bluuebunny/crossref_metadata_2025_split huggingface dataset:
Final results of a phase I study of lapatinib (LAP) and cetuximab (CET) in patients with CET-sensitive solid tumors.
Authors: Deeken John F. , Wang Hongkun , Marshall John , Subramaniam Deepa Suresh , Hwang Jimmy J. , He Aiwu Ruth , Ramos Corinne , Hardesty Rosemarie A. , Steadman Kenneth , Weiner Louis M. , Pishvaian Michael J. 
Published: March 2020

2616 Background: Acquired resistance to anti-EGFR MoAb therapy may be via EGFR-ErbB2 heterodimerization and pathway reactivation. Dual anti-EGFR treatment was recently found to be active in colon cancer. We performed a phase I trial of CET and LAP to determine the DLTs, MTD, and clinical activity of the combination. Methods: Pts received CET at 400mg/m2 then 250 mg/m2 weekly, combined with daily LAP in a 3+3 dose escalation trial. LAP dose levels (DL) were (1) 750mg, (2) 1000mg, and (3) 1250mg. Cycles lasted 3 weeks, toxicity was assessed through C2, and pts were restaged every 2 cycles. Baseline and post-C1 tumor biopsies were analyzed for phosphoprotein activation in 36 EGFR/ErbB2 pathway proteins. Germ-line pharmacogenetic (PGx) variations were correlated with efficacy and toxicity. Results: Between 10/2010 and 10/2012, 22 pts were enrolled - colon (8), lung (8), head and neck (4), and anal cancers (2) - and 59% had prior anti-EGFR therapy. 18 pts were evaluable for toxicity, and 18 for response. Mean treatment was 3.8 cycles (range 1 - 12); 3 patients are still on trial. One DLT occurred at DL1 (gr 3 rash) and DL2 (gr 3 diarrhea). No pt on DL3 experienced a DLT. No pt experienced a gr 4 toxicity; gr 3 toxicities anytime on therapy included rash (17%), diarrhea (6%), fatigue (6%), lymphopenia (6%), and hypomagnesemia (6%). Rash was experienced by 94% of pts (gr 1=50%, gr 2=28%, and gr 3=17%). Partial responses (PR) occurred in 4 pts (22%), stable disease (SD) in 8 (44%), and disease progression in 6 (33%), for a clinical benefit rate of 67%. Seven of 13 (54%) pts on prior EGFR therapy had SD or PR. Down-regulation of phosphorylated EGFR/ErbB2 pathway components correlated with response; distinct pathway components were up-regulated in non-responders, including PI3K, Jak/Stat, MAPK, and IGF. PGx variants in FcRII correlated with response (p=0.045); no variants correlated with toxicity. Conclusions: The RP2D is CET 250 mg/m2 weekly and LAP 1250mg daily. Treatment was well tolerated with few grade 3 toxicities and a significant 67% clinical benefit rate. Non-responders showed up-regulation of EGFR pathway components – components which are druggable, warranting further study. A trial in colorectal cancer is ongoing. Clinical trial information: NCT01184482.
First-in-human phase I study of CetuGEX, a novel anti-EGFR monoclonal antibody (mAb) with optimized glycosylation and antibody dependent cellular cytotoxicity.
