bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exposure-response (E-R) analysis of rilotumumab (R, AMG 102) plus epirubicin/cisplatin/capecitabine (ECX) in patients (pts) with locally advanced or metastatic gastric or esophagogastric junction (G/EGJ) cancer.
Authors: Zhu Min , Tang Rui , Doshi Sameer , Oliner Kelly S. , Kathman Steven , Gisleskog Per Olsson , Dubey Sarita , Jiang Yizhou , Donehower Ross C. , Iveson Timothy , Loh Elwyn 
Published: March 2020

2535 Background: R is an investigational, fully human monoclonal antibody to hepatocyte growth factor/scatter factor (HGF/SF), the only known MET receptor ligand. In a double-blind, placebo-controlled, phase 2 trial of 121 pts with G/EGJ cancer, R (7.5 or 15 mg/kg) + ECX showed trends for improved overall survival (OS) and progression-free survival (PFS) compared to ECX alone (placebo, P). Methods: E-R analyses were performed using pharmacokinetic (PK), biomarker, efficacy, and safety data. A population PK model was used to evaluate covariate effects (eg, demographics, ECX, and MET status) on R PK and predict individual R exposure (trough steady-state Cmin [C]). The effect of C on OS/PFS was evaluated with Kaplan-Meier estimates and Cox proportional hazards models. Covariate effects for OS/PFS were evaluated with multivariate analysis. The relationships between adverse events of interest (AEs), lab values, and C were analyzed with descriptive statistics and linear regression models. Results: R showed linear PKs that were unaffected by ECX or MET levels. Pts who received R + ECX were divided into low C (CL) and high C (CH) groups by the median C (94 µg/mL). Median PFS was 4.2, 4.5, and 6.9 months in the P, CL, and CH groups; median OS was 8.9, 9.5, and 13.3 months. Improved OS/PFS in CH and improved PFS in CH and CL groups (vs P) were seen after adjusting for baseline covariates. Pts with tumors that expressed high MET levels (METHigh: > 50% cells positive) showed greater improvement in OS in the CH vs CL group. No improvement in OS was seen in METLow pts (CH and CL groups) compared to placebo (see Table). No relationship was seen between R exposure and AEs or lab values. Conclusions: Higher R exposure was associated with improved OS/PFS in METHigh pts without increased toxicity, supporting further study of R + ECX in G/EGJ cancer. [Table: see text]
Phase I study of weekly oral docetaxel (ModraDoc001) plus ritonavir in patients with advanced solid tumors.
Authors: Marchetti Serena , Stuurman Frederik , Koolen Stijn , Moes Johannes , Hendrikx Jeroen , Thijssen Bas , Huitema Alwin D.R. , Nuijen Bastiaan , Rosing Hilde , Keessen Marianne , Voest Emile E. , Mergui-Roelvink M. , Beijnen Jos H. , Schellens Jan H. M. 
Published: March 2020

2550 Background: ModraDoc001 is a novel oral formulation containing docetaxel as a solid dispersion. Oral administration of docetaxel is feasible in combination with the CYP3A4 inhibitor ritonavir. Objectives were to determine the safety, maximum tolerated dose (MTD) and pharmacokinetics (PK) of weekly oral docetaxel (as ModraDoc001) in combination with ritonavir. Methods: Patients with advanced solid tumors, WHO PS ≤ 2, no concomitant use of MDR or CYP3A modulating drugs, adequate bone marrow (ANC ≥ 1.5x109 /L), liver (bilirubin ≤ 1.5xULN, ALAT/ASAT ≤ 2.5xULN) and renal function (creatinine ≤ 1.5xULN or clearance ≥ 50 ml/min) were eligible. Docetaxel (ModraDoc001 10mg capsule) and ritonavir (Norvir 100mg) were simultaneously given once weekly in a ‘3+3 cohort’ dose escalation design. MTD was defined as the highest dose resulting in <1/6 probability of causing a dose limiting toxicity in the first 4 weeks of treatment. This cohort was expanded with 6 patients. PK was determined on days 1 and 8. Results: 40 patients (25 male, 35 evaluable for safety) were enrolled in 6 dose levels (30/100, 40/100, 60/100, 80/100, 60/200 and 80/200 mg docetaxel/ritonavir). Common treatment related adverse events in the 4 highest dose levels were diarrhea (68%), nausea (62%) and fatigue (62%), mostly CTC grade 1-2 (80%, 95% and 73% respectively). Five patients experienced a DLT (grade 3 diarrhea (4), elevated ASAT/ALAT (1), grade 4 dehydration and grade 3 mucositis (1), grade 3 fatigue (2)). The MTD was 60 mg/200 mg docetaxel/ritonavir. Partial remission was seen in 4 patients (CUP, NSCLC, gastric and mamma ca) and sustained stable disease in 15 patients (6x NSCLC). Both drugs were rapidly absorbed after oral administration. Mean Tmax was 2.0 hours (CV=73%) for docetaxel. Cmax and AUC of docetaxel increased less than proportionally with dose to 162 ng/ml (CV= 67%) and 1615 ng/ml*hr (CV= 81%), respectively, in 15 patients at the MTD. Conclusions: At the MTD (once weekly 60 mg docetaxel and 200 mg ritonavir) ModraDoc001 is safe, well tolerated and shows encouraging antitumor activity. The exposure of docetaxel with this regimen is comparable to weekly intravenous administration of 35 mg/m2 docetaxel. Phase II studies in solid tumors are planned.
