julilili42/papers huggingface dataset:
Adjuvant therapy with pegylated interferon alfa-2a (PEG-IFN) versus low-dose interferon alfa-2a (IFN) in patients with malignant melanoma in stages IIa(T3a): IIIb (AJCC 2002)—Decog-trial.
2014-05-20

9071 Background: Adjuvant treatment with IFN improved disease free survival (DFS) and showed a trend for improving overall survival (OS). PEG-IFN has a prolonged half life time and is just given once weekly. This trial was designed to examine if PEG-IFN is superior to IFN in regard to distant metastasis free survival (DMFS), DFS and OS. Methods: In this multicenter, open-label, prospective randomized phase III trial, patients (pts) with resected cutaneous melanoma stage IIA(T3a)-IIIB (AJCC 2002) were randomized to receive IFN (3 MU subcutaneously [sc] 3x/week; 24 months) or to PEG-IFN (180 mcg sc 1x/week; 24 months). Randomization was stratified for tumor stage, number of metastatic nodes, patient’s age and previous interferon treatment. Primary endpoint was DMFS, secondary endpoints were OS, DFS, quality of life and tolerability. Sample size (880 pts) was calculated on an expected difference of 55% vs 45% in the 5 years DMFS rate and assuming 80% power (2-sided, significance level 5%). Non-parametric survival models using log-rank tests and Cox regression models were performed on the ITT population. Results: Of 909 pts enrolled, 907 (451 PEG, 458 IFN) were eligible for evaluation after a median follow-up of 5.0 years. Neither DMFS (PEG-IFN 65.1% vs IFN 70.2%, p=0.18; HR, 1.16; 95% CI, 0.92-1.5) nor OS (74.2% vs 74.8%, p=0.13; HR, 1.05; 95% CI, 0.81-1.37) nor DFS (57.9% vs 60.8%, p=0.49; HR, 1.06; 95% CI, 0.86 to 1.31) showed significant differences. Subgroup analyses of PEG-IFN vs IFN in pts +/- ulcerated primaries and of different tumor stages did not find differences in DMFS, OS or DFS. 118 pts (26.1%) in the PEG-IFN and 61 pts (13.3%) in the IFN population did not receive the scheduled full dose and length of treatment due to adverse events (p<0.001). Leucopenia (CTC grade 2+) and elevation of liver enzymes (grade 2+) were more frequent in the PEG-IFN arm (56% vs 23.5% LCP; 19.1% vs 9.4 % AST; 33.0% vs 16.5% ALT). Conclusions: PEG-IFN did not improve the outcome parameters over conventional IFN. CTC grade 2+ toxicity was significantly more pronounced and a higher percentage of pts under PEG-IFN discontinued treatment prematurely. Clinical trial information: NCT00204529.
RAGE ligand S100A8/A9 as a novel prognostic biomarker for high-risk melanoma patients.
2014-05-20

9070 Background: We have recently demonstrated that the receptor for advanced glycation end-products (RAGE) is a central driver of tumorigenesis by sustaining a chronic inflammatory tumor microenvironment. This study aimed at identifying novel prognostic biomarkers for melanoma by a hypothesis-driven approach linking RAGE signaling-related serum markers with clinical outcome of melanoma patients. Methods: Plasma concentrations of the soluble form of RAGE (sRAGE) were analyzed in 173 plasma samples of stage I-IV melanoma patients (cohort 1). Serum concentration of RAGE-related markers sRAGE, S100B, S100A8/A9, and HMGB1 were measured in an independent second cohort of 240 metastasized stage III-IV patients and compared to established prognostic markers including sub-stage and lactate dehydrogenase (LDH). All analyses were performed by enzyme-linked immunosorbent assays. Results: sRAGE was strongly associated with overall survival (OS) and progression-free survival (PFS) in cohort 1. A detailed analysis of different RAGE-related serum markers was thereafter performed in cohort 2. Analysis of OS of stage III patients showed that elevated S100A8/A9 independently increased mortal risk in addition to sub-stage IIIB or sub-stage IIIC as compared to sub-stage IIIA. Increased S100B, S100A8/A9, and HMGB1 were independently indicating worse PFS in stage III/IV patients. The analysis of S100A8/A9 and S100B was the best combination to predict PFS and improved the sensitivity to identify patients with later progression from 34.2% (S100B) to 58.2% (S100A8/A9 + S100B). Conclusions: The RAGE ligand S100A8/A9 is a powerful independent prognostic marker for OS of stage III patients and contributes substantially to standard biomarker S100B for the identification of patients with high risk for progression.
Impact of perioperative chemotherapy on survival in patients with advanced primary urethral cancer: Results of the international collaboration on primary urethral carcinoma.
2014-05-20

