bluuebunny/crossref_metadata_2025_split huggingface dataset:
The impact of brain metastases on overall survival (OS) in National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) clinical trials (CT) in advanced non-small cell lung cancer (NSCLC)
Authors: Bradbury P. A. , Twumasi-Ankrah P. , Ding K. , Leighl N. B. , Goss G. D. , Laurie S. , Shepherd F. A. , Seymour L. 
Published: August 2020

8075 Background: NSCLC patients (pts) with brain metastases (BMet) commonly are excluded from participating in clinical trials (CTs), based on perceptions of inferior outcomes. We evaluated the validity of this exclusion criterion, by investigating the OS of stage IV NSCLC pts with (BMet) and without (non-BMet) a prior history of BMet recruited to NCIC CTG CTs. Methods: This pooled analysis utilized data from BR.18 (paclitaxel/ carboplatin [PC] ± MMPI [BMS275291]), BR.21 (erlotinib vs. placebo), BR.24 (PC± VEGFR TKI [AZD2171]). Each trial permitted entry of pts with neurologically stable BMet, provided they had been treated and off corticosteroids (BR.24), or either treated or not but without corticosteroids (BR.18), or on a stable corticosteroid dose (BR.21). The primary end-point of these analyses was OS, evaluated in the pooled pt cohorts stratified by treatment arm, and in each trial individually. Results: Of 1,349 stage IV pts, 131 had a history of BMet. Of these, 103 (78%) pts had cranial radiation prior to randomization and 15 (11%) prior craniotomy. The median age of the BMet cohort was 56yrs vs. 61yrs for non-BMet cohort. There was no difference in baseline PS (BMet: PS 0–1 vs. 2 vs. 3 =74% vs. 21% vs.5%; non-BMet: 81% vs. 16% vs. 4%, p=0.16), weight loss (p=0.73) or hemoglobin (p=0.80) between the two cohorts. Female gender (41% vs. 33%, p=0.04) and adenocarcinoma (66% vs. 51%, p=0.005) was more common in the BMet cohort. There was no OS difference between the BMet and non-BMet cohort in the pooled analysis, stratified by trial (HR 1.05, 95%CI 0.85–1.28, stratified log-rank p=0.67), or in multivariate analysis adjusted for baseline covariates (AHR 1.12, 95%CI 0.91–1.37, p=0.31). There was also no OS difference between BMet and non-BMet pts when evaluated in each individual trial separately. Conclusions: Pts with a prior history of BMet have a similar OS to those pts without BMet in NSCLC in NCIC CTG CTs. In neurologically stable pts, BMet, should not be an exclusion criterion, while discontinuation or stable dose of corticosteroids appears a reasonable eligibility requirement. No significant financial relationships to disclose.
Prognostic factors in patients enrolled in clinical trials of second-line chemotherapy for advanced non-small cell lung cancer (aNSCLC): A pooled analysis of 11 randomized trials
Authors: Di Maio M. , Camps C. , Smit E. F. , Schuette W. , Georgoulias V. , Takeda K. , Quoix E. , Wachters F. M. , Gebbia V. , Gridelli C. 
Published: August 2020