Thymidylate synthase genotype specific dosing of capecitabine: Proof of concept phase I study.
Authors: Soo Ross A. , Lee Soo-Chin , Tan Wen-Lee , Wang Ling-Zhi , Lim Xn-Yii , Loh Marie , Tan Sing-Huang , Zee Ying Kiat , Wong Andrea LA , Chuah Benjamin , Chan Daniel Boon Yeow , Lim Siew Eng , Goh Boon C. , Soong Richie Chuan Teck , Yong Wei-Peng 
Published: March 2020

2551 Background: Thymidylate synthase (TYMS) is the target of fluoropyrimidines (FP). TYMS 3R3R is the predominant genotype in East Asian (EA) patients and is associated with increased TYMS expression, reduced FP related toxicity and relative FP resistance. Dose finding studies for FP were developed in Caucasians, a population that typically harbors TYMS 2R2R and 2R3R genotypes. We hypothesize the recommended phase II dose (RP2D) of capecitabine is higher in 3R3R and similar for 2R allele carriers compared to the FDA approved dose. Objectives 1) To determine the maximal tolerated dose (MTD) and RP2D of capecitabine in EA patients with advanced stage malignancy 2) To determine the safety and toxicity of this regimen and 3) To perform plasma pharmacokinetics (PK) of capecitabine and its metabolites. Methods: EA patients with advanced stage cancer were prospectively allocated into two cohorts: Group A (3R3R) and Group B (2R3R, 2R2R). In each cohort, dose escalation followed a standard phase I 3+3 design. Additional patients were treated at the R2P2 dose level (DL). Initial dose was 1250/m2 bd for 14 days q3w (DL 1) with 125 mg/m2 bd increments subsequently. Pharmacokinetics (PK) of capecitabine and its metabolites were performed using a LC-MS/MS method. Results: 23 patients (Group A=18; group B=5) received 94 cycles (median 2.5, range 1-8). Median age was 58 (range 34-74) years. Median turnaround time for TYMS genotyping was 1 day. In group A, grade 3-4 DLTs were seen in 3 patients: diarhoea, neutropenic fever, hand-foot syndrome, and mucositis. MTD was at DL 4 (1625mg/m2 bd) and the RP2D was 1500mg/m2 bd (DL 3). DL 3 was expanded to n=9. At DL 3, day 1 mean (± SD) capecitabine and 5FU Cmax was 12.3 ± 9.9 and 0.91 ± 0.73 µg/mL, respectively and AUC0 – t was 9.84 ± 5.53 and 1.21 ± 0.54 h*µg/mL, respectively. Compared with DL1, Cmax for capecitabine and 5FU was 2 and 2.02 fold higher and AUC 0-t was 1.49 and 1.59 fold higher at DL3. Accrual in group B was ceased at DL2 due to lack of patient enrolment; no DLT was seen. By ROC analysis, day 1 5FU AUC0 – t of 1.74 h*µg/mL predicted for DLT (p=0.022, sensitivity 100%, specificity 90%). Conclusions: In EA patients with TSER 3R3R, the RP2D was 1500 mg/m2 bd. The D1 5FU AUC0 – t at RP2D was 59% more than the FDA approved dose (DL1).