4587 Background: The present analysis aims to investigate the prognostic benefit of perioperative chemotherapy in patients undergoing surgery for primary urethral carcinoma. Methods: A total of 124 patients (86 men, 38 women) who were diagnosed with primary urethral carcinoma in ten tertiary international academic centers between 1993 and 2012, underwent surgery for primary treatment. Platinum-based neoadjuvant and adjuvant chemotherapy was administered in 18 (15%) and 21 (17%) patients, respectively. Kaplan-Meier analysis with log-rank testing was used to investigate the impact of perioperative chemotherapy on progression-free (PFS) and overall survival (OS). The median follow-up was 20 months (mean: 32 months; IQR: 4-48). Results: Median age at surgery was 67 years (IQR: 53-74). Receipt of neoadjuvant chemotherapy was associated with clinically node-positive tumor stage (cN+; p=0.009). Conversely, delivery of adjuvant chemotherapy was associated with locally advanced primary tumors (≥cT3; p=0.003). No further significant associations were found between perioperative chemotherapy and age, gender, tumor location (proximal vs. distal), underlying histology, tumor grade and use of palliative therapy. The 3-year PFS/3-year OS for patients with cN+-stage disease who underwent neoadjuvant chemotherapy was 40%/100%, compared to 0%/29% for no neoadjuvant chemotherapy (p=0.043 and p=0.034, respectively). By contrast, the 3-year PFS/3-year OS for patients with ≥cT3-stage disease who received adjuvant chemotherapy was 23%/46%, versus 20%/53% for no adjuvant chemotherapy (p=0.44 and p=0.20, respectively). The 3-year OS for patients with ≥cT3 and/or cN+ stage disease who received neoadjuvant chemotherapy was 100%, compared to 20% for adjuvant chemotherapy (p=0.031). Conclusions: In this series, patients who received neoadjuvant platinum-based chemotherapy for locally advanced primary urethral carcinoma exhibited improved survival compared to those who underwent immediate surgery and adjuvant chemotherapy.
A phase II, single-armed, multicenter trial of neoadjuvant vismodegib in patients with large and/or recurrent basal cell carcinoma: NICCI.
2014-05-20

TPS9116^ Background: Vismodegib is useful to treat locally advanced or metastatic basal cell carcinoma (BCC) but has not been evaluated for use in a neoadjuvant setting to shrink BCCs before surgery. This multicenter, non-randomized, single-armed phase II clinical study is performed to evaluate the efficacy of neoadjuvant vismodegib in patients with large or large recurrent basal cell carcinoma (BCC). Methods: The primary endpoint is to evaluate the efficacy of vismodegib as measured by the percentage of basal cell carcinomas that reach complete remission (CR, as determined by histopathology), partial remission (PR), or stable disease (SD) versus progressive disease (PD) after 12 weeks of treatment. Secondary endpoints include the assessment of i) size-reduction of BCC in cm2 as intended for excision (baseline vs. 12 weeks of treatment by planimetrics), ii) treatment-induced changes assessed by non-invasive imaging techniques (optional: in vivo confocal laserscan-microscopy, optical coherence tomography, high resolution ultrasonography) in correlation with histopathology, and iii) toxicity and tolerability including health-related quality of life questionnaire (Skindex-16) Study design: 75 patients with a BCC or recurrent BCC (≥ 2 cm in diameter in head/neck region, ≥ 5 cm for trunk/extremities plus at increased risk for cosmetic disfigurement or functional defects) will be enrolled. After 12 weeks of treatment with vismodegib 150mg/d all patients will receive micrographic excision of the remaining tumor area. Patients will be observed for one year. Documentation of the two-dimensional tumor size (in cm2) as intended for excision will be performed by planimetrics at the time of study inclusion, at week 13 before surgery and at the end of study. Clinical trial information: 2013-004767-31.
Vemurafenib treatment in patients with BRAF-mutated melanoma failing MEK inhibition with trametinib.
2014-05-20