8082 Background: Prognostic factors for newly diagnosed aNSCLC have been extensively studied, but less information is available on factors associated with outcome of 2nd-line treatment. Better knowledge of prognostic factors could be helpful to better select patients for further chemotherapy after failure of 1st-line treatment. Methods: The analysis is based on individual patient data collected for 2 meta-analyses on 2nd-line treatment of aNSCLC, one comparing weekly vs every 3 week docetaxel (Di Maio, J Clin Oncol 2007; 25:1377), and one comparing single-agent vs doublet chemotherapy (Di Maio, J Clin Oncol in press). Primary endpoint was overall survival (OS). All analyses were stratified by trial. Results: Out of 11 trials, 2 trials were excluded due to missing information on baseline characteristics considered in multivariate analysis. Of the other 9 trials (1239 pts), 1197 pts (97%) had complete information: 78%/22% males / females, 83%/17% younger / older than 70, 28%/59%/13% Performance Status (PS) 0 / 1 / 2, 18%/82% stage IIIB / IV, 32%/47%/21% squamous / adenocarcinoma / other histology. 84% were pretreated with platin and 44% had obtained objective response (OR) to 1st line treatment. With 956 deaths, median OS was 7.4 months. At multivariate analysis, prognosis was significantly influenced by gender (worse in males vs females, Hazard Ratio [HR] 1.23 [95%CI 1.04–1.45], p=0.01), by PS (worse in PS1 vs PS0, HR 1.36 [1.16–1.59], p=0.0001 and in PS2 vs PS0, HR 3.01 [2.41–3.76], p<0.00001), by tumor histology (better in adenocarcinoma vs squamous, HR 0.85 [0.73–0.99], p=0.04 and worse in other histology vs squamous, HR 1.27 [1.05–1.52], p=0.01), by stage (worse in stage IV vs IIIB, HR 1.28 [1.07–1.53], p=0.007), by type of previous treatment (worse for pts pretreated with platin vs pts not pretreated with platin, HR 1.49 [1.14–1.93], p=0.003), and worse for pts not obtaining OR vs pts obtaining OR during 1st line (HR 1.25 [1.10–1.44], p=0.001). Conclusions: In addition to patient-related (gender, PS) or tumor-related factors (histology, stage), prognosis of pts eligible for 2nd line treatment of aNSCLC is significantly conditioned by previous use of platin and response to 1st line treatment. No significant financial relationships to disclose.
Comparison of progression-free survival (PFS) and tumor response as endpoints for predicting overall survival (OS) in untreated extensive-stage small cell lung cancer (ED-SCLC): Findings based on North Central Cancer Treatment Group (NCCTG) trials
Authors: Foster N. R. , Qi Y. , Krook J. E. , Kugler J. W. , Kuross S. A. , Jett J. R. , Molina J. R. , Schild S. E. , Adjei A. A. , Mandrekar S. J. 
Published: August 2020

8085 Background: Historically, tumor response has been the primary endpoint in phase II (P2) trials in ED-SCLC. We investigated the suitability of alternate PFS based endpoints to predict OS as early evidence of efficacy in the P2 setting. Methods: Individual patient (pt) data from 942 pts from 11 previously untreated ED-SCLC P2 and phase III (P3) platinum- or paclitaxel-based treatment trials were pooled. Best response (BR), response confirmed (RC), objective status at 16 weeks (RR16), and PFS rate at 5 and 6 months were considered. Percent agreement (PA) and kappa (k) for PFS5, PFS6, BR, RC, and RR16 with OS at 12 months (OS12) was calculated on a per-pt basis and predictive utility was assessed using the area under the receiver operating characteristic (A- ROC) curve in logistic models. Cox models were used to assess the prognostic impact of the endpoints on subsequent survival, using landmark analysis. Results: The median OS and PFS were 9.6 m and 5.5 m, respectively. PFS5 and PFS6 had the highest PA, k, and A-ROC values, and were predictive of subsequent survival in the landmark analysis (p <0.0001; c-statistics ≥ 0.60). While RR16 and BR were significantly associated with subsequent survival (p<0.0001, c-statistics of 0.61 and 0.57, respectively) the PA, k, and A-ROC values were lower. Conclusions: PFS rate at 5 and 6 months is more predictive of 12-month OS and subsequent survival than tumor response in untreated ED-SCLC. PFS based endpoints should be routinely used as primary endpoints in P2 trials within ED-SCLC. [Table: see text] No significant financial relationships to disclose.
Safety and efficacy of YM155 in diffuse large B-cell lymphoma (DLBCL)
Authors: Cheson B. D. , Vose J. M. , Bartlett N. L. , Lopez A. , Van der Jagt R. H. , Tolcher A. W. , Weisenburger D. D. , Seiz A. L. , Shamsili S. , Keating A. T. 
Published: August 2020

