GEM) and related analogues. This can be attenuated via a c-Myc/Max heterodimerization inhibitor. Combination experiments showed that the addition of ADI-PEG20 to the combination of GEM and DTX was synergistic. In addition, this combination can be used to overcome intrinsic hENT related GEM resistance to increase GEM uptake. In vivo studies indicate that the triple combination was optimal for tumor growth inhibition providing the preclinical mechanisms and justification for the ongoing clinical trial NCT03449901 ADI-PEG 20 in Combination With Gemcitabine and Docetaxel for the Treatment of Soft Tissue Sarcoma.
Citation Format: Bethany C. Prudner, Richa Rathore, Abigail Godec, Samuel F. Chang, Angela Hirbe, Brian A. Van Tine. Preclinical justification for the Phase II clinical trial ADI-PEG 20 in combination with gemcitabine and docetaxel for the treatment of soft tissue sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT111.
Abstract CT116: Phase I/II study of dianhydrogalactitol (VAL-083) with radiation therapy in patients with newly diagnosed, MGMT-unmethylated glioblastoma
Authors: Chen Zhong-ping , Guo Chengcheng , Bacha Jeffrey , Langlands John , Steino Anne , Kwan Claire , Kanekal Sarath , Schwartz Richard , Lopez Lorena , Brown Dennis 
Published: August 2019

Abstract
Glioblastoma (GBM) is the most common and aggressive primary brain cancer. Current standard-of-care includes surgery followed by chemo-radiation and temozolomide. An unmethylated promoter for O6-methylguanine-DNA-methyltransferase (MGMT) is a validated biomarker for temozolomide-resistance and is strongly correlated with poor outcomes. Unmethylated MGMT represents the majority of newly diagnosed GBM tumors. VAL-083 is a first-in-class bi-functional DNA-targeting agent that has shown activity against GBM in NCI-sponsored clinical trials both as single agent and in combination with radiotherapy. VAL-083 induces interstrand cross-links at N7-guanine, leading to DNA double-strand breaks and cell-death. VAL-083’s unique mechanism-of-action circumvents MGMT-mediated chemoresistance, and it has demonstrated cytotoxicity in MGMT-unmethylated GBM cell-lines, cancer stem cells (CSCs) and in vivo models. Furthermore, VAL-083 acts as a radiosensitizer in GBM CSCs and non-CSCs. We completed a dose-escalation trial of VAL-083 in recurrent GBM, and a generally well-tolerated dosing regimen was selected for further clinical development. The present trial is an ongoing open-label, biomarker-driven, Phase I/II study to evaluate the tolerability and efficacy of VAL-083 in combination with radiotherapy in newly diagnosed MGMT-unmethylated GBM patients. A treatment regimen, consisting of a 6-week induction period of VAL-083 and concurrent radiation (2 Gy daily, 5 days/week) followed by up to 24 weeks of maintenance therapy with single-agent VAL-083, is being evaluated. The study is being conducted in two parts. The dose-confirmation part (20, 30, and 40 mg/m2/day IV infusion on days 1-3 of a 21-day cycle) has been completed, and the expansion part has been initiated in up to 20 additional patients at 30 mg/m2/day IV infusion on days 1-3 of a 21-day cycle. Tumor response will be assessed by MRI, according to RANO criteria. Efficacy endpoints include progression-free survival (PFS) and overall survival (OS). Additional endpoints include safety evaluations and pharmacokinetic assessments of plasma and CSF samples. Trial design, enrollment and safety data update will be provided at the meeting. Clinicaltrials.gov identifier: NCT03050736.
Citation Format: Zhong-ping Chen, Chengcheng Guo, Jeffrey Bacha, John Langlands, Anne Steino, Claire Kwan, Sarath Kanekal, Richard Schwartz, Lorena Lopez, Dennis Brown. Phase I/II study of dianhydrogalactitol (VAL-083) with radiation therapy in patients with newly diagnosed, MGMT-unmethylated glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT116.
Abstract CT152: A Phase II pilot trial of nivolumab (N) + albumin bound paclitaxel (AP) + paricalcitol (P) + cisplatin (C) + gemcitabine (G) (NAPPCG) in patients with previously untreated metastatic pancreatic ductal adenocarcinoma (PDAC)
Authors: Borazanci Erkut H. , Jameson Gayle , Korn Ronald Lee , Caldwell Lana , Ansaldo Karen , Hendrickson Kristin , Marceau Katie , Gosselin Kevin , Hoff Daniel D. Von 
Published: August 2019

Abstract
Background: Effective therapy for the treatment of PDAC remains one of the greatest unmet oncology clinical needs. The addition of C to G and AP has shown promising clinical data in a previously reported study [J Clin Oncol 35, 2017 (suppl 4S; abstract 341)]. In preclinical work, vitamin D (Vit D) analog therapy decreases myeloid derived suppressor cells and regulatory T cells, favorably influencing the immune environment. This trial combines AP/C/G with Vit D analog P and the anti-PD-1 antibody N as a combination therapy for patients with previously untreated metastatic PDAC. This trial evaluates the efficacy and safety of NAPPCG in that patient population (NCT02754726).
Methods: Eligibility criteria include Stage IV PDAC, no prior chemotherapy for systemic disease, KPS ≥ 70, and measurable disease. Doses are AP 125 mg/m2 undiluted, G 1000 mg/m2 in 250 ml of normal saline (NS), each infused over 30 minutes with C 25 mg/ m2 in 500 ml of NS infused over 60 minutes on days 1, 8, 22, and 29 of a 42-day cycle. N is given at a fixed dose of 240 mg as a 60 minute infusion on days 1, 15, and 29. P is given at a fixed dose of 25 µg IV twice weekly. Primary objective is to determine the efficacy of the combination for patients with previously untreated metastatic PDAC through determining CR, ORR, PFS, and OS. The secondary objective is to evaluate safety in patients with previously untreated metastatic PDAC.
Results: Trial was initiated May 2016 and 25 patients have been enrolled in the study and 24 are evaluable (baseline and ≥1 follow up CT scan). Most common drug-related grade (Gr) 3-4 adverse events (AE’s), are thrombocytopenia 76% (gr 3 = 44%, gr 4 = 32%) with no serious bleeding events, anemia 44% (gr 3 = 44%, gr 4 = 0%), and colitis 12% (gr 3 = 12%, gr 4 = 0%). By RECIST 1.1 criteria, response is 19 PR, 2 SD, 2 PD, yielding an 83% ORR. Median PFS is 8.17 months. Median OS is 15.3 months.
Conclusions: Although a small study, the high response rate is encouraging. The clinical trial is now being expanded. Supported by grants from the Seena Magowitz Foundation, Mattress Firm, Bristol Myers Squibb, and SU2C.
Citation Format: Erkut H. Borazanci, Gayle Jameson, Ronald Lee Korn, Lana Caldwell, Karen Ansaldo, Kristin Hendrickson, Katie Marceau, Kevin Gosselin, Daniel D. Von Hoff. A Phase II pilot trial of nivolumab (N) + albumin bound paclitaxel (AP) + paricalcitol (P) + cisplatin (C) + gemcitabine (G) (NAPPCG) in patients with previously untreated metastatic pancreatic ductal adenocarcinoma (PDAC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT152.