bluuebunny/crossref_metadata_2025_split huggingface dataset:
Diptheria toxin-interleukin 3 fusion protein therapy of patients with elderly or relapsed/refractory acute myeloid leukemia (AML)
Authors: Frankel A. E. , Weir M. A. , Hall P. D. , Hogge D. E. , Rizzieri D. A. 
Published: March 2020

6569 Background: To target myleoid leukemic stem cells in relapsed/refractory patients, we produced a recombinant protein composed of the catalytic and translocation domains of diphtheria toxin (DT388) fused to human interleukin 3 (IL3). DT388IL3 binds to IL3 receptors on leukemic progenitors; the toxin is internalized and enzymatically inactivates protein synthesis leading to programmed cell death. We prepared a clinical batch of DT388IL3 and obtained FDA approval for a phase I study. Patients and Methods: Relapsed/refractory or elderly (≥70 years) AML patients with normal organ function and low anti-DT antibody titers were consented and given 15 minute infusions of DT388IL3 on a M-W-F for two weeks schedule. Premedication was hydrocortisone, acetaminophen, and diphenhydramine. Inter-patient dose escalation was done. Five patients at 4 ug/kg, 6 patients at 5.32 ug/kg, and 2 patients at 7.07 ug/kg received all 6 planned doses. Results: Eighteen patients have been treated as of 1/06. Median age was 58 years (25–81). There were 9 males and 9 females. One patient had de novo AML; 7 patients were in second relapse; 6 patients were in third relapse and 4 patients had refractory AML. One patient each received an autologous stem cell transplant (SCT), and an allogeneic SCT. Cytogenetics were unfavorable in 3, intermediate in 10 and not done in 5 patients. One patient each had MDS-related AML and treatment-related AML. Drug-related side effects were mild and transient including grade 3 fever, grade 2 hypotension, chills and hypoalbuminemia. Responses seen to date have been transient including a reduction in bone marrow blast index (% cellularity × fraction blasts) of pretreatment 40%, 70%, 36% and 40% converting to 8%, 4%, 4% and 4% on day 15. Conclusions: The preliminary data suggests mild toxicity with biological activity. Dose escalation is planned as per protocol. No significant financial relationships to disclose.
Pharmacokinetics of an oral VEGF receptor tyrosine kinase inhibitor (PTK787/ZK222584) in patients with myelodysplastic syndrome (MDS): Cancer and Leukemia Group B Study 10105
Authors: Gupta P. , Miller A. A. , Owzar K. , Murry D. J. , Sanford B. L. , Vij R. , Yu D. , Hasserjian R. P. , Larson R. A. , Ratain M. J. 
Published: March 2020

6573 Background: Angiogenesis may contribute to the pathophysiology of myelodysplastic syndromes (MDS). PTK787/ZK222584 (PTK/ZK; Novartis and Schering AG) inhibits vascular endothelial growth factor (VEGF), platelet derived growth factor (PDGF) and c-kit receptor tyrosine kinases. Methods: We evaluated early toxicity and pharmacokinetics in a Phase II trial of PTK/ZK in patients with MDS. Patients received PTK/ZK 1,250 mg orally once daily on 28-day courses until disease progression or unacceptable toxicity. A two compartment model with first order absorption and an inducible clearance was fit to serial concentration time data using a MAP Bayesian algorithm as implemented in ADAPT II software. Results: We report preliminary toxicity and pharmacokinetics on 56 of 80 pts enrolled between March 2004 and January 2005. The most common CTC grade ≥2 non-hematological toxicities observed were fatigue, nausea, vomiting, dizziness and ataxia. The initial area under the concentration-time curve (AUCinit) ranged from 25.5–423.1 mg*h/L (mean, 105 mg*h/L). The induced AUC (AUCind) ranged from 8.2–265.3 mg*h/L (mean, 56.2 mg*h/L). There was a significant decrease in drug exposure (Hodges-Lehmann Estimate 45.2 mg*h/L [95% CI=30.5,60.0]; Wilcoxon signed rank test p <0.0001), likely due to CYP3A4 auto-induction. However, there was no statistical correlation between AUCinit and AUCind for individual patients. Because of marked inter-individual heterogeneity observed in AUCinit and AUCind, we examined if drug exposure correlated with toxicity during the first 2 courses. On exploratory analyses, there was no relationship between pharmacokinetic parameters (AUCinit, AUCind or a function of both AUCs) and the occurrence or grade of non-hematological toxicities. Conclusions: Drug exposure declined significantly within 7–14 days after starting treatment with PTK/ZK. In this sample, there was no statistical evidence suggesting that variability in drug exposure was associated with non-hematological toxicities of PTK/ZK in patients with MDS. No significant financial relationships to disclose.
Serial changes in bone marrow cellularity, reticulin fibrosis and microvessel density in patients with chronic myeloid leukemia (CML) in chronic phase treated with imatinib
Authors: Lokeshwar N. M. , Kumar L. , Vijayaraghavan M. , Dawar R. , Sharma A. , Kochupillai V. 
Published: March 2020

