bluuebunny/crossref_metadata_2025_split huggingface dataset:
Successful engraftment following reduced-intensity cord blood transplantation with fludarabine and oral busulfan for advanced hematologic diseases
Authors: Azuma T. , Kami M. , Kusumi E. , Sato Y. , Miura Y. , Komatsu T. 
Published: March 2020

7110 Background: Feasibility of reduced-intensity cord blood transplantation (RI-CBT) has been demonstrated in adult patients. Most researchers use preparative regimens containing total body irradiation (TBI) 2–4 Gy, while TBI causes considerable toxicities in elderly patients. We investigated the feasibility of RI-CBT using non-TBI regimen for the treatment of adult hematologic diseases. Methods: Nineteen patients (median age, 61, range, 38–74) with advanced hematological diseases were enrolled in this study. Fifteen patients had chemorefractory diseases at RI-CBT. Preparative regimen comprised fludarabine 180 mg/m2 and oral busulfan 8 mg/kg. Graft-versus-host disease (GVHD) prophylaxis was tacrolimus. Engraftment was defined as an absolute neutrophil count > 0.5 × 10E9/l. Primary graft failure was defined as the complete loss of donor-type hematopoiesis occurring without engraftment. Secondary graft failure was defined as the loss of donor-type hematopoiesis occurring after primary engraftment. Endpoint of this study was engraftment. Median follow-up of surviving patients was 24.7 months (range, 21.6–25.8). Results: All the patients tolerated the preparative regimen. Median dose of infused nuclear cells was 2.7x10E7/kg (range, 1.9–4.6). HLA disparity was found in 2/6 antigens (n=16) and 1/6 antigen (n=3). Eleven patients achieved engraftment at a median of day 18 (range, 9–30). Chimerism analysis was conducted in six of these eleven patients, and complete donor-type chimerism was documented within 30 days of transplant in five patients. Primary graft failure was diagnosed in two patients. The other six patients died without engraftment due to diffuse alveolar hemorrhage(n=1) and disease progression(n=5). No patients developed acute GVHD. Five of the 11 patients who achieved primary engraftment developed secondary graft failure. As of December 2006, four patients survived in complete remission with complete donor-type chimerism. Estimated 1-year overall survival rate was 21.1%. Conclusions: This study demonstrated the feasibility of RI-CBT using non-TBI regimen; however, high incidences of disease progression before engraftment and secondary graft failure were significant problems. No significant financial relationships to disclose.
Pharmacogenomic (PG) analysis of Japan-SWOG common arm study in advanced stage non-small cell lung cancer (NSCLC): A model for testing population-related pharmacogenomics
Authors: Gandara D. R. , Kawaguchi T. , Crowley J. J. , Moon J. , Kawahara M. , Teramukai S. , Williamson S. K. , Furuse K. , McLeod H. L. , Mack P. C. 
Published: March 2020

7500 Background: We have previously reported differences in outcomes (increased survival, neutropenia & febrile neutropenia) in Japanese versus US patients (pts) treated with a paclitaxel-carboplatin “common arm” in a prospectively designed fashion in 3 phase III trials (FACS, LC03, S0003) in advanced NSCLC (Gandara, ASCO 05 & Crowley, ASCO 06). We hypothesized that these findings were due in part to PG alterations in paclitaxel disposition. Methods: Genomic DNA was prospectively collected from pts in 2 of these phase III trials (LC03 [N=78, 37 on common arm] & S0003 [N=78]) with identical eligibility, staging, treatment plan (paclitaxel 225 mg/m2 & carboplatin AUC 6), response & toxicity criteria. Analysis for genotypic variants of CYP3A4, CYP3A5, CYP2C8, NR1I2–206, ABCB1, ERCC2 was performed by pyrosequencing, and results assessed by Cox model for survival/PFS & logistics regression for response/toxicity. Results: There was a significant difference between Japan & US pts in genotypes: CYP3A4*1b (p=0.01), CYP3A5*3c (p=0.03), ERCC2 k751q (p <0.001), and CYP2C8 r139k (p=.01). Genotypic correlations were observed between CYP3A4*1b for PFS (HR 2.75, 1.06–7.08, p=0.04) & ERCC2 k751q for response (HR 0.33, 0.13–0.84, p=0.02). There were no other statistically significant associations, although for grade 4 neutropenia, the HR for ABCB1 3425c->T was 1.84 (0.77–4.48), p=0.19. The low number of events for febrile neutropenia within this data set precluded assessment of this parameter. Additional PG testing is ongoing & will be presented. Conclusions: 1) Differences in allelic distribution for genes involved in paclitaxel disposition or DNA repair were observed between Japanese & US pts. 2) Statistically significant genotype-associated correlations were present for PFS (CYP3A4*1b) & response (ERCC2 k751q), but not for neutropenia (p=0.19). 3) The small sample size limits interpretation of these data. Further studies based on this common arm approach are warranted for the prospective study of population-related PGs where ethnic/racial differences in anti-neoplastic drug disposition are anticipated. [Table: see text]
Gene expression patterns of oncogenic signaling pathways provide a novel approach to targeted therapeutics in advanced non-small cell lung cancer (NSCLC)
Authors: Potti A. , Bild A. , Dressman H. , Kelley M. , Harpole D. , Nevins J. 