Phase I and pharmacokinetic (PK)/pharmacodynamic (PD) study of LY2334737, an oral gemcitabine prodrug, in patients (pts) with advanced solid tumors.
Authors: Faivre Sandrine J. , Olszanski Anthony J. , Weigang-Koehler Karin , Riess Hanno , Peng Guangbin , Callies Sophie , Benhadji Karim Adnane , Raymond Eric 
Published: March 2020

2554 Background: LY2334737 is a valproic acid-bound carboxylesterase-substrate prodrug of gemcitabine that can be given orally. The primary objective was to define the recommended phase II doses and schedules (sch) of administration of LY2334737 in 28-day cycles. Methods: Eligible pts (ECOG<2) had adequate hematologic, renal, and hepatic functions. In sch-A, LY2334737 was given every other day for 21 days. In sch-B, LY2334737 was given daily every other week. Dose escalation (3+3) was based on CTCAE V3 toxicities. Secondary objectives were PKs (LY2334737, dFdC, dFdU), PD biomarkers (dFdC DNA incorporation, Cytokeratin 18 - M30), and antitumor activity. Results: 57 pts (38 males, 19 females, median age 60 yrs) were treated using 7 dose-levels (40–100 mg/day). Pts received a median of 2 cycles. Dose limiting toxicities (DLTs) at cycle 1 (any dose level) consisted of diarrhea (2pt), AST elevation (1pt), lower extremity edema (1pt), QTC prolongation (1pt), and general deterioration (1pt). A total of 2/7pts treated with 100mg in sch-A and 1/4pts treated with 90mg in sch-B had DLTs. During dose escalation most frequent toxicities were 1) Sch-A (28 pts): nausea (10pts), pyrexia (9pts), vomiting (8pts), mucositis (6pts), anorexia (6pts), ALT elevation (5pts), asthenia (5pts), anemia (5pts), fatigue (4pts), chills (4pts), and lymphopenia (4pts). 2) Sch-B (29 pts): pyrexia (13pts), nausea (8pts), diarrhea (6pts), vomiting (5pts), chills (6pts), anemia (5pts), asthenia (6pts), AST elevation (6pts), ALT elevation (5pts), and fatigue (4pts). Nine pts had stable disease (3pts completed >6 cycles). PKs showed a dose-proportional increase in exposure of LY2334737 and dFdC with no accumulation after repeated dosing. dFdC is detected in the DNA of peripheral blood mononuclear cells (increasing amount with dose and over time after repeated cycle). In sch-A, we observed a significant increase in cytokeratin 18 M30 relative to baseline. Conclusions: LY2334737 displayed linear PK and acceptable safety profile in both schedules. The dose of 90mg given every other day is the recommended dose for phase II trials with LY2334737 (dose expansion is ongoing).
Human papillomavirus type 16 (HPV16) E6/E7-specific cytotoxic T lymphocytes (CTL) for immunotherapy of HPV-associated cancer (Ca).
Authors: Ramos Carlos Almeida , Narala Neeharika , Leen Ann M. , Gerdemann Ulrike , Sturgis Erich M. , Anderson Matthew L. , Savoldo Barbara , Heslop Helen E. , Brenner Malcolm K. , Rooney Cliona M. 
