bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lymphoid and myeloid biomarkers for clinical outcome of combined immunotherapy with granulocyte-macrophage colony-stimulating factor-tranduced allogeneic prostate cancer cells (GVAX) and ipilimumab in castration-resistant prostate cancer patients.
Authors: van den Eertwegh Alfons JM , de Gruijl Tanja , Santegoets Saskia , Stam Anita , von Blomberg Mary E , Hege Kristen , Sacks Natalie , Jooss Karin , Lowy Israel , Gerritsen Winald R. 
Published: March 2020

2562 Background: In a phase-I dose escalation trial in patients with castration-resistant prostate cancer we showed that GVAX and ipilimumab had an acceptable safety profile. Moreover, we observed tumor responses and prolonged survival as compared to the Halabi predicted overall survival (OS). However, ipilimumab can also lead to severe immune-related adverse events. To avoid unnecessary exposure to this risk, it is essential to identify biomarkers that correlate with clinical activity. Methods: Patients had castration-resistant prostate cancer and were chemotherapy-naïve. They received bi-weekly GVAX for a 24 week period combined with monthly intravenous administrations of ipilimumab. Each cohort of 3 patients received an escalating dose of ipilimumab at 0·3, 1·0, 3·0 or 5·0 mg/kg. In an expansion cohort 16 patients were treated with GVAX and 3·0 mg/kg ipilimumab. Flowcytometric monitoring of lymphoid and myeloid subsets in blood were performed. Results: We observed a significantly prolonged OS for patients with high pre-treatment frequencies of CD4+CTLA-4+, CD4+PD-1+, or differentiated CD8+ T cells, or low pre-treatment frequencies of differentiated CD4+ T cells or CD4+CD25hiFoxP3+ regulatory T cells. In contrast, increased frequencies of granulocytic Myeloid-Derived Suppressor Cells (MDSC) and high pre-treatment frequencies of monocytic CD14+HLA-DRlo/- MDSC were associated with reduced OS. Treatment-induced CD4+ T cell differentiation and CD4+ and CD8+ T cell activation was associated with clinical benefit. Moreover, treatment-induced activation of CD1c+ conventional Dendritic Cells (cDC) and 6-sulfo LacNAc+ inflammatory DC were associated with significantly prolonged OS. Conclusions: Together these data provide an immune profile to predict clinical outcome. Importantly, cluster analysis revealed pre-treatment, CRPC-associated expression of CTLA-4+ by CD4+ T cells to be a dominant predictor for OS after GVAX/ipilimumab. This potentially biomarker for patient selection should be validated in patients treated with ipilimumab.
A phase I study of MEHD7945A (MEHD), a first-in-class HER3/EGFR dual-action antibody, in patients (pts) with refractory/recurrent epithelial tumors: Expansion cohorts.
Authors: Cervantes-Ruiperez Andres , Juric Dejan , Hidalgo Manuel , Messersmith Wells A. , Blumenschein George R. , Baselga José , Roda Perez Desamparados , Dienstmann Rodrigo , Calles Antonio , Jimeno Antonio , Sanabria Sandra , Littman Catherine , Amler Lukas C. , Pirzkall Andrea , Tabernero Josep 
Published: March 2020