Authors: Fiedler Walter , Sessa Cristiana , Gianni Luca , Cresta Sara , Schulze-Bergkamen Henning , Weidmann Jens , De Dosso Sara , Tessari Anna , Salzberg Marc Oliver , Baumeister Hans , Danielczyk Antje , Dietrich Bruno , Nippgen Johannes , Goletz Steffen 
Published: March 2020

3008 Background: Epidermal growth factor receptor (EGFR) is a validated target in cancer. EGFR antagonists in clinical use do not exploit the full potential of this target. CetuGEX is an IgG1 mAb against EGFR. Fully human and optimized glycosylation lead to a 10- to 250-fold improvement of ADCC-mediated tumor cell killing in all FcγRIIIa allotypes and lack of immunogenic carbohydrate-chains, compared to cetuximab. Methods: Eligible patients with advanced solid tumors, progressing after standard treatment, were enrolled into this phase I, first-in-human, multicenter, single agent dose escalation trial. PK, PD and immunological parameters were assessed. Endpoints were safety and tolerability and secondarily pharmacokinetics, immunogenicity and anti-tumor activity. Results: 41 patients were treated on a q1w (8 dose levels from 12 to 1,370 mg flat dose), or q2w (990 mg flat) schedule. 25 pts had received at least 8 weekly doses (per protocol population [PP]).The most frequently observed drug-related AE were nausea (20%), vomiting (20%), hypertension (20%), almost all low grade and acneiform dermatitis (25%), only grade 1 or 2. Infusion-related reactions (IRR), virtually restricted to the first infusion, were associated with cytokine secretion: IL-6, IL-8, TNFα, IFNγ and IP-10 as marker of macrophage activation. Optimization of infusion scheme and premedication reduced IRRs in severity and frequency from 76% to 57% mainly of low grade. Blood NK cells were reduced as sign of redistribution. Activity was seen over all dose levels. One patient with NSCLC achieved a complete response. One patient with metastatic colorectal cancer had a partial response, another 2 patients with esophageal and gastric cancer without measurable disease at study entry had marked improvement of symptoms and normalization of tumor markers. Additional 15 pts had stable disease lasting from 8 weeks to over a year, including several minor responses, leading to a clinical benefit rate of 46% (19/41) in the overall and 76% (19/25) in the PP population. PK supports q1w and q2w dosing. Conclusions: CetuGEX shows clear signs of activity and acceptable toxicity. Phase II will soon be initiated. Clinical trial information: NCT01222637.
Highlighting the challenge of delayed overall survival (OS) curve separation in immunotherapy clinical trials.
Authors: Steele Savanna D. , Wang Song , Solinger Alan , Combest Austin J. , Bonneterre Marie-Edith Anne , Reitsma Dirk J. 
Published: March 2020

3009 Background: Cancer immunotherapy holds great potential but can elicit delayed responses, unlike chemotherapy. A delay in the separation of OS curves (between the control and treatment arms) has led to difficulty in achieving adequate power for OS analysis (Hoos A, Ann Oncol. 2012). Since combining immunotherapies, such as an anti-CTLA4 and an anti-PD-1, may increase the percentage of subjects achieving durable responses (Curran MA, PNAS. 2010), we sought to determine how adding a complementary immunologic agent to the currently-approved ipilimumab would impact delay in OS curve separation. Arbitrarily assuming that treatment effect on OS was doubled, we determined how various delays in OS curve separation might impact sample sizes. Methods: We evaluated three dual-immunotherapy clinical trial scenarios in which the separation of OS curves either remained the same, decreased, or increased. Baseline OS estimates were from pivotal trial data for ipilimumab in melanoma (Robert C et al, NEJM. 2011). SAS PROC POWER with piecewise linear survival curve was then used to determine approximate corresponding sample sizes. Results: See Table. Conclusions: Demonstrating significance in order to gain regulatory approval is important for providing potentially life-saving medications. For trials evaluating dual-immunotherapies, despite doubling treatment effects, delays in OS curve separation of up to 6 months would require over 2700 subjects to reach statistical power. In an era where treatments are increasingly personalized, these numbers will be difficult to achieve, underscoring the importance of novel trial designs incorporating Bayesian hierarchical modeling, precompetitive collaborations, and/or the use of state-of-the-art predictive biomarkers. [Table: see text]
Mucin 1 (MUC1) expression in patients (pts) with early stage non-small cell lung cancer (NSCLC): Relationship between immunohistochemistry (IHC), tumor characteristics, and survival.