8502 Background: Survivin is a member of the inhibitor of apoptosis proteins (IAPs) family which is responsible for preservation of cell viability and regulation of mitosis in tumor cells. YM155, a survivin suppressant, has exhibited anti-tumor activity in solid tumors and non-Hodgkins lymphoma (NHL), including DLBCL patients enrolled in Phase I and Phase II monotherapy studies. Methods: Two studies enrolled 43 DLBCL patients; a Phase I study enrolled patients with solid tumors and NHL (n=1 relapsing DLBCL and n=1 refractory DLBCL), and a Phase II study enrolled refractory DLBCL patients (n=41). YM155 was administered at 4.8 mg/m2/day (Phase I) and at 5 mg/m2/day (Phase II) as a 168-hour continuous infusion in a 21 day cycle. Patients could continue to receive YM155 until disease progression or unacceptable toxicity. Results: Data are presented for the first 27 patients (Phase I and Phase II) who have completed therapy. Median age was 61 (23–80) years and 63% were male. Three patients (11%) had partial responses (PR) confirmed by independent review using Cheson criteria (N=2; 1999 criteria and N=1; 2007 updated criteria). All responders received 2 prior regimens. Two responders were refractory to their last regimen and one had relapsed approximately 2 years after stem cell transplant (SCT). One patient responded after 2 cycles, completed 5 total cycles and proceeded to SCT (disease-free > 3.7 years post SCT). A second patient responded after 3 cycles, completed 7 total cycles and proceeded to SCT in OCT08. The third patient responded after 12 cycles and received 26 total cycles (1.5 years) before disease progression. The most common (>4%), treatment-related grade 3/4 adverse events included anemia (16.0%) and neutropenia, fatigue, hemoglobin decrease and deep vein thrombosis (8.0% each). Conclusions: YM155 is well tolerated and has modest single-agent, anti-tumor activity in relapsed/refractory DLBCL patients. Because of single-agent activity and preliminary data showing synergism when YM155 is combined with other agents additional clinical studies are being planned. [Table: see text]
Long-lasting responses after four doses of rituximab in Waldenström's macroglobulinemia: Clinical value of minor responses: A follow-up of the Eastern Cooperative Oncology Group E3A98 trial
Authors: Gertz M. A. , Abonour R. , Heffner L. T. , Greipp P. R. , Uno H. , Rajkumar S. V. 
Published: August 2020

8513 Background: Waldenström's macroglobulinemia is a low-grade lymphoplasmacytic lymphoma that is responsive to rituximab. Uniform response criteria define an objective response as a 50% reduction in the IgM level, and a minor response as a 25% reduction in IgM level. No publications in the literature exist that justify the use of the minor response. Clinicians who treat patients that achieve a minor response are left uncertain as to whether the response is adequate and patients should be monitored for progression or whether they should be considered therapy failures and crossover to an alternate chemotherapy regimen in an effort to achieve a deeper response. Methods: 69 patients, 34 previously untreated, and 35 previously treated (but rituximab naive) were included. All patients were treated with a single four-week course of rituximab 375 mg/m2 and were monitored with no further therapy until progression. Results: There were 19 objective and 17 minor responses out of 69 eligible patients (52.2%). Response rate and progression-free survival (26.6 mo) were similar whether patients were previously untreated or previously treated. Previously treated rituximab-naïve and previously untreated patients had, five-year survivals of 48% and 85%, respectively. There was no difference in overall or progression free survival between patients who achieved an objective response when compared to those who achieved a minor response. There was no difference between objective and minor responders by age, time from diagnosis to treatment in the treated group, bone marrow lymphoplasmacytes, hemoglobin level, creatinine, IgM level, or M-spike. The pre-treatment level of IgM did not predict overall survival, progression-free survival, time to progression, or response rate (All p>0.05). This lack of significance was found whether IgM was assessed as a continuous or discrete variable. Conclusions: These results reconfirm rituximab's efficacy as a single-agent for the treatment of Waldenström's macroglobulinemia, and patients who have a 25–50% reduction in their IgM protein derive significant clinical benefits that are durable and appear to not have an impact on overall survival. No significant financial relationships to disclose.
In vivo activity of rituximab-CpG oligodeoxynucleotide conjugate against rituximab-resistant human CD20+ B-cell lymphoma
Authors: Timmerman J. , Betting D. , Yamada R. , Hurvitz S. , Steward K. , Said J. , van Rooijen N. , Kafi K. 
Published: August 2020