6596 Background: Imatinib Mesylate, a BCR-ABL tyrosine kinase inhibitor produces sustained complete hematological response (CHR) in CML patients in chronic phase. There is a paucity of information on the effects of imatinib on the bone marrow (BM) morphology and angiogenesis. We evaluated the sequential changes in these parameters in 22 CML chronic phase patients treated with first line imatinib (400 mg) and compared with 10 controls (non-hematological malignancies). Methods: Trephine BM biopsies were evaluated by means of morphology, morphometry, Gomori’s stain and CD 34 staining. Reticulin fibrosis was graded from grade 1 to grade 4. Microvessel density (MVD) was calculated by counting the microvessels in hot spots (400 ×). Final value was mean of 10 fields. Total vascular area (TVA) was calculated by image analysis and expressed as percentage of the total area. Results: 22 patients were included in the study. Median age was 34 years (range 20–58 years). All patients attained a CHR at a median of 18 days. Major cytogenetic response was seen in 64%, minor response in 27% and no response in 9% of patients. Baseline BM cellularity was increased in all patents as compared to controls. The median cellularity at 6 months and 1 year was decreased to 60% and 50% respectively. The median grade of reticulin fibrosis at baseline was grade 3 as compared to controls (median grade 1). There was a significant decrease in reticulin fibrosis at 6 months and 1 year (median-grade 1, p=0.04). The median MVD at baseline was 8.25 (range 6–26) and was increased as compared to controls (median MVD-3.6). There was a significant decrease in MVD at 6 months and 1 year (median MVD-4.0, p=0.04). Similarly the TVA decreased from 6.2% at baseline to 4.3% at 1 year. These changes correlated with the cytogenetic responses. Two patients who had disease progression during therapy showed reversal in the bone marrow changes. Conclusions: Imatinib Mesylate produces significant effects on bone marrow morphometry and angiogenesis in patients with CML in chronic phase. There is a consistent decrease in bone marrow cellularity, reticulin fibrosis and microvessel density during therapy. No significant financial relationships to disclose.
Randomized trial of high-dose chemotherapy with autologous haematopoietic stem cell support vs. standard-dose chemotherapy in breast cancer patients with 10 or more positive lymph nodes: Overall survival after 6 years of follow up
Authors: Zander A. R. , Kroeger N. , Schmoor C. , Krueger W. , Moebus V. , Frickhofen N. , Metzner B. , Schultze W. , Berdel W. , Koenigsmann M. , Thiel E. 
Published: March 2020

672 Background: Investigation of high dose chemotherapy (HD-CT) supported by autologous hematopoietic stem cell transplantation compared with standard dose chemotherapy (SD-CT) as adjuvant treatment in patients with primary breast cancer and 10 or more axillary lymph nodes. Methods: Between November 1993 and September 2000 307 patients were randomized to receive the following cycles of Epirubicin (90 mg/m2), Cyclophosphamide (600 mg/m2) intervenously (every 21 days) either HD-CT of Cyclophosphamide (1500 mg/m2), Thiotepa (150 mg/m2) and Mitoxantrone (10 mg/m2) intervenously for 4 consecutive days followed by stem cell transplantation or standard dose chemotherapy SDCT in 3 cycles of Cyclophosphamide (500 mg/m2), Methotrexate (40 mg/m2) and Fluoruracil (600 mg/m2) intervenously on days 1 and 8 every 28 days. The primary end points were event-free survival and overall survival. Results: After a median follow-up of 6.1 years 166 events with respect to event-free survival (SD-CT: 91, HD-CT: 75) and 123 with respect to overall survival (SD-CT: 66 and HD-CT: 57) have been observed. The hazard ratio of HD-CT versus SD-CT is estimated as 0,80, p = 0,15. The hazard ratio for overall survival for high dose chemotherapy versus standard dose chemotherapy is estimated as 0,84, p = 0,33. Analysing the effect of treatment on event-free survival premenopausal patients, patients with tumor grade III and ER-positive patients had a better outcome with HD-CT with an interactive effect of 2.5 and 1.4. The significance was only shown in grade III patients in favour of HD-CT, (p = 0,049). The interactive effect of HD-CT with prognostic factors did not reach significance for overall survival. Conclusion: Even with a follow-up of 6.1 years there was only a trend in favour of high dose chemotherapy with respect to overall survival but without a statistical significance. A proper meta-analysis needs to be undertaken for an evaluation of subgroups of patients which might benefit from this treatment approach. No significant financial relationships to disclose.
Effect of zoledronic acid (Zol) compared with pamidronate (Pam) on disease progression in breast cancer (BC) patients with bone metastases stratified by baseline characteristics
Authors: Hei Y. , Lipton A. , Shirina N. , Chen Y. M. , Xie T. 
Published: March 2020