Authors: Mitchell Paul Leslie , Battye Shane , John Tom , Murone Carmel , Knight Simon , Bode Gerd , Schroeder Andreas , Asadi Khashayar 
Published: March 2020

3011 Background: MUC1, a glycoprotein highly expressed in many malignancies, is being explored as an antigen for immunotherapy. How best to measure MUC1 expression as well as its prognostic value in NSCLC are still under discussion. Methods: TMAs were constructed using triplicate 1mm cores of FFPE tumour and stained with 214D4 (recognises protein core) and MA695 (recognises carbohydrate epitope) anti-MUC1 antibodies (abs). TMAs were assessed for polarisation, both cyto and mem staining intensity (scored 0-3) and proportion cells +ve (0-100%; scored 0–5), averaged for multiple cores. A composite score (intensity x cells +ve) was derived, ranging from 0–15 (3+ in >75% cells). Results: TMAs from 521 pts were analysed: male 362 (69.5%); never smoking 35 (7%); adeno 259 (49.7%), squamous 180 (34.5%), large cell 39 (7.5%); nodal N0 340 (65.3%), N1 71 (13.6%), N2 107 (20.5%). Results of IHC staining intensity, proportion positive cells and depolarisation were very similar for the two abs. There was high concordance in the composite score for the abs (R2=0.71, p<0.0001). Polarisation was discordant in 7.9% of cases. For 77 cases with paired primary/ N2 nodal tissue, mean 214D4 scores were 8.3 and 8.9 and MA695 10.6 and 9.9 respectively. Discordant staining in primary but not in node was seen in 5.2% and 10.4% with 214D4 and MA695 respectively. Increased expression as assessed by 214D4 (HR=1.26; 95% CI 1.014-1.565, p=0.04 log rank test) and MA695 (HR=1.20, 95% CI 1.042-1.605; p=0.02) was associated with improved survival. The prognostic value of depolarisation has yet to be analyzed. Conclusions: Over 93% of cases were MUC1 IHC positive. Composite scores for the 2 abs were highly correlated and depolarisation largely concordant. MUC1 expression was generally maintained in paired primary/nodal tumour. Increased expression of MUC1 was associated with improved survival however further investigation is needed to determine which abs best predict outcomes. [Table: see text]
Outcome with stereotactic radiosurgery (SRS) and ipilimumab (Ipi) for malignant melanoma brain metastases.
Authors: Shoukat Sana , Marcus David Mitchell , Rizzo Monica , Lawson David H. , Liu Yuan , Khan Mohammad Khurram 
Published: March 2020

3032 Background: SRS with Ipi for brain metastases from malignant melanoma has been explored for overall survival (OS) (Knisely JP, Yu JB, Flanigan J, et al. Radiosurgery for melanoma brain metastases in the ipilimumab era and the possibility of longer survival. J Neurosurg. 2012;117:227-33). We present the first retrospective analysis to determine if this combination is safe and improves OS, while accounting for lactate dehydrogenase (LDH). Methods: Patients with melanoma brain metastases who underwent SRS between 1998-2010 (n=124) were compared with those who additionally received Ipi (n=11). The primary endpoint was median OS from time of SRS, calculated using Kaplan-Meier method. Cox proportional hazard model was carried out for univariate and multivariable survival analysis. The secondary endpoints were local control at initial site of SRS, anywhere intra-cranial failure, need for repeat SRS, and toxicity. Results: Median OS for the entire cohort was 6.9 months. Patients in the Ipi group had an improved median OS of 28.3 months vs. 6.8 months in the non-Ipi group (p = 0.013). No difference was noted in local control, anywhere intracranial failures, toxicity (radionecrosis, hemorrhage, patient reported memory deficits), or need for repeated SRS. MVA (Table) showed that Ipi independently predicted for improved OS even when taking into account LDH and ECOG performance status. The only confounding factor within the Ipi group was younger age of the Ipi cohort (43 vs. 55 yrs, p = 0.006). Conclusions: Use of SRS with Ipi appears to be safe and associated with an impressive increase in median OS in patients with brain metastases from malignant melanoma; this combination should be further investigated. [Table: see text]
Intraperitoneal radioimmunotherapy (RIT) for desmoplastic small round cell tumor (DSRCT): Initial results from a phase I trial.
Authors: Modak Shakeel , La Quaglia Michael P. , Carrasquillo Jorge A. , Zanzonico Pat , Enero Catherine , Pandit-Taskar Neeta , Kang Hye Jin , Cheung Nai-Kong V. 