9061 Background: Trametinib was shown to improve progression-free and overall survival in patients with metastatic melanoma with a BRAF V600E or V600K mutation as compared with chemotherapy in the METRIC trial. However, the median duration of response was 5.5 months and median progression-free survival was 4.8 months in the Trametinib group. Vemurafenib and Ipilimumab were still investigational when this trial was initiated but were available in clinical trials for post-protocol treatment. Methods: In this phase III trial 98 patients out of the 322 patients of the intent to treat population who had metastatic melanoma with a V600E or V600K mutation received Vemurafenib (960mg twice daily orally). We present data of patients with complete information on initiation and discontinuation date of Vemurafenib and investigator reported response. Results: With a median follow-up of 18.3 months, the median progression free survival (PFS) was 5.2 months with 95% CI 3.7-5.7 and a range of 0.5-27.5+ months. The 6 months PFS was 40.1%. The median overall survival (OS) was 8.3 months with 95% CI 7.1-10.6 and a range of 0.5-27.5+. The 6 months OS was 68.1%. Nineteen patients achieved a partial response and one a complete response. Conclusions: Treatment with vemurafenib had an impact on progression free survival post trametinib treatment in patients receiving a MEK inhibitor in first or second line setting. Sequencing BRAF inhibitors with MEK inhibitors and combinations are currently under investigation.
Efficacy of HSV-TK+ suicide gene donor lymphocytes after haploidentical transplantation (haplo-HSCT): Preliminary results of randomized TK008 study.
2014-05-20

7003 Background: Haploidentical family donors represent the ideal solution to offer for every patient with high risk leukemia the potential cure of hematopoietic stem cell transplantation. Extensive application of haplo-HSCT is limited by high rate of late transplant related mortality (TRM) and relapse associated with the inadequate immune reconstitution (IR) due to ex vivo T cell depletion or in vivo post-transplant cyclophosphamide administration for severe graft-vs-host disease (GvHD) prevention. Methods: In a haplo-HSCT phase III trial (TK008, NCT00914628), we infuse donor lymphocytes genetically engineered to express the suicide gene herpes simplex thymidine kinase (TK cells) to induce early IR after a T cell depleted graft. Key inclusion criteria are acute leukemia at high risk in patients lacking an HLA-matched donor. Control arms include T cell depleted or post HSCT cyclophosphamide haplo-HSCT. We enrolled 25 patients in 8 centres in Europe and US; 17 were assigned to experimental arm, 15/17 were in complete remission at HSCT. Hypothesis testing: 1-year disease free survival (DFS) 30% (control) vs 52% (TK arm). Results: Results are presented only for patients enrolled in the experimental arm at November 2013 last follow-up. TK cells were given to 13 patients; IR was obtained in 9/13 patients after a median of 2 TK cell monthly infusions; median time from last infusion to IR (CD3+>100/μL) was 28 days (95% CI 24-41). Six pts developed GvHD (2 grade I, 2 grade II and 2 grade III) that was always abrogated by suicide gene induction; no progression from acute to chronic GvHD and no GvHD-related death occurred. IR obtained with TK cell infusion correlated with rapid development of a wide T cell repertoire and detection of high frequencies of T-cells specific for opportunistic pathogens. At a median follow-up of 473 days, by ITT analysis, 1-year overall survival is 89% (+ 10), DFS and immunosuppression-free survival is 80% (+ 10), 1-year TRM is 11% and relapse incidence is 8%. Conclusions: Preliminary results of this ongoing phase III trial confirm safety and potential benefit in improving survival of the T-cell gene transfer technology integrated with T cell depleted haplo-HSCT. Clinical trial information: NCT00914628.
A single arm, open-label multicenter phase II trial of everolimus in patients with relapsed/refractory germ cell cancer (RADIT).
2014-05-20

e15535 Background: Patients (pts) with relapsed or refractory metastatic germ cell cancer (GCC) after multiple lines of standard chemotherapy have a very poor prognosis. The mTOR inhibitor everolimus has been approved for the treatment of patients with renal cancer, neuroendocrine tumors, or breast cancer, and was assessed as a treatment option for GCC pts. Methods: GCC pts with disease progression or relapse after high-dose chemotherapy and/or at least two lines of cisplatin-based chemotherapy were eligible for study inclusion. In addition, prior combination chemotherapy with gemcitabine, oxaliplatin +/- paclitaxel was mandatory. The primary trial endpoint was treatment efficacy, defined as ≥25% of pts progression-free at 12 weeks. Twenty-five evaluable pts were needed, assuming a 20% two-sided type 1 error and 95 % power to reject the null hypothesis of 5% of patients progression-free after 12 weeks. Secondary endpoints were objective response rate, disease control rate (SD + PR + CR), progression-free survival, overall survival, and the safety profile of everolimus. Results: Twenty-five patients from 6 German study centers were treated with everolimus 10 mg orally daily until disease progression, unacceptable toxicity, or study discontinuation for other reasons between December 2010 and January 2014, when the trial was closed for recruitment. No unexpected serious safety events were observed requiring premature termination of the trial. At a pre-planned interim analysis after inclusion of 13 pts, predefined efficacy criteria for study continuation were met. Efficacy and safety analyses are ongoing. Conclusions: Efficacy of everolimus in heavily pretreated GCC pts was sufficient to justify continuation of the trial in the second stage. Accrual was concluded in January 2014, and primary and secondary endpoint analyses are ongoing. Clinical trial information: NCT01242631.
Determining the glioma CpG island methylator phenotype, 1p/19q codeletion, and MGMT promoter methylation from epigenome-wide methylation data in the biomarker cohort of the NOA-04 trial.
2014-05-20

