tbuckley/cabot-search huggingface dataset:
Predictors of outcome for pemetrexed (Pem) in metastatic NSCLC (mNSCLC).
Authors: Cortney Vanderbilt Jones, Lingling Du, Paul Elson, Tarek Mekhail, Nathan A. Pennell, Nooshin Hashemi Sadraei
Journal: Journal of Clinical Oncology (2013)

e19025 Background: Pemetrexed (Pem) is the first agent showing different efficacy based on histology in the treatment (tx) of NSCLC. Our goal was to identify outcome predictors in patients (pts) with metastatic NSCLC (mNSCLC) treated with pem. Methods: Retrospective data of pts with mNSCLC who received pem were analyzed. Variables included demographics, ECOG performance status (PS), disease sites, pre/post-pem tx, and toxicities. Clinical benefit defined as complete response (CR), partial response (PR), and stable disease (SD) &gt;6 months, progression-free survival (PFS), and overall survival (OS) were analyzed using logistic regression and Cox proportional hazards model. Results: 240 pts were included. 55% male, 84% smokers. 68% adenocarcinomas, 10% squamous/adenosquamous carcinomas. Median age 64 years (range 34-84). Pem was given for a median of 4 cycles (range 1-73), as 1st line in 20% and 2nd line in 50%, given as a single agent in 69%. The most common toxicities were constitutional (50%) and GI related (29%). 31% of pts achieved CR (n=4) or PR, 33% progressed, 36% had SD. Front-line pem use (p=.0003), adenocarcinoma histology (p=.05), and non-pulmonic metastatic sites ≤2 (p=.01) were independent predictors of clinical benefit, with response rate of 71% for pts with all three features, compared to only 7% for pts with none of these features. Multivariable analysis of survival data revealed ECOG PS &gt;1, non-pulmonic metastatic sites&gt;2, and squamous/poorly differentiated histology predicted poor PFS and OS. In addition, interval from diagnosis to start of pem &lt;12 months and male gender predicted poor PFS, while former/current smoker predicted poor OS. Pts with favorable features had a median PFS of 7.7 months, compared to 2.1 months with unfavorable features (p&lt;.0001). A median OS of 16 months was achieved in pts with favorable features, compared to 5.9 months with unfavorable features (p&lt;.0001). Conclusions: Front-line pem use, adenocarcinoma histology, and ≤2 non-pulmonic metastatic sites predict better response to pem. Poor PS, &gt;2 non-pulmonic metastatic sites, squamous/poorly differentiated histology predict poor PFS and OS. An analysis of biomarkers is ongoing.
Phase II study of trastuzumab with irinotecan in HER2-positive metastatic or advanced gastric cancer patients previously treated with trastuzumab and failed: HGCSG 1201/OGSG1205.
Authors: Yasuyuki Kawamoto, Takashi Meguro, Satoshi Yuki, Hiroshi Nakatsumi, Takahide Sasaki, Kazuteru Hatanaka, Minoru Uebayashi, Ichiro Iwanaga, Nobuhiko Abe, Michio Nakamura, Hiroyuki Okuda, Kazunori Eto, Ayane Oba, Masakazu Abe, Koji Oba, Taroh Satoh, Yuh Sakata, Naoya Sakamoto, Yoshito Komatsu
Journal: Journal of Clinical Oncology (2017)

151 Background: Some phase II and III studies of second-line chemotherapy for metastatic or advanced gastric cancer have been reported in recent years. Irinotecan is one of the standard regimen for second-line therapy. On the other hand, the efficacy of continuing trastuzumab (Tmab) beyond progression in patients (pts) who had previously been treated with Tmab plus standard first line chemotherapy has not been reported. We conducted this study to assess the efficacy and safety of Tmab with irinotecan in HER2-positive gastric cancer pts previously treated with Tmab (UMIN ID: 000007636). Methods: Patients with HER2-positive metastatic or advanced gastric cancer who were previously treated with Tmab and failed were included. Pts received Tmab every 3 weeks and irinotecan every 2 weeks. Primary endpoint was response rate (RR), and secondary endpoints were progression-free survival (PFS), six-month survival rate, safety, sub-group analysis by HER2 status (IHC 3+ group, IHC 2+/FISH positive group), and so on. Results: Only 16 pts were enrolled from 9 institutions in three years during a pre-planned registration period. We stopped this study on the way, unfortunately. In a total of 16 pts, one patient was excluded and 15 were analyzed. Median age was 65, male/female; 9/6, ECOG PS 0/1; 8/7, and IHC 3+/IHC 2+ and FISH positive; 10/5, respectively. Response rate was 7% and disease control rate was 53%. Median PFS and overall survival (OS) were 2.4 (95%C.I.; 0.0-5.2 months) and 9.7 months (95%C.I.; 8.2-11.2 months), respectively. Six-month PFS rate was 13%. In sub-group analysis by HER2 status, median PFS of IHC 3+ and IHC 2+/FISH positive were 2.2 and 2.4 months, respectively. Median OS of each groups were 8.8 and 10.8 months. The most frequently reported grade 3-4 adverse events were neutropenia (40%), anemia (27%), anorexia (33%), and fatigue (33%). Conclusions: This study was closed prematurely due to poor accrual. It seemed that continued use of Tmab and irinotecan beyond disease progression has not significant clinical benefit in HER2-positive metastatic or advanced gastric cancer pts previously treated with Tmab. Clinical trial information: UMIN000007636.
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: Matthew John Barth, Stanton Goldman, Lynette Smith, Sherrie L Perkins, Bruce Shiramizu, Thomas G. Gross, Lauren Harrison, Warren Sanger, Mark B Geyer, Lisa B. Giulino, Mitchell S. Cairo
Journal: Journal of Clinical Oncology (2013)