Published: March 2020

3033 Background: DSRCT, a rare sarcoma of adolescents and young adults usually arising from the peritoneum, is lethal in >80% of patients despite aggressive multimodality therapy. Recurrences often present as multifocal peritoneal implants, making it uniquely suited for intraperitoneal (IP) targeting. We hypothesized that targeted radiotherapy may improve local control and reduce relapses. IP RIT, by virtue of prolonged residence time and slow transfer to the circulation, may selectively target IP DSRCT while minimizing organ toxicity. The anti-4Ig-B7H3 murine monoclonal antibody 8H9 binds to 96% of primary DSRCT (Med Pediatr Oncol 39:547). 131I-8H9 injected intra-Ommaya is safe (J Neurooncol 97:409). Methods: We initiated a phase I study to test the safety of IP RIT with 131I-8H9. Cohorts of 3-6 patients were treated with 131I-8H9 at escalated doses from 30mCi/m2-60mCi/m2 as a single IP injection. A tracer dose of 2mCi124I-8H9 was given IP before 131I-8H9 to acquire PET images and biodistribution data. Pharmacokinetics (PK) was studied using serial blood draws. Results: 15 heavily prior-treated patients: 13 with DSRCT, 2 with rhabdomyosarcoma received 30, 40, 50mCi/m2 131I-8H9 (3 at each dose level) or 60mCi/m2 (n=6). Dose-limiting toxicity was not seen. Three patients (n=1 each) had transient, self-limiting, possibly therapy-related grade 3 toxicities: neutropenia, hepatic transaminase elevation and thrombocytopenia. No patient required hematopoietic stem cell rescue. Blood half life was 32.5±11.5h (n=12) and mean peritoneal residence time was 14.6h (n=3). Mean absorbed dose to blood based on blood sampling was 0.56±0.21 rad/mCi (n=14). Mean absorbed doses (rad/mCi) to kidney, liver, lung and spleen were 1.72, 1.92, 0.64 and 1.03 respectively (n=3). Dehalogenation was insignificant: >80% iodine remained protein-bound in blood (n=10). 6/7 DSRCT patients treated without evaluable disease remain in remission at a median of 11.1 months post 131I-8H9. Conclusions: IP 131I-8H9 was safe and 124I-8H9 provided valuable PK and dosimetry data. Since maximum tolerated dose was not reached we have expanded patient accrual to a planned dose of 90mCi/m2. Clinical trial information: NCT01099644.
HER2 evaluation process for neoadjuvant targeted therapies in breast cancer.
Authors: Mizuno Yoshio , Takeda Naoko , Yamada Junichi , Abe Hiroaki , Inoue Yuko , Seto Hiroshi , Sato Kazuhiko ,   Tokyo-West Tokushukai Hospital
Published: March 2020

3034 Background: Treatment with a combination of HER2-targeted therapies has emerged as an addition of trastuzumab to neoadjuvant chemotherapy regimens in breast cancer patients and it goes on increasing. For clinical HER2 determination, immunohistochemical (IHC) analysis is an attractive method and all IHC 2+ cases are categorized as equivocal and should be reflexed to fluorescence in situ hybridization (FISH) testing. However, research in recent years with respect to false-negative cases for HER2 testing have been reported, and it comes to the question of what considering the indication for trastuzumab in the neoadjuvant chemotherapy. To clarify these controversial points in applying the results of HER2 testing in the clinical setting, we performed a retrospective analysis of core needle biopsy (CNB) and surgical specimen results. Methods: 422 patients underwent primary operations for early breast cancer at Tokyo-West Tokushukai Hospital (Tokyo, Japan) from October 2008 to December 2012. Among these patients, 262 patients who received CNB prior to operation were enrolled. Those patients who received preoperative chemotherapy or had DCIS were excluded. With regard to diagnostic criteria, HER2 positivity was defined as either 3+ by IHC or FISH analysis amplification ratio of ≥2.2. In addition, if in any cases which CNB samples or surgical specimens showed HER2-positive had defined true HER2-positive cases, we assessed the false-negative results of the HER2 test via IHC using CNB samples and surgical specimens. Results: In a matched cohort of 262 patients, 59 cases showed HER2-positive (five cases were CNBs negative to surgical specimens positive, 14 cases were CNBs positive to surgical specimens negative, and 40 cases were both positive). If we decide for selection of trastuzumab target cases by CNBs only, we make mistakes in indications of trastuzumab for five (8.5%) of 59 HER2-positive cases who were CNBs negative to surgical specimens positive. Conclusions: There are quite a few cases show false negatives for HER2 testing in CNB samples. In cases of considering the indication for trastuzumab in the neoadjuvant chemotherapy, even if the CNB samples resulted in negative, we consider that retesting with FISH analysis should be carried out.