2017 Background: Molecular biomarkers, including isocitrate dehydrogenase 1 or 2 (IDH1/2) mutation, 1p/19q codeletion and O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation, improve prognostication and may even guide treatment decisions in patients with World Health Organization (WHO) grade III gliomas. At present, each marker is individually tested by distinct assays. Illumina Infinium HumanMethylation450 BeadChip arrays (HM450) allow the determination of large-scale methylation profiles and genome-wide DNA copy number changes, enabling molecular subgrouping of tumors. Algorithms have been developed to detect the glioma CpG island methylator phenotype (G-CIMP) associated with IDH1/2 mutation, as well as 1p/19q codeletion and MGMTpromoter methylation, using this assay. Methods: Here, we investigated the diagnostic and prognostic performance of these algorithms in the biomarker cohort (n=115 patients) of the NOA-04 trial, which centrally assessed IDH, 1p/19q and MGMTstatus using established single marker tests. Results: Concordance for IDH and 1p/19q status was very high: In 92% of cases, the HM450 and the reference data agreed. In discordant cases, survival analysis by Kaplan-Meier and Cox regression analyses suggested a more accurate assessment of the biological phenotype by HM450 analysis. The HM450-derived MGMT-STP27 model to calculate MGMT promoter methylation probability revealed this aberration in a significantly higher fraction of cases than conventional methylation-specific PCR (MSP), with 87/91 G-CIMP positive tumors predicted as MGMTpromoter-methylated. Fitting a new model for these tumors resulted in an area under the curve of 0.84. Conclusions: G-CIMP and 1p/19q codeletion are reliably detectable by HM450 analysis and associated with prognosis in the NOA-04 trial. Efforts are required to resolve the discrepancy between the MGMT-STP27 and MSP data for MGMT promoter methylation status. Overall, our data suggests that HM450 analysis may be able to replace individual marker tests for routine assessment of anaplastic gliomas.
Development of a novel nomogram predicting nonsentinel lymph node metastases among patients with breast cancer after neoadjuvant chemotherapy (NACT): A transSENTINA substudy.
2014-05-20

1100 Background: The optimal timing for sentinel lymph node biopsy (SLNB) in the setting of NACT is still unclear. Recent studies such as SENTINA suggest that performing SLNB in patients with a cN+ status before, converting to cN0 after NACT (arm C) results in a non-acceptable false-negative rate. Therefore, there is a need to predict non-SLN status and tailor axillary surgery after NACT. The goal of this study was to develop an optimized nomogram based on data from SENTINA trial patients. Methods: The SENTINA trial with 1,737 patients from 104 institutions was previously described in detail. 181 patients in arm C were analyzed as a development set. Risk factors for non-sentinel node involvement have been selected based on prior univariate logistic regression analysis using a threshold of p<=0.2 and subsequent multivariable logistic regression using a backward selection procedure applying the likelihood ratio test. Validation of the model was carried out using a leave-one-out-validation (LOOV). The performance of the nomograms was evaluated by the area under the receiver operator curve (AUC). Results: Selected variables of the final prediction model comprised number of positive resected lymph nodes (OR=1.656, CI: 1.025-2.677, p=0.039), sonographic diameter of largest lymph node (OR=1.126, CI: 1.037-1.223, p=0.005) and tumor diameter after NACT (OR=1.180, CI: 0.962-1.447, p=0.112). A preliminary nomogram was built and yielded a mean AUC of 0.75252 (SD=0.004576, min=0.748, max=0.766) in LOO-validation. Selecting a cutpont of 36%, a sensitivity of 82% and a specificity of 49% may be reached. Additional analyses are ongoing and results will be presented. Conclusions: We developed a nomogram for prediction of non-sentinel lymph node metastases following NACT using the SENTINA patient database. The nomogram yielded AUC values comparable to previously presented nomograms. A provisional cutpoint for clinical decision making is described. External validation is planned.
IMPACT trial: Predictive factors for maintenance therapy with MGN1703 in patients with metastatic colorectal carcinoma.
2014-05-20