Published: March 2020

7503 Gene expression profiles reflect unique aspects of individual tumors and may characterize tumor heterogeneity in NSCLC. We used gene expression signatures that reflect the deregulation of major oncogenic signaling pathways (Ras, PI3 kinase, Akt, Src, β-catenin, E2F, and Myc) to identify patterns of pathway activation in 118 samples from patients with recurrent (n = 69) and metastatic (n = 49) NSCLC. These individuals, in particular, the patients with metastatic disease are likely to be resistant to standard chemotherapy pointing to the need for alternative therapeutic options. As one approach to this challenge, we used Affymetrix expression data to identify patterns of pathway deregulation in patients with advanced (recurrent/metastatic) disease and compared them to our previously described data on early stage NSCLC (n = 91). Unique to the recurrent and metastatic disease cohorts, a majority of the tumors (greater than 80%) had deregulation of multiple signaling pathways. In particluar, NSCLC tumors with deregulated Src and Myc pathways had a much worse prognosis than those with deregulated Ras and Akt pathways [median survival: 15.5 months vs. 55.3 months, hazard ratio: 2.6, p < 0.01]. Further, using cell proliferation assays, we have shown that the predicted deregulation of Ras, Src and PI3K pathways was directly proportional (p < 0.01, log rank test) to the sensitivity of NSCLC cell lines (n = 17) to agents that specifically target these pathways, suggesting that an ability to profile the status of oncogenic pathways in a tumor sample provides an opportunity to better characterize the oncogenic process in patients with recurrent and advanced NSCLC. More importantly, such a strategy provides a novel approach to targeted therapeutics in NSCLC by guiding the appropriate use of pathway specific inhibitors. Finally, data on gene expression patterns involving other signatures representing unique cancer biology relevant to NSCLC (e.g. hypoxia, chromosomal instability, and angiogenesis) will be also be presented. No significant financial relationships to disclose.
High correspondence between EGFR mutations in tissue and in circulating DNA form non-small-cell lung cancer (NSCLC) patients (p) with poor performance status (PS)
Authors: Moran T. , Paz-Ares L. , Isla D. , Cobo M. , Massuti B. , Insa A. , Queralt C. , Pradas A. , Taron M. , Rosell R. 
Published: March 2020

7505 Background: We evaluated the correspondence between EGFR mutations in NSCLC tissue and matched serum DNA and the value of EGFR mutations as a serological marker. Methods: 121 Spanish stage IV NSCLC p received customized first- or second-line erlotinib monotherapy based on the presence of EGFR mutations in the tumor tissue. Serum genomic DNA was obtained from all p prior to erlotinib administration. EGFR exon 19 deletions were studied by length analysis of fluorescently labeled PCR products and the exon 21 L858R mutation by a PCR Taqman assay. Results: The EGFR mutation status in the serum was consistent with that in the tumor tissue of 82/121 p (68%) and of 15/16 p (93.8%) with PS 2 had mutations. Overall, 64.3% of p had an exon 19 deletion and 35.7% had L858R. 78% of mutations were found in females (P=0.01) and 77.6% in never-smokers (P=0.07). Response rate was 88% in p with mutations only in the tumor and 87% in p with mutations in tumor and serum. Complete responses were observed in 20% of p with mutations in tumor and serum vs 4% of p with mutations only in tumor (P=0.09). With a median follow-up of 6.8 months (m) (range, 1.2–17.6), time to progression (TTP) and median survival have not been reached. A trend to better outcome was seen in p without serum EGFR mutations. TTP was longer for p with EGFR exon 19 deletions (not reached) than for p with L858R (7.7 m) (P=0.02). TTP for p with PS 2 with exon 19 deletions was not reached, while it was 2.7 m for p with L858R (P=0.17). Conclusions: EGFR mutations in serum could be a non-invasive source of information on the genotype of the original tumor cells and could be a useful tool to predict p response to erlotinib, especially in p with poor PS. No significant financial relationships to disclose.