2568 Background: Dysregulated human epidermal growth factor receptor tyrosine kinase (HER RTK) signaling is an important driver of tumor growth, metastasis, and survival. Extensive co-expression and heterodimerization suggest that simultaneous blockade of multiple HER RTKs may be more effective than blockade of a single RTK. MEHD is a novel dual-action human IgG1 antibody. Each antigen-binding fragment blocks ligand binding to HER3 or EGFR, and intended to inhibit signaling from all major ligand-dependent HER dimers. MEHD has single-agent activity in multiple tumor models including models resistant to anti-HER3 or anti-EGFR. Methods: This Phase I study evaluated safety, tolerability, pharmacokinetics (PK), and pharmacodynamic (PD) activity of intravenous MEHD every 2 weeks (q2w). Tumor PD assessments were pre- and post-dose FDG-PET and IHC for pS6, pPRAS40 or pERK in tumor biopsies. Tumor CT assessments were performed q8w. No dose-limiting toxicity (DLT) was observed in six 3+3 cohorts from 1-30 mg/kg (n=30). We report results from 4 tumor-specific cohorts receiving 14 mg/kg MEHD (recommended Phase II dose). Results: As of 21 Nov 2011, 36 pts (CRC=12, NSCLC=9, SCCHN=10, pancreatic=5), median age 62.5 (35–87), all PS 0-1, median # prior regimens 3.5 (1-8), received a median of 4 doses (1-9) of MEHD; 18 pts remain on study. PK data are consistent with human anti-EGFR antibodies. No related Grade (G) ≥3 adverse events (AEs) have been observed. Common related G1/2 AEs included rash/dermatitis (53%), diarrhea (36%), fatigue (22%), paronychia (19%), dry skin, nausea, and decreased appetite (all 17%), asthenia and stomatitis/oral pain (all 14%). Related AEs ≤ 24 h after first infusion included G1/2 headache (42%), fever (33%), and chills (17%), and decreased in intensity and frequency with later infusions. Early PD data indicate target inhibition in 8/36 pts (SCCHN=2, NSCLC=2, CRC=4), and best response by RECIST includes 2 PR (both SCCHN), 6 pts with SD ≥ 8 weeks (NSCLC=2, CRC=4), 7/8 previously treated with EGFR inhibitors. Conclusions: MEHD at 14 mg/kg q2w has an encouraging safety profile and evidence of anti-tumor activity. Phase II studies are planned.
Messenger RNA vaccination and B-cell responses in NSCLC patients.
Authors: Sebastian Martin , von Boehmer Lotta , Zippelius Alfred , Mayer Frank , Reck Martin , Atanackovic Djordje , Thomas Michael , Schneller Folker , Stoehlmacher-Williams Jan , Goekkurt Eray , Bernhard Helga , Groeschel Andreas , Scheel Birgit , Koch Sven D. , Lander Thomas , Rippin Gerd , Wiegand Volker , Gnad-Vogt Ulrike Senta , Kallen Karl-Josef , Knuth Alexander 
Published: March 2020

2573^ Background: Vaccination with mRNA is a novel technology in cancer immunotherapy. CV9201 consists of self-adjuvanted mRNA molecules (RNActive) coding for five non small cell lung cancer (NSCLC)-associated tumor antigens (MAGE-C1, MAGE-C2, NY-ESO-1, BIRC5, 5T4). We report final results of a phase I/IIa trial of CV9201 in patients (pts.) with NSCLC. Methods: Pts. with stage IIIB/IV NSCLC with a response or stable disease after first-line chemotherapy or chemoradiation were eligible. Cohorts of 3 pts. were treated at three dose levels (400µg, 800µg and 1600µg CV9201) and observed for DLTs to select the highest tolerated dose for phase IIa. Primary endpoint was safety and tolerability; secondary endpoints were immune response, clinical efficacy and survival. Pts. received up to five vaccinations of CV9201 within 15 weeks. Antigen-specific immune responses against each of the 5 antigens were measured at baseline, and two weeks after the 3rd and 5th vaccination. Frequency of lymphocyte subsets and expression of activation and maturation markers were measured and retrospectively correlated with immunological and clinical parameters. Results: 46 pts. were included (9 phase I; 37 phase IIa); No DLTs occurred, and the 1600 µg dose was investigated in phase IIa. The most frequent related adverse events were mild to moderate injection site reactions and flu-like symptoms. 3 patients (7%) had potentially related grade 3 AEs (fatigue, injection site granuloma, asthma attack) and no related SAEs were reported. There were no objective responses. Data on PFS and survival will be presented. Antigen specific immune responses against at least one antigen were induced in 65% of pts. (39% cellular and 49% humoral). Consistently, a significant ≥2 fold increase of pre germinal center B cells (pGCB) was observed in 61% of pts. This increase of pGCB correlated significantly (p=0.0028) with increase of total CD4 effector T cells. Frequency of CD 4 T Reg cells did not increase during treatment. Conclusions: Vaccination with CV9201 has a favorable safety profile and induces T and B cell responses against all included antigens. Vaccine-induced increase of pGCB is a new finding and might be used as a biomarker in cancer immunotherapy.
Randomized phase II trial of multipeptide vaccination with or without a single pre-vaccine dose of denileukin diftitox in advanced melanoma.
Authors: Gajewski Thomas , Matijevich Karen , Zha Yuanyuan 
Published: March 2020