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/m 2 ) 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 &lt;2xULN. Children (&lt;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]
Treatment of advanced ovarian and endometrial cancer in the phase I setting: A single center experience.
Authors: Wei Peng, Anthony W. Tolcher, Kyriakos P. Papadopoulos, Muralidhar Beeram, Drew Warren Rasco, Allan J. White, Lon S. Smith, Ronald L. Drengler, Leslie Smetzer, Theresa A. Mays, Brianne Kaiser, Rebecca Arcos, Cathy Alvarez, Cally Claiborne, Gina L. Mangold, Michael Jude Wick, Amita Patnaik
Journal: Journal of Clinical Oncology (2014)

e13509 Background: Targeted therapy of recurrent/metastatic ovarian and endometrial cancer remains of great interest but has not been established as standard of care. We analyzed a series of patients treated with targeted anti-cancer agents alone (group S) or in conjunction with cytotoxic therapies (group C) in the phase I setting to determine which approach would yield greater potential for benefit. Methods: We reviewed the records of 46 patients with recurrent or metastatic ovarian and endometrial cancer, who were previously treated with paclitaxel and carboplatin, and were enrolled onto a series of phase I trials. Treatment outcomes were evaluated and were correlated with treatment modalities. Results: 46 patients were enrolled onto 40 different trials, with a total of 72 enrollments; 65 of the enrollments having disease assessment, of which 56 had measurable disease. The confirmed ORR (overall response rate) of the 65 enrollments was 7.7% and mTTF (median time to treatment failure) was 2.9 months (95%CI 1.7m-4.1m). For the 56 enrollments with measurable disease, the confirmed ORR and mTTF in group C and group S were 31.2% (5/16) and 6.0m (95%CI 2.5m-9.5m), 0% (0/40) and 2.1m (95%CI 1.8m-2.4m), respectively. The confirmed ORR and mTTF were superior in group C (p value=0.001, respectively). TRR (Tumor regression rate) in group C and group S was 68.8% (11/16) and 32.5% (13/40), respectively (p=0.012). Conclusions: Ovarian and Endometrial cancer patients treated with combinations of targeted therapies plus cytotoxics had improved ORR, mTTF and TRR in the phase I setting compared with targeted therapies alone. Rationally designed combinations of targeted therapies with cytotoxics deserve further evaluation in the future for this indication.
A multicenter prospective study on the efficacy and safety of denosumab in gastrointestinal cancer patients receiving short-term periodic steroid premedication for prevention of chemotherapy-induced nausea and vomiting: ESPRESSO-02/HGCSG1602.
Authors: Michio Nakamura, Masataka Yagisawa, Kentaro Sawada, Tetsuhito Muranaka, Hiroshi Nakatsumi, Yasuyuki Kawamoto, Satoshi Yuki, Masayoshi Dazai, Atsushi Ishiguro, Yoshimitsu Kobayashi, Susumu Sogabe, Takuto Miyagishima, Ichiro Iwanaga, Miki Tateyama, Kazuteru Hatanaka, Kota Ono, Yuh Sakata, Yoshito Komatsu
Journal: Journal of Clinical Oncology (2017)