Serum lactate dehydrogenase (LDH) as a prognostic selection criterion for ipilimumab treatment in metastatic melanoma.
Authors: Blank Christian U. , Kelderman Sander , van Tinteren Harm , Heemskerk Bianca , van den Brom Rob , Hospers Geke A. , van den Eertwegh Alfons JM , Kapiteijn Ellen , De Groot Jan Willem , Jansen Rob L. , Fiets W. Edward , Krzystanek Marcin , Szallasi Zoltan , Furness Andrew James Scott , Renn Alex , Gore Martin Eric , Lorigan Paul , Schumacher Ton , Haanen John B. A. G. , Larkin James M. G. 
Published: March 2020

3036 Background: Ipilimumab, a CTLA4 blocking antibody, has been shown to improve survival in metastatic melanoma patients in phase III trials. However, only a subset of patients experiences long-term survival benefit. Therefore, we analysed two independent retrospective sets of patients treated in ‘real world’ settings to identify prognostic factors that correlate with better outcome after ipilimumab therapy. Methods: Advanced melanoma patients, eligible for ipilimumab therapy, were treated in the Dutch and UK Expanded Access Programs (EAP) and after European licensing on the 3mg/kg schedule. Baseline characteristics and peripheral blood parameters were assessed and patients were monitored for the occurrence of adverse events and responses. Results: A total of 166 patients were enrolled in the Dutch EAP. Best overall response rate and disease control rate were (DCR) 17% and 35%. Median follow-up was 17.9 months, with a median progression free survival of 2.9 months. Median overall survival (OS) was 7.5 months, and OS at 1 year 37.8% and at 2 years 22.9%. Univariate analysis revealed that gender, age, Breslow thickness, baseline and week 6 lymphocyte count (ALC), and prior treatment had no influence on OS, while mWHO, M stage, baseline LDH, S100, erythrocyte sedimentation rate (ESR), and the slope of ALC did. In a multivariate model only baseline LDH and ESR remained as significant independent prognostic factors. The relevance of LDH was validated in an independent cohort of 68 patients from the UK. Stratifying the patients in the NL cohort according to LDH levels (≤upper limit normal (ULN), 54.4% of patients versus >2xULN, 16.9% of patients) separated into groups of patients observing DCR of 48% versus 14%, and median OS of 13.7 versus 3.1 months, while toxicity was similar in both groups (48% and 41%). None of the patients was alive at 15 months after treatment if baseline LDH was >2xULN in both the NL and UK cohorts. Conclusions: Overall survival upon ipilimumab treatment is lower in an expanded access population as compared to phase III trials. LDH >2xULN at baseline is a potential prognosticator in patients receiving ipilimumab and should be considered in guiding ipilimumab treatment initiation.
Blinatumomab exposure and pharmacodynamic response in patients with non-Hodgkin lymphoma (NHL).