Published: March 2020

2558 Background: Vaccines prevent HPV-associated Ca, but their benefits in established Ca are disappointing: although these tumors express viral E6 and E7 antigens (Ags) immune responses are limited even after vaccination, likely due to negative environmental cues that block tumor recognition and T cell (TC) activation in vivo. We postulated that ex vivo stimulation of TCs in an immunologically favorable milieu would allow us to reactivate tumor-directed CTLs from Ca patients and benefit the recipients on reinfusion. Methods: We studied 68 patients with HPV+ Ca. To detect HPV16 E6/E7-specific TCs (HPV-TCs) in blood, we measured the IFNγ ELISpot responses of TCs stimulated by monocyte-derived dendritic cells (DCs) loaded with pepmixes (peptide libraries of 15-mers overlapping by 11 aa) spanning E6/E7. Because HPV-TCs from these patients may be anergized by their tumors, potent Ag presenting strategies might be required for reactivation, and thus we stimulated these cells in the presence of IL-6, -7, -12 and -15, as we have shown that these can induce responses to poorly immunogenic Ags. Results: We successfully reactivated HPV-TCs from 8/16 cervical and 33/52 oropharyngeal Ca patients. We could expand these HPV-TCs to clinically useful numbers by using patient B-cell blasts (BBs) as APCs. Stimulation of DC-stimulated HPV-TCs by E6/E7 pepmix-loaded BBs further expanded (3.8 ± 1.5×/round) HPV-TC lines, which phenotypically are almost exclusively composed of TCs (98 ± 3% CD3+), with a variable proportion of mostly effector memory (CD45RA–, CD45RO+, CD62L– and CCR7–) CD4+ and CD8+ cells (37 ± 28% and 49 ± 27%, respectively). The viral/tumor associated epitopes recognized mapped to E6 aa 49-71, 77-91 and 125-143, and E7 aa 1-19 and 73-87. The expanded cells from patients killed E6/E7+ targets (specific lysis up to 45-61% vs. 0-8% in controls, 40:1 E:T ratio). Conclusions: We have developed a system that allows the robust generation of HPV-directed CTLs from patients with HPV16+ Ca, which recognize specific epitopes in tumor-associated Ags. Our lines have the potential to be used for adoptive cellular immunotherapy of HPV+ Ca.
IFN-γ to improve immunotherapy for melanoma.
Authors: Donia Marco , Hansen Morten , Sendrup Sarah Louise , Ellebaek Eva , Iversen Trine Zeeberg , Andersen Mads Hald , thor Straten Per , Svane Inge Marie 
Published: March 2020

2565 Background: Adoptive cell therapy (ACT) with tumor infiltrating lymphocytes (TILs) holds the promise to change the long-term prognosis of patients with metastatic melanoma. In this study we have explored strategies to improve the efficacy of cell products for infusion through tumor immune-sensitization. Methods: We examined whether objective responses in our pilot ACT trial (NCT937625) were associated with the number of tumor-reactive T cells infused. Subsequently, we assessed the ability of immune-sensitizing agents to modulate the constitutive response of 12 clinical grade TIL products to matched autologous short-term cultured melanoma cell lines. Results: Our data showed that a high absolute number of infused tumor-reactive T cells is critical to achieve an objective response. In addition, a defective population of tumor-specific CD8+ and CD4+ T cells unable to exert antitumor effector functions ex vivo was detected in most TIL products. However, an antitumor specific response could be restored by pretreatment of the autologous tumor cells with low dose IFN-γ. Of note, IFN-γ treatment was invariably associated with increased cancer immunogenicity as demonstrated by up-regulation of MHC molecules. Conclusions: Combination strategies represent the next frontier of cancer immunotherapy. Although previous trials in melanoma showed that IFN-γ does not mediate clinical benefit when used as monotherapy, our findings show that its ability to increase tumor cell immunogenicity may enhance the efficacy of current immune-based therapies such as ACT through improved activation of pre-existing but unresponsive tumor specific lymphocytes. Therefore, additional studies on the possibility of a sequential combination of low dose IFN-γ and ACT are highly warranted.
Human pharmacokinetic (PK) characterization of the novel dual-action anti-HER3/EGFR antibody MEHD7945A (MEHD) in patients with refractory/recurrent epithelial tumors.