2582 Background: The efficacy of immunotherapy approaches such as vaccines in melanoma appears limited, in part, due to immune suppressive mechanisms in the tumor microenvironment. One of these mechanisms is the presence of CD4+CD25+FoxP3+ regulatory T cells (Tregs). It has been hypothesized that strategies to reduce Treg numbers should improve the efficacy of melanoma vaccines. Methods: The study design was to randomize 24 HLA-A2+ patients to receive vaccine alone or denileukin diftitox (18 mcg/kg i.v.) as a single dose 4 days prior to the first vaccination. The vaccine formulation consisted of 4 melanoma antigen peptides (derived from MelanA, gp100, MAGE3, and NA17A) emulsified in Montanide and GM-CSF, administered i.d./s.c. every 2 weeks. The primary endpoints were assessment of depletion of Tregs from the peripheral blood, and measurement of antigen-specific CD8+ T cell responses by ELISPOT. Secondary endpoints included clinical response and analyses of the tumor microenvironment for changes in Treg infiltration. Results: The treatment was well tolerated. Enrollment was halted at 16 patients when it was clear that immune response endpoints would not be reached. There was no significant decrease in Treg numbers, nor was there an increase in vaccine-induced T cell responses, when patients received denileukin diftitox prior to vaccination. In patients with biopsiable tumors, there was no decrease in Tregs in metastatic lesions post-versus-pre-treatment. Of the 9 patients who showed clinical benefit (1 PR, 8 SD), 4 of them received denileukin diftitox and 5 did not. Estimated time to progression was 146 days in the group that received denileukin diftitox and 131 days in the group that did not. Conclusions: Denileukin diftitox given as a single dose prior to vaccination was not sufficient to deplete Tregs or improve the potency of this melanoma vaccine. Alternative strategies to reduce Tregs, such as multiple doses of denileukin diftitox or anti-CD25 mAbs, should be considered.
Multivariate screening of prognostic factors to identify a novel, simple, and objective marker to optimize patient selection and predict survival benefit in early-phase trials.
Authors: Stavraka Chara , Pinato David James , O'Cathail Sean Micheal , Williams Farah J , Seckl Michael , Blagden Sarah Patricia 
Published: March 2020

2608 Background: Several prognostic indices have been devised to optimize patient selection for phase I trials. However, there is no consensus as to the optimal score and none qualifies as a marker of response. We developed a simple score through a multivariate screening of individual variables and compared its performance with existing prognostic scores including the Royal Marsden, Nijmegen and Prince Margaret Hospital scores. Methods: We retrospectively analyzed characteristics and outcomes of 120 referrals to our phase I center (2007 - 2011). Independent predictors for overall survival (OS) were identified from univariate (Kaplan Meier) and multivariate (Cox regression) analyses and used to create the Hammersmith Hospital score (HS). This was compared with the other indices for predicting progression free survival (PFS), OS and 90 day mortality (90 DM). Multivariate logistic regression and ROC curves were used to estimate 90 DM and c-index was used to estimate the prognostic ability of the different indices. Changes in HS following treatment (ΔHS) were calculated at 6 weeks RECIST in a subset of patients receiving targeted therapies (n= 50). Results: Median age was 62 years (range: 28 – 80); median OS 4.3 months (range: 0.2 – 39); 34% male; 25% PS>1. Multivariate screening identified albumin <35 g/L, lactate dehydrogenase (LDH) >450 U/L and sodium <135mmol/L as the strongest independent predictors of OS (p<0.05). These were entered into a 3-point score (HS) that classifies patients as being at high risk (score 2-3) vs. low risk (score 0-1) of worse OS (HR= 5.8, p<0.001), PFS (HR= 2.7, p= 0.04) and 90 DM (OR= 5.9, p= 0.001). All scores predicted for OS on univariate analysis (p<0.05). On multivariate analysis HS performed best to predict OS (HR= 3.9, p<0.001 C-index score= 0.71), PFS (HR= 2.6 p= 0.04) and 90 DM with area under the ROC curve 0.71. ΔHS independently predicted for OS (p<0.001), with worsening of the score reflecting poorer OS. Prospective validation is ongoing. Conclusions: HS is a simple score that outperforms other prognostic indices. This can be used to select individuals for future studies as well as an additional marker of response.
Should patients with extrapulmonary small cell carcinoma receive prophylactic cranial irradiation? An Irish experience.
Authors: Naidoo Jarushka , Deady Sandra , Comber Harry , Calvert Paula 
Published: March 2020