678 Background: Zol has been shown to significantly reduce the risk of skeletal complications compared with Pam in BC pts with bone metastases. Zol has also demonstrated antitumor effects in animal models of human BC and significantly delayed bone lesion progression in pts with renal cancer. To assess whether Zol may reduce the risk of overall disease progression compared with Pam, we conducted a retrospective analysis of BC pts enrolled in a large randomized, controlled trial. Methods: Patients treated with Zol or Pam were retrospectively stratified by baseline characteristics, including Brief Pain Inventory (BPI) composite pain score, time from initial cancer diagnosis to development of bone metastases, and duration of cancer. The relative risk of overall disease progression during 25 months on study was analyzed using the Cox proportional hazards model. Results: Median BPI pain score at baseline was 2.75, median time to development of bone metastases was 44 months, and median time with cancer was 58 months for all patients. In the subset of pts with a baseline BPI score ≥ 2.75 (n = 556), treatment with Zol significantly reduced the risk of disease progression by 21% compared with Pam (hazard ratio [HR] = 0.793; P = .018). Similarly, among pts who developed bone metastases < 44 months from initial diagnosis of cancer (n = 564) and pts with cancer for < 58 months (n = 563), treatment with Zol reduced the risk of disease progression by approximately 20% compared with Pam (HR = 0.805; P = .026 and HR = 0.800; P = .023, respectively). Conclusions: Zol significantly reduced the risk of overall disease progression compared to Pam in specific subsets of pts with higher pain scores and shorter time to development of bone metastases. This exploratory analysis suggests that Zol has potential antitumor effects that may reduce the risk of disease progression in this patient population. These results are consistent with published reports and provide the initiative for further investigations with additional clinical studies. [Table: see text]
EGFR mutation and copy number, EGFR protein expression and KRAS mutation as predictors of outcome with erlotinib in bronchioloalveolar cell carcinoma (BAC): Results of a prospective phase II trial
Authors: Miller V. A. , Zakowski M. , Riely G. J. , Pao W. , Ladanyi M. , Tsao A. S. , Sandler A. , Herbst R. , Kris M. G. , Johnson D. H. 
Published: March 2020

7003 Background: Erlotinib produces dramatic responses in a subset of patients with NSCLC. Mutations in the EGFR tyrosine kinase domain, EGFR amplification or polysomy and EGFR overexpression on immunohistochemistry have all been associated with sensitivity and benefit; pts with KRAS mutation are commonly resistant to this agent. These correlative studies were prospectively undertaken to characterize the ability of these markers to predict response rate, time to progression and survival in pts with BAC treated with the EGFR-TKI, erlotinib. Methods: One hundred and two patients received erlotinib as part of a phase II trial in BAC (Kris, Proc ASCO 2005); 84 had one or more correlative studies completed. Analysis of EGFR exons 19 and 21 (n=82) (Pao, et al PNAS 2004), EGFR IHC (n=62) (DAKO) was performed and EGFR copy number was determined by chromogenic in situ hybridization (CISH) (n=74) (Zymed); detection of ≥ 4 signals per cell was considered evidence of amplified copy number. KRAS exon 2 (n=79) testing was performed by direct sequencing. Fisher’s exact test was used to study the association of each feature in pts with partial response or no partial response. Time to progression and survival were analyzed with log-rank test. Results: See table below. Conclusions: 1) EGFR exon 19 or 21 mutation is a powerful predictor of response and TTP but not OS in pts with BAC treated with erlotinib. 2) CISH ≥4 is associated with response and improved TTP but not OS. 3) Patients with both EGFR mutation and amplification fare well supporting the concept of “oncogene addiction”; erlotinib should be considered as initial therapy in this population. 4) EGFR amplification without mutation is uncommon. 5) There is no clear utility of EGFR IHC in clinical decision making. 6) The presence of KRAS mutation predicts resistance to erlotinib. Supported, in part, by Genentech. [Table: see text] [Table: see text]
Phase III randomized study of vinorelbine (V), gemcitabine (G) followed by docetaxel (D) (VGD) versus paclitaxel (P) and carboplatin (C) (PC) in patients (pts) with advanced non-small cell lung cancer (NSCLC) (Japan Multinational Trial Organization LC00–03)
Authors: Kawahara M. , Ogawara M. , Nishiwaki Y. , Kubota K. , Komuta K. , Minato K. , Fujita Y. , Origasa H. , Fukushima M. , Furuse K. 
Published: March 2020