Authors: Hidalgo Manuel , Calles Antonio , Juric Dejan , Dienstmann Rodrigo , Roda Perez Desamparados , Messersmith Wells A. , Blumenschein George R. , Baselga José , Tabernero Josep , Cervantes-Ruiperez Andres , Jimeno Antonio , Jin Denise , Bai Shuang , Gurevich Pavel , Nijem Ihsan , Holden Scott N. , Davis John D , Halpern Wendy , Pirzkall Andrea , Xin Yan 
Published: March 2020

2567 Background: MEHD is a novel dual-action human IgG1 antibody that blocks ligand binding to HER3 and EGFR, and elicits antibody-dependent cell-mediated cytotoxicity (ADCC). MEHD demonstrates single-agent activity in a broad panel of tumor models, including models resistant to anti-HER3 or anti-EGFR treatment alone. The objective of this analysis was to characterize the PK of MEHD associated with body weight (BW)-based dosing used in a phase I study in patients with epithelial tumors and to evaluate the potential for using fixed dosing in future studies. Methods: Preliminary non-compartmental and population PK analyses were performed using patient data from the dose-escalation stage [1, 4, 10, 15, 22, and 30 mg/kg every two weeks (q2w)] and expansion stage (14 mg/kg q2w) of the phase I study. Patient demographic data and other relevant clinical covariates were evaluated in the population analysis. PK simulation of 1000 subjects with a log-normal BW distribution was performed to compare the inter-individual variability of MEHD exposure following fixed or BW-based dosing. Results: As expected,MEHD exhibited nonlinear PK. In the noncompartmenal analysis, the apparent clearance (CL) decreased in a dose-dependent fashion (about 40 to 9.9 mL/day/kg from 1 to 30 mg/kg) and approached linearity at doses >10 mg/kg (q2w). In the population analysis, the PK profile of MEHD was well described by a two compartment model with linear and nonlinear clearance. The target-mediated clearance was consistent with that of anti-EGFR antibodies. The nonspecific CL and central volume of distribution (V1) values were approximately 6 mL/day/kg and 52.4 mL/kg, respectively. BW had a moderate effect on V1, but not on CL. PK simulations suggest that, compared with BW-based dosing, fixed dosing would result in less inter-individual variability in MEHD exposure. Both 1100 mg q2w or 1650 mg q3w of MEHD achieve the targeted therapeutic exposure. Conclusions: The dual-action antibody MEHD demonstrated PK consistent with anti-EGFR antibodies. Fixed dosing of MEHD on an every 2 or 3 week schedule is supported.
Effect of matrix metalloproteinase-2 on antitumor immunity.
Authors: Godefroy Emmanuelle , Gallois Anne , Manches Olivier , Jotereau Francine , Bhardwaj Nina 
Published: March 2020

2570 Background: Cancer cells, including melanoma, can be highly resistant to traditional treatments such as chemotherapy and radiotherapy. As a result, a lot of effort has been put into developing immune therapies to treat cancer patients. The main barrier to design effective immunotherapies is the immunosuppression induced by the tumor. Matrix metalloproteinase-2 (MMP-2) is over-expressed in most cancers including melanoma, and its expression is associated with increased dissemination and poorer survival/prognosis. Here, we uncovered an immunosuppressive role of MMP-2 in inducing ineffective/detrimental TH2 immune responses and its underlying mechanisms. Methods: Human dendritic cells (DCs) were cultured in the presence of MMP-2 or various TLR agonists. DCs responses were monitored using immunostaining, ELISA or cytometric bead array methods. Autologous CD4+ T cells were stimulated using these conditioned tumor-associated antigen (TAA)-pulsed DCs. TAA-specific CD4+ T cells were cloned and characterized using the same techniques as for DCs. Results: Herewe showed that MMP-2-conditioned human DCs primed naïve CD4+ T cells into an inflammatory TH2 phenotype, i.e. mainly secreting TNFα, IL-4 and IL-13 and expressing GATA3. Accordingly, we detected MMP-2-specific CD4+ T cells displaying the same inflammatory TH2 profile in tumor-infiltrating lymphocytes from melanoma patients. We revealed the underlying mechanisms: on the one hand, MMP-2 was found to degrade the type-I IFN receptor IFNAR1, thereby preventing STAT1 phosphorylation, which is necessary for IL-12 production. On the other hand, MMP-2 triggers the Toll-like receptor (TLR)-2 on DCs, which leads to NF-kB activation and OX40L expression. Both lack of IL-12 and over-expression of OX40L were found responsible for skewing T cell responses towards a detrimental TH2 phenotype. Conclusions: MMP-2, therefore, acts as an endogenous TH2 "conditioner" and may underlie the prevalence of detrimental TH2 responses in cancer. Our findings also described the responsible MMP-2-dependent mechanisms, which open the way to novel therapeutic strategies and/or targets to skew anti-tumor CD4+ T cell responses towards a more efficient anti-tumor TH1 phenotype to treat cancer patients.