TPS809 Background: We previously reported that short-term periodic premedication of glucocorticoids (GCs) used with chemotherapy for gastrointestinal cancer (GIC) caused the reduction of bone mineral densities (BMD) and the increase of serum bone alkaline phosphatase (BAP) (ESPRESSO-01 study; ASCO-GI 2016 Abst.523). Surprisingly, it seems that the BMD decreasing levels due to only the 16-week GC usage in GIC chemotherapy were comparable to that of the 12-month adjuvant aromatase inhibitor therapy for early stage breast cancer patients or the 12-month androgen deprivation therapy for nonmetastatic prostate cancer patients. So we conducted this study to evaluate the efficacy and safety of denosumab for prevention of chemotherapy-induced BMD decreasing. Methods: This is a multicenter single-arm prospective study to evaluate the efficacy and safety of denosumab in GIC patients receiving the short-term periodic steroid premedication. The key eligibility criteria are as follows: 1) Histologically confirmed adenocarcinoma in GIC, including esophageal, gastric, pancreatic, and biliary cancer. ; 2) A schedules of periodical intravenous steroid administration as premedication that was weekly, biweekly, and triweekly, and in which &gt; 4-week steroid-free intervals were not allowed. ; 3) High risk patient with steroid induced secondary osteoporosis. ; 4) No prior treatment for osteoporosis. The dose of denosumab (Prolia) is 60mg administered as a single subcutaneous injection within a week before the induction of chemotherapy. All participants should receive adequate calcium and vitamin D supplementation. The primary endpoint is to investigate the BMD change and bone turnover markers (serum NTX and BAP levels) between baseline and 16 weeks after induction of chemotherapy. And the secondary endpoints are to compare and evaluate the difference of primary site, treatment regimen, dose intensity of steroids, newly bone fractures, and the FRAX output. This study is sponsored by Hokkaido Gastrointestinal Cancer Study Group. Clinical trial information: UMIN000023855.
Antiemesis prophylaxis among breast cancer (BC) patients receiving highly emetogenic chemotherapy.
Authors: Mariana Chavez-Mac Gregor, Weiguo He, Hui Zhao, Linda S. Elting, Sharon Hermes Giordano
Journal: Journal of Clinical Oncology (2015)

e12005 Background: Chemotherapy-induced emesis has important medical implications and is associated with a decrease in QoL. According to guidelines, patients receiving highly emetogenic chemotherapy should receive a 5-HT3 antagonist and steroids, and since 2006, also a NK1-antagonist. We evaluate adherence to antiemesis prophylaxis guidelines among BC patients treated with AC, FAC and TAC. Methods: 5,569 patients >65 years, diagnosed between 2005-2009 were identified in the SEER/TCR-Medicare database and 25,971 patients <65 years, diagnosed between 2005-2012 in the MarketScan database. All patients were treated with adjuvant AC, FAC or TAC. Antiemetics given within 1 day of the 1st cycle of chemotherapy were recorded and adherence with NCCN guidelines was determined according to treatment year. Descriptive statistics and logistic regression models were used. Results: 22.4% of patients in the SEER/TCR-Medicare and 28.2% in MarketScan cohorts received guideline-adherent prophylaxis. There was a dramatic decrease in guideline-adherence in 2006 with an increase in the adherence according to time. Reason for guideline non-adherence after 2006 was lack of NK1 administration in 82.7% and 83.3% of the cases in SEER/TCR and MarketScan respectively. In multivariable analysis, year of treatment and time to initiation of chemotherapy was associated with guideline adherence in both cohorts. In SEER/TCR, AA patients (OR 0.62 95% CI 0.41, 0.94) were less likely to receive guideline-adherent prophylaxis. In MarketScan, compared to patients treated with AC, those receiving FAC (OR 0.24; 95% CI 0.18-0.32) and TAC (OR 0.87; 95% CI 0.78-0.96) were less likely to receive guideline-adherent treatment. Conclusions: A large proportion of breast cancer patients treated with AC, FAC or TAC do not receive guideline-adherent antiemesis prophylaxis. Guideline non-adherence was associated with lack of NK1-antagonist use. Variation in adherence according to year shows slow uptake of changes made in the guidelines. 2005 2006 2007 2008 2009 2010 2011 2012 2013 Adherence % (SEER/TCR-Medicare) 83.7 1.0 2.7 3.5 15.6 19.6 - - - Adherence % (MarketScan) 87.8 0.9 1.4 3.3 26.5 33.3 46.5 55.6 56.4
Clinical benefit of zoledronic acid for the prevention of skeletal complications in patients with prostate cancer based on history of skeletal complications
Authors: J. L. Chin, F. Saad, D. M. Gleason, R. Murray, S. Tchekmedyian, P. Venner, L. Lacombe, J. J. Vinholes, M. Zheng, Y.-J. J. Hei
Journal: Journal of Clinical Oncology (2004)