Efficacy of the anti-insulin like growth factor I receptor (IGF-IR) antibody CP-751871 in combination with paclitaxel and carboplatin as first-line treatment for advanced non-small cell lung cancer (NSCLC)
Authors: Karp D. D. , Paz-Ares L. G. , Blakely L. J. , Kreisman H. , Eisenberg P. D. , Cohen R. B. , Garland L. , Langer C. J. , Melvin C. L. , Gualberto A. 
Published: March 2020

7506 Background: CP-751871 is a fully human, IgG2 monoclonal antibody against the IGF-IR active in preclinical models of NSCLC. Methods: We are conducting a phase II, randomized, non-comparative study in ten centers to evaluate the safety and efficacy of combination paclitaxel (T), carboplatin (C) and CP-751871 (I) versus TC alone in stage IIIB, IV or recurrent, treatment-naive NSCLC pts with performance status 0–1. The statistical hypotheses are 28% (null) versus 40% (response of interest). Pts are randomized (2:1) to T (200 mg/m2), C (AUC of 6) and I (10 mg/kg), or TC alone every 3 weeks for up to 6 cycles; pts receiving TCI with response (PR) or stable disease following discontinuation of chemotherapy are eligible to continue I as single agent until disease progression. Pts progressing on TC alone are eligible to receive I as single agent or in combination with TC at the judgment of the investigator. Responses are assessed by investigator using RECIST. Results: An interim analysis for futility has been conducted with 73 pts enrolled: 48 treated with TCI; 25 with TC. TCI was well tolerated. All causality grade 3,4 toxicity included (TCI, TC): hyperglycemia (20%, 10%), fatigue (15%, 8%), neutropenia (13%, 20%) and neuropathy (10%, 4%). 22/48 pts receiving TCI (46%) and 8/32 pts on TC (32%) had objective responses. Furthermore, 14 out of 27 TCI pts (52%) with non-adenocarcinoma responded to treatment. In addition, a PR was observed in 1 out of 4 TC pts who elected to receive single agent I after progression on TC alone. Conclusions: CP-751871 appears safe in combination with TC. Interim TCI activity warranted further investigation. An additional 83 pts will be enrolled to assess further the safety and efficacy of this combination treatment. [Table: see text]
Phase III study of vinflunine versus docetaxel in patients (pts) with advanced non-small cell lung cancer (NSCLC) previously treated with a platinum-containing regimen
Authors: Krzakowski M. , Douillard J. , Ramlau R. , Jassem J. , Szczesna A. , Zatloukal P. , von Pawel J. , Hansen O. , Sun X. 