8529 Background: The anti-CD20 monoclonal antibody rituximab (R) is a mainstay in the treatment of B cell non-Hodgkin's lymphoma (NHL), exerting anti-tumor effects via antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity, and apoptosis induction. Toll-like receptor 9 agonist CpG oligodeoxynucleotides (CpG) are potent activators of ADCC and T cell immunity, and have been studied for anti-NHL effects when administered by systemic or intratumoral routes. We sought to optimize the delivery of CpG to sites of NHL to improve R efficacy. Methods: We utilized an aggressive syngeneic human CD20-expressing murine B cell lymphoma (38C13-huCD20) to study the in vivo augmentation of R efficacy by CpG. Established tumors in immunocompetent mice were treated with R plus CpG given systemically, intratumorally, or chemically linked to antibody using maleimide-sulfhydryl chemistry (D. Betting et al, J. Immunol. 2008; 181: 4131). Results: 5- to 7-day established tumors were completely resistant to single agent R. Combining intratumoral, but not systemic administration of CpG with R resulted in tumor eradication from up to 42% of mice (p < 0.0003 vs. R alone, CpG alone, R + systemic CpG). Mechanistic studies indicated that both natural killer cells and complement participated in the cure of tumors by intratumoral CpG + R, by increasing tumor cell sensitivity to complement and ADCC lysis, and by augmenting the cytotoxicity of ADCC effectors. To overcome the need for repeated direct intratumoral injections and allow precise targeting of CpG to tumor cells, we chemically linked CpG to R using a cleavable linker. A single i.v. injection of this R-CpG conjugate achieved eradication of established tumors from 100% of mice. In contrast, equivalent doses of unlinked i.v. R + CpG, CpG alone, or R alone cured only 8% of mice. Thus, combining CpG with R was most effective using direct conjugation to the antibody. Conclusions: In conclusion, enhancement of R efficacy required sustained intratumoral delivery of CpG to maximize anti-tumor responses. R-CpG conjugate efficiently eradicated an established B cell lymphoma that is fully resistant to single-agent R. Clinical testing of anti-CD20-CpG conjugates against B cell NHL is thus warranted. [Table: see text]
First results of long-term rituximab maintenance treatment in follicular lymphoma: Safety analysis of the randomized phase III trial SAKK 35/03
Authors: Taverna C. J. , Bassi S. , Hitz F. , Mingrone W. , Pabst T. , Cevreska L. , del Giglio A. , Vorobiof D. A. , Simcock M. , Ghielmini M. 
Published: August 2020

8534 Background: Rituximab maintenance has been shown to be effective in patients with follicular lymphoma. The optimal duration of maintenance remains unknown. Methods: We prospectively registered 270 patients with untreated, chemotherapy resistant or relapsed follicular lymphoma. All patients received rituximab induction consisting of 4 weekly doses (375 mg/m2). Responding patients (PR and CR) were randomized to a short maintenance consisting of four doses of rituximab (375 mg/m2) every two months (arm A) or prolonged maintenance consisting of rituximab every two months for a maximum of five years or until progression or unacceptable toxicity (arm B). Primary endpoint was event-free survival. Here we present the safety analysis. Results: From October 2004 to November 2007 165 patients were randomized, 82 in arm A and 83 in arm B. The median follow up is 22.7 months. A total of 442 hematological and non-hematological adverse events were observed, 27 of grade 3 and 6 of grade 4. Five subsequent cancers and 9 grade 3 and 4 infections were reported. Grade 3 and 4 neutropenia occurred in 5 patients, decreased levels of IgG were observed in 19 patients. Four grade 3 infections occurred after 2 years of maintenance. In arm B, maintenance was stopped due to unacceptable toxicity (fever) in 1 patient after 18 months and due to subsequent breast cancer in 1 patient after 20 months. One patient died 4 months after randomization because of ileus and consecutive peritonitis; considered to be unrelated to therapy. Twenty-nine patients are on maintenance for two or more years of which 6 patients are on for three or more years. In this analysis, median duration of the prolonged maintenance is 23.7 months. Conclusions: Rituximab maintenance beyond two years is feasible. We do not have evidence for increased toxicity after 2 years of maintenance. However, close follow up of patients under prolonged rituximab maintenance is necessary. The trial has been closed for accrual but there are still patients on treatment. [Table: see text]
Phase II trial of combination of bortezomib and rituximab in relapsed and/or refractory Waldenstrom macroglobulinemia
Authors: Ghobrial I. M. , Matous J. , Padmanabhan S. , Badros A. , Chuma S. , Leduc R. , Rourke M. , Kunsman J. , Harris B. , Warren D. , Richardson P. 
Published: August 2020