7013 Background: Our phase II study of non-platinum VGD for advanced NSCLC demonstrated excellent results with the median survival time (MST) of 15.7 mos and a 1-year survival rate of 59% (Brit J Cancer 88:42,2003). A phase III trial was performed to determine the survival benefit of VGD compared with PC for advanced NSCLC as a Japan-SWOG Lung Cancer Common Arm Trial. Methods: Between Mar 2001 and Apr 2005, 401 chemo-naïve NSCLC pts with Stage IIIB with pleural effusion or Stage IV without brain metastasis, who had ECOG PS 0–1, were randomized to VGD; V 25 mg/m2 iv and G 1000 mg/m2 iv, days 1, 8, every 21 days for 3 cycles followed by D 60 mg/m2 iv, d1, every 21 days for 3 cycles or PC; C AUC=6 iv and P 225 mg/m2 iv, day 1, every 21 days for 6 cycles. The primary endpoint was overall survival (OS). For a two-sided test at the 5% level of significance and power of 85%, the number of pts required to detect a 40% difference in MST was 400. Results: 393 pts (196 VGD, 197 PC) were evaluable for response, OS and toxicity. Baseline demographics were balanced (VGD vs PC): median age 65 yrs(both arms);male(74 vs 69%); PS 0 40%(both arms);Stage IIIB (17 vs 18%); Ad/Sq (66%/23% vs 76%/15%). There were 238 deaths with a median follow-up of 23 mos. 49% in VGD and 29% in PC arm completed 6 cycles (p=0.00005). Response rates in arms VGD/PC were 23% vs 36% (p= 0.008). There were no significant differences in progression free survival, OS, 1- and 2-yr survivals between VGD and PC arms: 5.9 vs 6.0 mos (p=0.95, Log rank), 13.1 vs 13.8 mos (MST, p=0.28, Log rank), 55.6 vs 55.5%, and 27.6 vs 31.8%. Grade 3/4 toxicities in arms VGD/PC were: neutropenia (G4) (30 vs 54%, p<0.00001), thrombocytopenia (4 vs 6%), febrile neutropenia (20 vs 19%), neuropathy (2 vs 21%, p<0.00001), pulmonary (9 vs 2%, p=0.0006). There were 2 treatment-related deaths (pneumonitis) in VGD arm. Conclusions: Non-platinum triplet chemotherapy had comparable activity in pts with advanced NSCLC. The VGD had significantly less myelosuppression, but more pulmonary toxicity than PC. No significant financial relationships to disclose.
Updated report of a phase III study of induction therapy with gemcitabine + carboplatin (GC) followed by either delayed vs. immediate second-line therapy with docetaxel (D) in advanced non-small cell lung cancer (NSCLC)
Authors: Fidias P. , Dakhil S. R. , Lyss A. P. , Loesch D. M. , Waterhouse D. , Cunneen J. , Ye Z. , Tai F. , Obasaju C. K. , Schiller J. H. 
Published: March 2020

7032 Background: GC is an active regimen in patients with advanced NSCLC. For non-progressors after induction treatment, optimal timing of sequential therapy is unclear. Is it best to sequence immediately to an active non-cross resistant agent or delay the introduction of this agent until time of disease progression (PD)? This trial was designed to answer this question. Methods: Pts with Stage IIIB or IV NSCLC were enrolled. G 1000mg/m2 was administered on day 1,8 followed by C at AUC 5.0 on day 1. After 4 cycles, non-progressers were then randomized to immediate D (75mg/m2 administered on day 1 every 3 wks) or delayed D (pts were observed until first evidence of PD). Conclusions: This study confirms that it is possible to deliver docetaxel immediately following four cycles of GC without significantly increasing toxicity. The response rate of 42.1% and clinical benefit rate (CR+PR+SD) of 88.2% observed in the immediate D arm compares favorably with the rates of 6.1% and 60.6% of the delayed D arm. Additional toxicity and response information will be available at the time of the meeting. [Table: see text] [Table: see text]
Comparison of docetaxel and vinca alkaloid, alone or in combination with other chemotherapy agents, in the first-line treatment of advanced non-small cell lung cancer (NSCLC): A meta-analysis
Authors: Douillard J. Y. , Fossela F. , Georgoulias V. , Pujol J. L. , Kubota K. , Monnier A. , Takeda K. , Cucherat M. , Laporte S. 
Published: March 2020