Correlation of interferon-g (IFN-γ) response with survival in a phase II hyperacute (HAL) immunotherapy trial for non-small cell lung cancer (NSCLC).
Authors: Morris John Charles , Rossi Gabriela R. , Harold Nancy , Tennant Lucinda , Ramsey William Jay , Vahanian Nicholas N. , Link Charles J. 
Published: March 2020

2571 Background: Lung cancer is the leading cause of cancer-related mortality. Patients progressing after initial systemic therapy have a poor prognosis. Thus, new therapies are needed. HAL immunotherapy exploits the hyperacute rejection of a xenotransplant as defense mechanism to initiate anti-tumor immune response by administering genetically modified allogeneic tumor cells expressing the αGal moieties on their cell surface. HAL immunotherapy utilizes αGal epitopes and natural human antibodies (Ab) against these targets as the proposed mechanism for anti-tumor immunity. Methods: We completed a phase II study of HAL immunotherapy in patients with metastatic or recurrent NSCLC, age ≥18, ECOG PS ≤2, ≤2 prior systemic therapies. Trial objectives were to determine response rate, safety and immunological responses. Patients received 300 x 106 HAL cells every 2 weeks for 8 doses. Response was determined using RECIST and adverse events were assessed using CTCAE v3. Immune responses were assessed by changes in serum anti-αGal titers and IFN-γ response. Results: Twenty-eight patients were treated. Eight (29%) demonstrated stable disease (SD) ≥16 wks including one patient that initially progressed and later regressed, surviving over 40 months. Median overall survival (OS) was 11.3 months (95% CI 3.8-21.9). Post vaccination, all patients responded by increasing anti-αGal Ab levels (2-100 fold) and 61% (11/18) of tested patients showed increases in IFN-γ levels (by ELISPOT). Interestingly, patients with increased IFN-γ responses after vaccination (>10-500 fold-increase compared to baseline) had a median survival of 21.9 months compared to 5.5 months in patients with lesser IFN-γ responses after vaccination (p<0.001). In addition, patients with higher IFN-γ responses showed reactivity to a NSCLC cell line that was not a component of HAL, suggesting cross-priming to shared tumor antigens. Conclusions: HAL immunotherapy is safe and feasible. The median survival compared favorably to that reported in patients receiving 2nd line chemotherapy for relapsed or advanced NSCLC. The correlation between IFN-γ response and survival is highly encouraging.
Does the addition of molecular targeted therapy to standard treatments lead to better or worse outcomes overall? A systematic review of EGFR-targeted therapies used in combination with standard treatments.
Authors: Rauw Jennifer , Ennis Marguerite , Krzyzanowska Monika K. , Sridhar Srikala S. 
Published: March 2020

2572 Background: Combining novel targeted therapies with standard treatment is a common strategy in drug development. The primary aim of this systematic review was to provide a summary of the outcomes from studies combining EGFR targeted therapy (ETT) with standard treatments. Methods: A PubMed (1975-Jan, 2012) and ASCO (2005-2011) abstract database search was performed. Eligible studies were RCTs that compared standard therapies (chemotherapy, radiation therapy, or hormonal therapy) to standard therapy plus an ETT. Efficacy outcomes: overall survival (OS), progression free survival (PFS), objective response rate (ORR) time to progression (TTP), clinical benefit rate (CBR), and toxicity (total and grade 3+) were recorded. If any toxicity was significantly more frequent in one arm it was coded as such. Results: 128 studies (60 manuscripts, 68 abstracts) met criteria. Median study enrolment was 230 patients, with breast, lung, and colorectal cancer as the main tumor sites. ETT, cetuximab (41%), trastuzumab (19%), gefitinib (13%), erlotinib (13%), and lapatinib (16%), was combined with platinums, 5FU, taxanes, nucleoside analogs; hormonal therapy and/or radiation therapy. Refer to the table for efficacy results. Most frequent toxicities (common and grade 3+) in the combined arm were rash, diarrhea, hematological toxicity and fatigue. Conclusions: Despite enthusiasm for combining standard treatments with targeted therapies, we have demonstrated mixed efficacy results, with marginal benefit and worse toxicity. Quality of life (Q of L) was rarely reported. A similar analysis is underway for VEGFR, and mTor inhibitors, but raises the question of how best to approach the question of combination therapy. [Table: see text]