3615 Background: The immunomodulator MGN1703, a TLR-9 agonist, has shown good safety profile in patients with metastatic solid tumors. The IMPACT trial was conducted to assess clinical efficacy, safety, and immunological effects of MGN1703 as maintenance therapy twice weekly. Methods: The international randomized (2:1) double-blind placebo-controlled phase 2 IMPACT trial in mCRC patients with disease control after 1st-line chemotherapy by FOLFOX/XELOX or FOLFIRI +/- bevacizumab. After randomization of 59 out of 129 planned patients (43 MGN1703, 16 placebo) the trial was prematurely closed due to slow recruitment. Results: A superior effect of MGN1703 compared to placebo was shown: HR for the primary endpoint PFS on maintenance was 0.55 (p=0.041) by local and 0.56 (p=0.070) by independent assessment. For PFS from start of induction therapy the HR was 0.50 (p=0.022) and 0.49 (p=0.030), respectively. Notably, at time of study closure 4 MGN1703 patients were still free of PD and continued in compassionate use. A possible predictive effect was identified by Cox regression analyses: HR of 0.07 (p<0.0001) for patients with normal CEA and 0.39 (p=0.005) for patients with an objective response. Evaluation of biological activity via cell populations and chemokine serum levels confirmed immune system activation in MGN1703 patients. Cox regression and ROC analyses identified of activated NKT-cells (CD3+/CD56+/CD69+) at baseline as potentially predictive for a benefit from MGN1703 treatment (HR: 0.27, p=0.007). Study treatment was well tolerated: 32.6% vs. 18.8% of patients (MGN1703 vs. placebo) had drug-related AE and in only 1 patient per arm it was of grade 3 (MGN1703: sensory polyneuropathy, placebo: papular exanthema). Seven SAEs were reported of which only 1 was possible drug-related (moderate atypical pneumonia). Conclusions: Following induction chemotherapy, MGN1703 maintenance in mCRC patients is associated with improved PFS and an activation of the innate and adaptive immune system. Treatment was safe and well tolerated. There is preliminary evidence that CEA levels, tumor response, and activated NKT cells before start of MGN1703 therapy allow for identification of benefitting patients. Clinical trial information: NCT01208194.
Population PK/PD analysis of the pan-HDAC inhibitor resminostat.
2014-05-20

e13527 Background: Resminostat, an oral pan-HDAC inhibitor, was investigated in various oncological indications. To investigate pharmacokinetic (PK) and pharmacodynamic (PD) properties of resminostat, a population PK/PD model was established to quantitatively describe the time course of HDAC inhibition. Methods: PK and PD data from a clinical Phase I study in patients with solid tumors were included in the analysis. Single dose PK data of 100 mg, 200 mg, 400 mg, 600 mg and 800 mg dose groups were fitted simultaneously to a two-compartment model. A transit compartment model captured a delayed drug input. Collected PD data comprised pan-HDAC inhibition measured ex vivo in leukocytes of 18 patients using the fluorogenic substrate Boc-K(Ac)-AMC. Deacetylation results in trypsin cleavage and released AMC dye is quantified. Several PD models were explored. Model selection and diagnosis was performed applying information criteria, goodness-of-fit plots and visual predictive checks. Results: Ex vivo measured pan-HDAC inhibition by resminostat could successfully be described by a population PK/PD model. Maximum HDAC inhibition occurs within 2 h after dosing and transiently reaches a maximum > 90% inhibition at dose levels of 600 mg and 800 mg. Half-life (t1/2) of PD response is relatively short per se (≈ 6 h), but still 2-times the terminal t1/2 of PK. HDAC inhibition is described by a receptor on/off model. Derived apparent KDamounts to 454 ± 168 nM, closely matching values from leukocytes spiked with resminostat (570 ± 260 nM). HDAC inhibition was also evaluated in Phase II studies in patients with Hodgkin’s lymphoma or hepatocellular carcinoma. PD characteristics like onset, duration and intensity of response could be confirmed. Simulation of alternative dosing schemes revealed improved target coverage over a 24 h period upon BID dosing. This scheme was implemented in a Phase I/II trial with resminostat in colorectal carcinoma patients, where biomarker dynamics were confirmed. Conclusions: The established model accurately describes the clinical PK/PD relationship of resminostat. The model will be used to inform future trial designs. Ex vivo HDAC inhibition measured in peripheral blood represents a robust PD marker to monitor target engagement.