Published: March 2020

7511 Background: Vinflunine (VFL) is a new microtubule inhibitor of the vinca alkaloid class with clinical activity in NSCLC (J. Bennouna, BJC, 2006). Single-agent efficacy and safety of VFL and docetaxel (DTX) were compared in the 2nd line chemotherapy. Methods: Open-label, multi-center, randomised, phase III study in platinum pre-treated locally advanced/metastatic NSCLC pts. At least 275 pts were to be randomized by arm to receive VFL (320 mg/m2, 20-min IV infusion) or DTX (75 mg/m2, 1-hour IV infusion with dexamethasone over 3 days) every 3 weeks. The primary endpoint was progression free survival (PFS), with a non-inferiority analysis based on a 10% difference (types I and II error rates: 5%, 20%). Results: From 06/03 to 03/05, 551 pts were randomized (VFL: 274; DTX: 277) and 547 treated (411 men, 136 women); median age 61 years [range 22–83]; ECOG PS 0–1: 89%; metastatic: 90%. All pts were platinum pre-treated, in combination with a vinca alkaloid (22%), paclitaxel (21%), or gemcitabine (48%). A total of 950 [1–20] and 1,025 [1–18] cycles were given with VFL and DTX respectively. Grade 3/4 toxicities were low in both arms: neutropenia (33% vs 30%), anemia (8% vs 3%), thrombocytopenia (2% vs <1%), febrile neutropenia (3% vs 5%), fatigue (11% vs 6%), vomiting (2% vs 1%), abdominal pain (4% vs <1%), constipation (7% vs <1%). Overall incidence of alopecia was: 20% vs 35%, nail disorders 1% vs 6%, injection site reaction 25% vs 1%, peripheral neuropathy 11% vs 15%, diarrhea 6% vs 12%. Efficacy: All efficacy endpoints were similar: median PFS (2.3 vs 2.3 months, HR:1.004 [95% CI: 0.841–1.199]), independent review response rate (4.4% vs 5.5%), stable disease (36.0% vs 39.6%), disease control (40.4 vs 45.1), median overall survival (6.7 vs 7.2 months, HR: 0.973 [0.805–1.176]). Conclusion: VFL shows efficacy equivalent to docetaxel in 2nd line NSCLC chemotherapy. Low, manageable but different toxicity profiles were observed in either arm. Vinflunine offers a new and useful alternative for the 2nd line treatment of pts with this disease. No significant financial relationships to disclose.
A phase III study of Æ-941 with induction chemotherapy (IC) and concomitant chemoradiotherapy (CRT) for stage III non- small cell lung cancer (NSCLC) (NCI T99–0046, RTOG 02–70, MDA 99–303)
Authors: Lu C. , Lee J. J. , Komaki R. , Herbst R. S. , Evans W. K. , Choy H. , Desjardins P. , Esparaz B. T. , Truong M. , Fisch M. J. 
Published: March 2020

7527 Background: Æ-941 is a shark cartilage extract with antiangiogenic properties. We conducted a placebo-controlled trial testing Æ-941, with IC and CRT, in unresectable stage III NSCLC. Methods: Eligibility criteria included performance status (PS) < 2, weight loss < 10%. Subjects received one of two treatment regimens depending on site of enrollment: carboplatin (C) (AUC 6) and paclitaxel (P) (200 mg/m2) × 2 cycles followed by CRT (60 Gy/30 fractions) with weekly C (AUC 2) and P (45 mg/m2) × 6 doses or cisplatin (CDDP) (75 mg/m2, d1) and vinorelbine (V) (30 mg/m2, d1 and 8) × 2 cycles followed by CRT (60 Gy/30 fractions) with CDDP (75 mg/m2, day 1) and V (15 mg/m2, d1 and 8) × 2 cycles. Subjects were randomized to receive Æ-941 (Arm A) or placebo (Arm B), 120 mL orally twice daily, at the start of IC and continuing after CRT as maintenance therapy. Randomization was stratified for stage, gender, and type of chemotherapy. The primary endpoint was overall survival (OS), with a planned sample size of 756 subjects providing 80% power to detect a 25% difference in OS, assuming a control arm median survival time (MST) of 13 months, type I error 0.05. Results: Between 6/00 and 2/06, 384 subjects were enrolled onto the trial and randomized. In 2/06 the trial was closed to new patient entry due to insufficient accrual. This final analysis is based on 379 randomized and eligible subjects (188 arm A, 191 arm B). Subject characteristics: 60% male, median age 63 years (range 37–84), 56% stage IIIB, 58% C-based chemotherapy, median follow-up 3.7 years. There was no significant difference in OS between arms A and B, with MSTs of 14.4 (95% CI 12.6–17.9) and 15.6 (95% CI 13.8–18.1) months, respectively (log-rank p=0.73). OS by pre-specified stratification factors: stage IIIB vs IIIA (MST 13.9 vs. 17.4 months, p=0.25), C vs. CDDP chemotherapy (MST 14.4 vs. 16.7 months, p=0.13), and male vs. female (MST 15.7 vs. 15.1 months, p=0.74). The study drug was well tolerated. Fewer subjects in arm A experienced grade 3 or higher adverse events (66% vs. 77%, p=0.018). Conclusions: The addition of Æ−941 to IC and CRT does not improve OS in patients with unresectable stage III NSCLC. No significant financial relationships to disclose.