2609 Background: Extrapulmonary small cell carcinoma (EPSCC) is a rare disease. Management is based on small cell lung carcinoma, and experience of disease biology on single institution studies. Prophylactic cranial irradiation (PCI) is not routinely administered in EPSCC. This study investigates the role of PCI in EPSCC, by analyzing the incidence, treatment and survival of patients with brain metastases in a national cohort. Secondary aims were to investigate disease biology and epidemiology. Methods: An audit was undertaken of patients diagnosed with primary EPSCC from the National Cancer Registry of Ireland, between 1995-2007. The number of patients who developed brain metastases, received cranial radiotherapy, and their survival data, were documented. Patient and disease characteristics, treatment, and survival data stratified by stage and primary site, were tabulated. Results: 280 patients were found. 141 (50.4%) patients were male, and 139 (49.6%) were female. 186 (66.4%) patients had extensive stage disease, 65 (23.2%) had limited stage disease, and in 29 (10.3%) patients the stage was not known. 17 patients (5.4%) developed brain metastases, 11 of which (64.7%) received cranial irradiation. These patients had a median progression-free survival (PFS) of 5.2 months, and a median overall survival (OS) of 10.2 months. The commonest primary sites were the oesophagus (n=43, 15.4%), cervix uteri (n=17, 6.0%), bladder (n=13, 4.6%) and prostate (n=10, 3.6%). There were 315 events of distant metastasis, and 21 local recurrence events. The commonest metastatic sites were the liver, 110 (34.9%), lymph nodes 58 (20.7%), lung 38 (12.1%), and bone 36 (12.8%). The median PFS and OS for limited stage EPSCC was 8.8 months and 14.9 months, and 1.5 months and 2.3 months for extensive stage EPSCC. Conclusions: Brain metastases were uncommon in this cohort (5.4%), and patients lived longer, suggesting a low rate of mortality from brain metastases. PCI is thus probably not warranted in EPSCC. Prospective data are necessary to support PCI in EPSCC. This is one of the largest datasets on EPSCC, providing insights into disease biology.
Phase I study of BPM 31510 in advanced solid tumors: Updated analysis of a novel treatment with promising activity.
Authors: Hendifar Andrew Eugene , Chawla Sant P. , Quon Doris , Chua Victoria S , Fernandez Lita , Nagre Sandeep , Okunnu Marita , Chmielowski Bartosz , Singh Arun S. , Akmaev Slava , Chatman David , McCook John , Luan Shen , Sarangarajan Rangaprasad , Song Paul Y. , Narain Niven R 
Published: March 2020

3015 Background: BPM 31510 is a novel small molecule that targets the metabolic machinery of the cancer microenvironment to reverse the aerobic glycolytic phenotype of cancer cells. Effector downstream signaling results in re-capitulation of BCL-2 mediated apoptosis and disruption in tumor vasculature by modulation of VEGF. (NR Narain et al., Proceedings of AACR Meeting Abstracts 2011). Methods: A standard 3+3 phase I, dose-escalation study design was used in patients with advanced solid tumors refractory to standard treatment. Primary objectives were establishment of the maximum tolerated dose (MTD) and safety/pharmacokinetic (PK) correlates. Secondary objectives included exploratory pharmacodynamics (PD) and preliminary efficacy (RECIST-1.1) of BPM 31510 in sequential cohorts of 3 to 6 pts. Results: At time of submission, 34 patients with advanced cancer who had failed multiple chemotherapeutic regimens had been enrolled in 7 dose cohorts (ranging from 5.6 mg/kg to 78.2 mg/kg). Patients received a median of 2 cycles (1-7). 2 patients have had grade 3 elevation in PT/INR, otherwise there have been no grade 3/4 treatment related toxicities to date. The pharmacokinetics of BPM 31510 are linear and there were no sex differences in the parameters normalized by dose and body surface area. Tmax and Cmax are associated with the end of the infusion. The values for t1/2 ranged from 2.18 to 13.3 hr, with little or no dependence of t1/2 on dose. Objective tumor responses have been noted at the dose of 58.6mg/kg with 1 partial response (myxoid liposarcoma) and 1 minor response (pleomorphic sarcoma). Six patients (19%) have had disease stabilization (> 4 months). Conclusions: Interim data from this phase I study indicate that BPM 31510 is well tolerated with no dose limiting toxicities to date. A partial response and minor response were observed and correlates with dose escalation. Taken together, there is strong rationale for further clinical development of this compound as an anti-cancer agent.
Phase I trial of the polo-like kinase (Plk) inhibitor volasertib (BI 6727) combined with cisplatin or carboplatin in patients with advanced solid tumors.
Authors: Dumez Herlinde , Gombos Andrea , Schöffski Patrick , Gil Thierry , Vulsteke Christof , Meeus Marie-Anne , Cescutti Jessica , Munzert Gerd Michael , Pilz Korinna , Awada Ahmad 
Published: March 2020