7034 Background: Taxanes and vinca alkaloids are commonly used agents, in first-line therapy of advanced NSCLC. As some data in comparative studies have suggested possible differences in survival and safety, we performed a meta-analysis in order to assess the potential benefit of docetaxel-based regimens in comparison with vinca alkaloid-based regimens, in terms of overall survival (OS) and toxicity. Methods: MEDLINE, CANCERLIT and Cochrane Library searches were supplemented by information from clinical study reports and by manual searching of relevant meeting proceedings. Only randomized trials comparing docetaxel-based chemotherapy to vinorelbine- or vindesine-based chemotherapy were included. Outcomes recorded were OS and neutropenia. Fixed-effects and random-effects models were used to estimate the pooled hazard ratio (HR) of OS and the odds ratio (OR) of neutropenia. A HR or OR less than 1 indicates that docetaxel is superior to vinca alkaloids. Heterogeneity was assessed using the Cochran Q-test. Results: The seven selected trials (six using vinorelbine as vinca alkaloid) yielded a total of 2,867 patients (docetaxel regimens: 1,638; vinca alkaloid regimens: 1,229). Docetaxel was combined with a platinum compound in three trials, with gemcitabine in two trials and used as monotherapy in two trials. The vinca alkaloid was combined with a platinum compound in six trials, and used alone (vinorelbine) in one. The pooled estimate of the OS shows a significant improvement in favor of docetaxel (HR=0.89, 95%CI [0.82;0.96], p=0.03), this benefit persisting after exclusion of the vindesine study (HR=0.90 [0.83;0.98]) and also after excluding monotherapy regimens (HR=0.89 [0.82;0.97]. While neutropenia was common, it was significantly less frequent with docetaxel (OR=0.60 [0.39;0.92], p=0.019), as was febrile neutropenia (OR=0.60 [0.39;0.96], p=0.034). Conclusions: The results of this meta-analysis support the superior efficacy (OS) and safety (neutropenia and febrile neutropenia) of docetaxel in first-line therapy of advanced NSCLC as compared with vindesine or vinorelbine. Detailed results, as well as subgroup analyses, will be presented at the meeting. [Table: see text]
Analysis of prognostic factors in patients with advanced relapsed/refractory NSCLC: Cox regression analysis of a randomized phase III trial comparing docetaxel and paclitaxel poliglumex (PPX)
Authors: Bonomi P. , Langer C. , O’Brien M. , O’Byrne K. , Bandstra B. , Paz-Ares L. , Ross H. , Sandler A. , Socinski M. 
Published: March 2020

7040 Background: A phase III trial compared PPX to docetaxel as 2nd-line treatment in pts with relapsed/refractory advanced NSCLC (STELLAR 2). While overall survival was similar between arms, the need for supportive measures to manage the effects of myelosuppression was significantly reduced in the PPX arm. The current analysis was performed to evaluate determinants of survival in the 2nd-line treatment of NSCLC. Methods: STELLAR 2 enrolled 849 pts, 427 on PPX and 422 on docetaxel; all patients were included in the analysis. Randomization between the study arms was stratified by tumor stage, performance status (PS), start of frontline chemotherapy (< 4 mo vs more than 4 mo), gender, and prior taxane therapy. Univariate and multivariate Cox regression analyses were performed to evaluate the impact of baseline characteristics on overall survival (OS). Results: At randomization, 29% of pts had received prior taxane, 14% were PS2, 80% had stage IV disease, and 31% had started frontline therapy within the prior 4 months. Risk factors significantly affecting survival as determined by multivariate analysis are listed in the table . These factors were consistent when treatment was added to the model. Prior exposure to taxane was not predictive of survival; tumor stage was a significant univariate predictor (p=0.0349), but had relatively less impact in the multivariate model. Conclusion: These analyses identified several factors associated with reduced survival benefit from standard second line therapy. Consequently, alternative treatment strategies may be necessary in patients with poor prognosis. For example, more tolerable agents may enhance the benefit/toxicity ratio in these patients. [Table: see text] [Table: see text]