Phase II open-label study to investigate efficacy and safety of PTK787/ZK 222584 (PTK/ZK) orally administered once daily or twice daily at 1,250 mg as second-line monotherapy in patients (pts) with stage IIIB/IV non-small cell lung cancer (NSCLC)
Authors: Gauler T. C. , Besse B. , Meric J. B. , Gounant V. , Fischer B. , Overbeck T. , Krissel H. , Laurent D. , Soria J. C. , Eberhardt W. E. 
Published: March 2020

7541 Background: Overexpression of vascular endothelial growth factor receptor (VEGF-R) in NSCLC-tumors is linked to poor prognosis and shorter overall survival (OS). PTK/ZK is a novel, oral, anti-angiogenic compound blocking all currently known VEGF receptors (VEGF-R 1–3). Methods: A prospective, single-arm, multi-center, proof-of-principle phase II study to investigate efficacy and safety of PTK/ZK in pretreated pts with stage IIIB/IV NSCLC. Only one platinum-based chemotherapy regimen was allowed as first-line treatment. 55 pts each were planned to receive a fixed dose of 1,250 mg PTK/ZK once daily (qd) or twice daily (500 mg a.m. + 750 mg p.m.) (bid) for continuous treatment until disease progression or unacceptable toxicities. Response evaluation was based on RECIST. A disease stabilization of at least 12 weeks was defined as clinically relevant drug activity. Additional biomarker evaluation included DCE-MRI and serum proteomics. Results: Enrolment is completed with 54 pts starting qd and 58 pts starting bid treatment. Most frequent adverse events in both cohorts were nausea (44%), vomiting (40%), and dizziness (34%). Three possibly related deaths were observed, 2 due to pulmonary hemorrhage and 1 due to pulmonary embolism. Best response by RECIST for the qd cohort (n=54) include 1 pt with a confirmed partial response (cPR) (2%), 32 pts (59%) with stable disease (SD) at week 4, hereof 18 pts (33%) for at least 12 weeks, and 21 pts (39%) with progressive disease (PD); for the bid cohort (n=57) 4 pts with cPR (7%), 18 pts (32%) with SD (=12 weeks), 19 pts (33%) not yet evaluated, and 16 pts (28%) with PD. Progression free survival (PFS)/OS were 2.4/7.0 months (mo) for the qd vs. 3.7/6.8 mo for the bid cohort. Conclusions: These results suggest that both qd and bid second-line treatment with single-agent PTK/ZK is generally safe and well tolerated. In this unfavorable pt population a considerably high rate of disease control could be achieved. Four pts with PR out of 38 evaluated pts in the bid cohort might indicate additional benefit of bid dosing. Final data of the primary endpoint (efficacy) for both cohorts will be presented at the meeting. [Table: see text]
Efficacy and safety of continuous daily sunitinib dosing in previously treated advanced non-small cell lung cancer (NSCLC): Results from a phase II study
Authors: Brahmer J. R. , Govindan R. , Novello S. , Rosell R. , Belani C. P. , Atkins J. N. , Gillenwater H. H. , Tye L. , Chao R. , Socinski M. A. 