3018^ Background: Volasertib (V) is a first in class, selective and potent cell cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting Plk. This phase I study evaluates dose-limiting toxicities (DLT), maximum tolerated dose (MTD), safety and pharmacokinetics (PK) of V combined with cisplatin (Cis) or carboplatin (Ca). Methods: Sequential cohorts of patients (pts) received a single 2h infusion of V with Cis (arm A) or Ca (arm B) every 3 wks. Cis and Ca were given for up to 6 cycles (Cy); V was continued until progression or intolerance. MTD was the highest dose at which ≤1/6 pts experienced a DLT in Cy 1. MTD cohorts were expanded to 12 DLT-evaluable pts to further characterize safety. Results: As of January 11 2012, 61 pts (arm A: 30; arm B: 31) were treated. Pt characteristics were (arm A/B): median age 55/58 yrs, male 16/18 pts, ECOG PS 0: 13/14 pts, PS 1: 17/17 pts. Tumors included (pts): non-small cell lung cancer (15); sarcoma (8); colorectal cancer (6); melanoma (4); urothelial cancer (4); other (24). Pts received V + Cis for a median [range] of 3.5 Cy [1-6], V + Ca for 2 Cy [1-6] and V for 3.5 Cy [1-20] in arm A and 2 Cy [1-14] in B. PK analyses are ongoing. MTD was reached at V 300 mg + Cis 100 mg/m2 and V 300 mg + Ca AUC 6. Five partial responses (PR) were seen. 15/30 pts in arm A and 12/31 in B achieved stable disease (SD) or PR. PR or SD for >6 Cy was observed in 6/30 pts and 5/31 pts in arms A and B, respectively. Conclusions: In this phase I study, V in combination with Cis or Ca at full single-agent doses was well tolerated. Furthermore, several objective responses and cases of sustained SD were observed in heavily pretreated pts with advanced solid tumors.[Table: see text]
A phase Ib study of the Akt inhibitor GDC-0068 with docetaxel (D) or mFOLFOX-6 (F) in patients (pts) with advanced solid tumors.
Authors: Saura Cristina , Jones Suzanne , Mateo Joaquin , Hollebecque Antoine , Cleary James M. , Roda Perez Desamparados , Zhu Jin , Musib Luna C. , Patel Premal H. , Cervantes-Ruiperez Andres , Isakoff Steven J. , Soria Jean-Charles , Molife L Rhoda , Tabernero Josep , Bendell Johanna C. 
Published: March 2020

3021 Background: Activation of the Akt pathway is observed in multiple tumors and may contribute to chemoresistance. GDC-0068 is an ATP-competitive small molecule inhibitor of all three isoforms of Akt; in a phase Ia study, it was well tolerated with maximum tolerated dose (MTD) of 600 mg daily (21 days on/7days off) and pharmacodynamic down-regulation of Akt signaling in tumors at doses ≥100 mg. In vitro, GDC-0068 shows synergism with cytotoxic agents. This phase Ib study defines the dose limiting toxicities (DLT), MTD, safety and pharmacokinetics (PK) of GDC0068 in combination with D and F. Methods: Using a 3+3 designeligible patients (pt) with advanced/metastatic solid tumors were treated with either D, 75 mg/m2 day 1 and GDC-0068 daily on days 2-15 of a 21 day cycle (Arm A); or F, bolus 5FU 400mg/m2, leucovorin 400 mg/m2, oxaliplatin 85 mg/m2 all day 1, and infusional 5FU 2400mg/m2 for 46 hours and GDC-0068 daily on days 1-7 of a 14 day cycle (Arm B). PK sampling was performed in Cycles 1 and 2. Results: 23 pts have enrolled; Arm A (GDC-0068, mg): 100 (n=3), 200 (n=4), and 400 (n=5); Arm B:100 (n=6) and 200 (n=5). Median prior therapies = 3. GDC-0068-related adverse events in ≥ 10% of pts were diarrhea, nausea, vomiting, fatigue, and decreased appetite. All GDC-0068-related AEs were grade 1 or 2, except one grade 4 neutropenia in Arm A. No DLTs have been reported to date. Preliminary data show no alteration in the PK of GDC-0068, D or F compared to phase Ia or historical data. Two heavily pretreated pts with cervical and PTEN-loss colon cancers treated in Arm B demonstrated both RECIST partial response and tumor marker decrease by first CT evaluation. Conclusions: The combination of GDC-0068 with D or F is well-tolerated and shows early signs of anti-tumor activity. Dose-escalations continue.