8535 Background: This phase II study aimed to determine safety and activity of weekly bortezomib in combination with rituximab in patients with relapsed/refractory Waldenstrom macroglobulinemia (WM). Methods: Patients who had at least one previous therapy for WM and who had relapsed or refractory disease were eligible. NCI CTCAE v3.0 was used for toxicity assessment. All patients received bortezomib IV weekly at 1.6mg/m2 on days 1, 8, 15, q 28 days × 6 cycles, and rituximab 375 mg/m2 at days 1, 8, 15, 22, on cycles 1 and 4. Results: 37 pts (26 men and 11 women, median age 62 years, range 42 - 73) have been treated to date. The median number of lines of prior treatment was 3 (range 1 - 5). All patients had received prior rituximab and 5 pts received prior bortezomib. The median IgM at baseline was 3540 mg/dL (range 700-10,800). The median follow up is 12 months (range 5 - 26 months). Thirty-five pts are evaluable for response. Complete remission and near complete remission occurred in 2 (6%), partial remission in 17 (48%), and minimal response in 10 (29%). Progressive disease occurred in 1 (3%) and stable disease occurred in 5 (14%). Most patients achieved response rapidly within 3 months of therapy (2–7 months). Rituximab flare occurred only in 6 patients (20%). At 24 months of follow up, 8/35 pts have shown relapsed disease. The median time to progression and duration of response has not been reached. Patients tolerated therapy well without significant toxicities: grade 3 peripheral neuropathy occurred in only 2 pts. Grade 1 and 2 neuropathy occurred in 10 pts (26%). Other grade 3 and 4 toxicities included neutropenia in 5 patients, and anemia and thrombocytopenia in 4 patients. Grade 5 pneumonia and viral infection occurred in 1 patient who was within the first cycle of therapy and did not receive herpes zoster prophylaxis. Attributable toxicities otherwise proved manageable with appropriate supportive care and the combination was generally well tolerated. Conclusions: The combination of weekly bortezomib and rituximab has been well tolerated and demonstrates encouraging activity, with CR+ PR + MR in 83% of evaluable patients with relapsed WM. No significant peripheral neuropathy has been observed to date with this regimen. [Table: see text]
PX-171–004, a multicenter phase II study of carfilzomib (CFZ) in patients with relapsed myeloma: An efficacy update
Authors: Vij R. , Wang M. , Orlowski R. , Stewart A. K. , Jagannath S. , Kukreti V. , Le M. H. , Kunkel L. , Siegel D. 
Published: August 2020

8537 Background: Carfilzomib (CFZ) is a proteasome inhibitor, active against hematologic malignancies. Preclinically, CFZ overcomes bortezomib (BTZ) resistance in multiple tumors, including myeloma (MM). PX-171–004 is an ongoing Phase II study evaluating safety and efficacy of CFZ in MM patients with relapsed disease after 1–3 prior therapies. Overall Response Rate (ORR) of 35.5% for all subjects was previously reported (ASH 2008); updated data are now available. Methods: Patients were divided into two cohorts: BTZ-naïve and BTZ-exposed. CFZ 20 mg/m2 was administered Days 1, 2, 8, 9, 15 and 16 in a 28-day cycle, for up to 12 cycles. Dexamethasone 4 mg po was administered prior to each dose in Cycle 1. The primary endpoint was ORR, defined as Partial Response (PR) or better. Secondary endpoints included Duration Of Response (DOR) and Time To Progression (TTP). Results: 31 patients were enrolled; 14 (45%) BTZ-naïve and 17 (55%) BTZ-exposed. Of the BTZ-exposed cohort, 2 subjects received BTZ exclusively as a single agent, 6 had BTZ in a chemotherapy combination, and 9 received BTZ in a transplant regime. Overall, 23 (74%) subjects had > 1 prior therapy and 27 (87%) received transplant. In BTZ-naïve patients, CFZ achieved an ORR of 57%; median DOR of 8.6 mos (range >1.9 to >9.7 mos). To date, 7 patients (50%) remain progression free and 3 patients have completed 12 cycles. The median follow-up was 10 mos and the median TTP has not been reached. For the BTZ- exposed group, CFZ achieved an ORR of 18%; median DOR not yet reached (>8.5 mos) (range >1 d to >8.5 mos). 7 patients (41%) are progression free and 3 patients have completed 12 cycles. Median follow-up and TTP were 9.2 and 8.9 mos, respectively. Conclusions: These preliminary results demonstrate that single-agent CFZ is tolerable for at least 1 yr and achieves sustained responses in relapsed MM. Prior BTZ mono/combination therapy does not preclude durable response with CFZ. These data support continuing evaluation of CFZ in the treatment of relapsed MM. [Table: see text] [Table: see text]