Published: March 2020

7542 Background: Sunitinib malate (SU), an oral, multitargeted tyrosine kinase inhibitor of VEGFRs, PDGFRs, KIT, RET, and FLT3, has demonstrated activity in recurrent advanced NSCLC on the 4/2 schedule (4 weeks [wks] on treatment followed by 2 wks off), with a partial response (PR) rate of 11% (Socinski, ESMO 2006). A continuous dosing (CD) schedule of SU was additionally evaluated for safety and efficacy in this multicenter phase II study. Methods: Eligible patients (pts) had stage IIIB/IV NSCLC previously treated with 1–2 chemotherapy regimens, ECOG PS =1, and adequate organ function. Pts with brain metastases or recent gross hemoptysis were excluded. Pts received oral SU 37.5 mg/day continuously in 4-wk cycles. The primary endpoint was objective response rate per RECIST. Secondary endpoints included progression-free survival (PFS), overall survival, and safety. Results: Forty-seven pts were treated on the CD schedule: median age 60 yrs (range 37–81); male 57%; ECOG PS 0/1/2 49%/49%/2%; adenocarcinoma 53%, squamous cell carcinoma 15%, other 32%; median number of SU cycles initiated: 3 (range 1–10). One pt (2%) had a confirmed PR and 8 pts (17%) had stable disease >3 months. Median PFS was 12.1 wks (95% CI: 8.6–13.7). SU was generally well tolerated; most adverse events (AEs) were grade 1/2 and included fatigue/asthenia, pain/myalgia, nausea/vomiting, diarrhea, dyspnea, and stomatitis/mucosal inflammation. Grade =3 AEs included fatigue/asthenia (15%), hypertension (6%), hypoxia (6%), dyspnea (4%), and hemoptysis (2%). Treatment-related serious AEs included congestive heart failure (CHF; 1 pt), gastrointestinal bleeding (1 pt), hypomagnesemia (1 pt), and hypoxic respiratory failure (1 pt). One pt died due to possible treatment-related CHF. Conclusions: SU on a CD schedule is associated with an acceptable safety profile when administered to previously treated NSCLC pts, and there is documented preliminary evidence of activity, with 1 PR and a median PFS of 12.1 wks. These data support further study of continuous dosing of SU in combination with other treatments for NSCLC. No significant financial relationships to disclose.
A phase II study of enzastaurin as second- or third-line treatment of non-small cell lung cancer (NSCLC)
Authors: Bepler G. , Oh Y. , Burris H. , Cleverly A. , Lahn M. , Herbst R. S. 
Published: March 2020

7543 Background: Enzastaurin, an oral serine/threonine kinase inhibitor, suppresses signaling through PKC and the PI3K/AKT pathway, induces tumor cell apoptosis, reduces proliferation, and suppresses tumor-induced angiogenesis. Over-expression and activity of PKC and PI3K/AKT are associated with poor prognosis and treatment resistance in NSCLC. This multicenter phase II trial of enzastaurin as second- and third-line treatment of NSCLC determined the rate of progression-free survival (PFS) at 6 months (mos). Secondary objectives included safety and the rate of overall survival (OS) at 12 mos. Methods: Eligibility included metastatic (stage IV and wet IIIB) NSCLC and prior platinum-based chemotherapy. Patients (pts) received 500 mg of oral enzastaurin, once daily, until disease progression or unacceptable toxicity occurred. All pts were eligible for 2nd or 3rd line treatment. Results: In the 54 pts enrolled [54% M, 46% F; median age: 63 (range: 43–82); 22.2% stage III, 77.8% stage IV, ECOG PS=2], adenocarcinoma was the most frequent diagnosis (67%). Prior therapies included radiotherapy (74%) and EGFR inhibitors (28%). At the final analysis, the median PFS was 1.9 mos (95% CI: 1.7–1.9), and the PFS rate at 6 mos was 14% (95% CI: 4.4%–23.6%). The median OS was 9.9 mos (95% CI: 6.5–14.6). The OS rate at 12 mos was 46.3% (95% CI: 32.1%–60.5%). Nineteen pts (35%) had stable disease (SD); none had a complete or partial response. Ten (19%) pts were on-study for =6 cycles, 3 of whom continued for >10 months. The most common toxicity, fatigue (grade =2, n=15), occurred within 1 week of enrollment and was not reported in pts with SD. Grade =3 toxicities observed were ataxia (n=1), fatigue (n=2), thrombo-embolism (n=1), and anemia (n=1). Two pts discontinued due to fatigue and dizziness. Five pts died on-study and 4 within 30 days of discontinuation due to PD. Post-study chemotherapy (n=28) included bevacizumab, erlotinib, pemetrexed, gemcitabine, cisplatinum and paclitaxel. Conclusion: Although no objective tumor responses occurred, 14% of the pts were progression-free at 6 months. Based on encouraging survival and tolerability data, further evaluation of enzastaurin as a single agent or in combination, is warranted in NSCLC. No significant financial relationships to disclose.