Authors: Hijazi Youssef , Klinger Matthias , Schub Andrea , Wu Benjamin , Zhu Min , Kufer Peter , Wolf Andreas , Nagorsen Dirk 
Published: March 2020

3051 Background: Blinatumomab (AMG 103) is an investigational, bispecific, T cell engaging (BiTE) antibody targeting CD19-expressing B cells. We describe the exposure-pharmacodynamic (PD) response of blinatumomab in patients with NHL, using a quantitative pharmacology approach. Methods: In a phase 1 study, 76 patients with NHL received blinatumomab by continuous intravenous infusion (cIV) at doses of 0.5 to 90 μg/m2/d in 4- or 8-week cycles. Pharmacokinetics (PK) was determined. PD responses evaluated included lymphocytes and cytokines measured during treatment, and sum of the products of the greatest diameters of tumor size in lymph nodes (SPD) at the end of treatment. Blinatumomab concentration at steady state (Css) and the cumulative area under the concentration (AUCcum)–time curve over the period before the evaluation of SPD were used to evaluate the exposure-SPD relationship. Results: Blinatumomab showed linear PK. Early PD responses were characterized by B cell depletion, T cell redistribution, and transient cytokine release. Following cIV at doses from 0.5 to 90 μg/m2/d, B cells declined at a first-order rate with a dose-dependent rate constant, ranging from 0.16 to 1.0 h-1. Complete B cell depletion was achieved within 48 hours at doses ≥5 μg/m2/d. A dose-independent decrease in T cell counts was observed within 24 hours after dosing, and T cells returned to baseline within 2 weeks of treatment. Cytokine elevation occurred in some patients and was dose-dependent. Blinatumomab exposure-SPD relationship was best described by an inhibitory Emax model (E = E0-(Imax*C)/(IC50+C)). According to the model estimation, a 50% reduction in SPD would be achieved when Css is 2141 pg/mL and AUCcum is 1381 h*μg/L, equivalent to a blinatumomab dose of 54 µg/m2/d given over 27 days. Conclusions: B lymphocytes were completely depleted from the circulation at blinatumomab doses ≥5 μg/m2/d. Depletion was faster at higher doses. Higher blinatumomab Css and AUCcum were associated with better tumor reduction. Tissue accessibility may explain the higher dose requirement for SPD reduction versus peripheral B cell depletion. The PK/PD model has utility for the design of future studies of blinatumomab in NHL. Clinical trial information: NCT00274742.
Rituximab pharmacokinetics in children and adolescents with de novo intermediate and advanced mature B-cell lymphoma/leukemia: A Children’s Oncology Group (COG) report.
Authors: Barth Matthew John , Goldman Stanton , Smith Lynette , Perkins Sherrie L , Shiramizu Bruce , Gross Thomas G. , Harrison Lauren , Sanger Warren , Geyer Mark B , Giulino Lisa B. , Cairo Mitchell S. 
Published: March 2020

3055 Background: The COG trial ANHL01P1 was undertaken to determine pharmacokinetics (PK) and safety following the addition of rituximab (R) to FAB/LMB 96 chemotherapy in children and adolescents with stage III/IV mature B-NHL and B-ALL±CNS disease. Methods: Patients received R (375mg/m2) on day -2 and 0 of two induction cycles and day 0 of two consolidation cycles. R levels were measured prior to any antibody infusion, during induction cycles (1 hour prior and 30-60 minutes after each R dose) and following consolidation cycles (1, 3, 6 and 9 months after last R dose). R was measured by ELISA with goat anti-rituximab antibody as the capture reagent and goat anti-mouse IgG-conjugated to horseradish peroxidase as the detection reagent. R terminal half-life (t½) was calculated if at least 3 time points after the last dose were measurable in an individual subject. Results: Serum R levels are reported in the Table. Highest peak levels were achieved following the second dose of each induction cycle with sustained troughs and a t½ of 26-29 days. Group C patients tended to have lower R levels than Group B. Patients with LDH ≥2xULN were noted to have lower R levels during induction 1 compared to those with LDH <2xULN. Children (<13 years) exhibited higher peak concentrations, similar trough levels and a shorter t½ than adolescents (≥13 years). None of these differences reached significance after adjusting for multiple comparisons. Conclusions: R can be safely added to FAB chemotherapy with high early R peak/trough levels and a long terminal half-life. The efficacy of R combined with FAB chemotherapy is currently being investigated in an ongoing international intergroup trial. Clinical trial information: NCT00057811. [Table: see text]