4576 Background: We previously reported the efficacy and safety of 4 mg zoledronic acid (Zol) at 15 mo compared with placebo in patients with bone metastases from prostate cancer (Saad et al. J Natl Cancer Inst. 2002;94:1458–1468). We report here the results of a retrospective analysis performed to determine the clinical benefit of Zol in men with prostate cancer based on patients' history of skeletal complications before study entry. Methods: Data were analyzed for patients treated with 4 mg Zol or placebo every 3–4 weeks for 24 months. Patients were retrospectively stratified according to history of a skeletal-related event (SRE) before study entry. Results: Of 422 patients randomized to 4 mg Zol or placebo, 147 completed the 15-month study and 133 elected to enter 9-month extension. Approximately one third of patients had an SRE before study entry. In the placebo group, 51% of patients with a history of an SRE developed an on-study SRE vs 47% of patients without an SRE before study entry. Regardless of SRE history, Zol treatment reduced skeletal morbidity compared with placebo. Multiple event analysis demonstrated that among patients with an SRE before study entry, the risk of developing an SRE was reduced by 40% for patients treated with Zol 4 mg vs placebo (hazard ratio = 0.603; P = .028). For patients without an SRE before study entry, the risk of developing an on-study SRE was also reduced (33%) relative to placebo (hazard ratio = 0.670; P = .027). In the placebo group, median time to first SRE appeared to be shorter for patients with a prior SRE vs no prior SRE. However, in both stratification groups Zol 4 mg extended median time to first SRE relative to placebo (361 days vs 258 days for placebo in patients with a prior SRE and 499 days vs 337 days for placebo in patients without a prior SRE; P = .066 and .065, respectively). Conclusions: This exploratory analysis suggests that Zol provides clinical benefit in patients with advanced prostate cancer and bone metastases independent of their prior history of skeletal complications. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Pharmaceuticals Corp.
A phase Ib/II study of second-line therapy with panitumumab, irinotecan and everolimus (PIE) in metastatic colorectal cancer (mCRC) with KRAS wild type (WT): Biomarker substudy.
Authors: Amanda Rose Townsend, Jennifer Hardingham, Niall C. Tebbutt, Christos Stelios Karapetis, Nimit Singhal, Rohit Joshi, Sue Yeend, Pamela Cooper, Hilary Dorward, Timothy Jay Price
Journal: Journal of Clinical Oncology (2017)

643 Background: Inhibition of mTOR in addition to EGFR may overcome upstream resistance to EGFR inhibitors in CRC. This phase Ib/II study evaluated the efficacy and safety of irinotecan, panitumumab and everolimus (Townsend et al. ESMO 2016).These are the results of the biomarker substudy. Methods: Patients with KRAS exon 2 WT mCRC after failure of fluoropyrimidine based therapy received IV irinotecan (200mg/m2) and panitumumab (6mg/kg) 2 weekly. Everolimus dose was 5mg orally alternate days for dose level 1/expansion, and 5mg daily for level 2. Survival outcomes were calculated using Kaplan-Meier method. DNA was isolated from FFPE tumour sections for whole exome sequencing. Reads were mapped to hg19 reference genome and variants called using GATK tool. RAS/RAF mutations (MT) identified were correlated with response (Fishers exact test), progression free survival (PFS) and overall survival (OS). Filtering for variants in genes associated with progressive disease (PD) was performed. Results: 48 patients were enrolled. 33 had adequate tissue and outcome data for analysis (29 dose level 1, 4 level 2). Median age 63 yrs (41-82), M/F 23/10, ECOG 0/1 17/16. 14 (42%) had partial response (PR), 15 (45%) stable disease (SD) as best response. Median PFS was 5.3 ms and OS 11.1 ms. Three patients had RAS MTs (KRAS exon 2 G12V, KRAS exon 3 Q61H, NRAS exon 2 G12D) and 5 BRAF V600E MT. 2/3 RAS MT had SD and 1/3 PR. 3/5 BRAF MT had SD and 2/5 PD. 13/25 all WT had PR (52%) and 10/25 (40%) SD. BRAF V600E was associated with poorer PFS v WT (median 2.7 v 6.1 ms; P &lt; 0.0001). In all WT patients median PFS was 5.8 ms and OS 12.2 ms. In exploratory analysis 4 patients were heterozygous for PPP1R17 L12V variant (rs3735422) which correlated with PD in 3/4 (P = 0.003) and worse PFS (P = 0.0001). On multivariate analysis (COX regression) BRAF V600E MT and PPP1R17 L12V remained associated with worse PFS (p = 0.005 &amp; p = 0.001 respectively). Conclusions: No responses were seen in patients with BRAF MT. One of 3 with RAS MT had a PR suggesting mTOR inhibition may overcome resistance in this group however this may represent purely a chemotherapy effect. PPP1R17 L12V variant should be validated in larger cohorts. Clinical trial information: NCT01139138.
Deletion and mutation of IL10RA gene on chromosome 11q23 to avert CpG-B oligodeoxynucleotides-induced apoptosis of human chronic lymphocytic leukemia B cells.
Authors: Xueqing Liang, Veronika Bachanova, Wei Chen
Journal: Journal of Clinical Oncology (2013)

3023 Background: Targeting TLR9 expressed on human CLL cells with CpG-B oligodeoxynucleotides leads to IL-10-induced tyrosine phosphorylation of STATs and apoptosis of B-CLL cells. However, B-CLL cells from a small subset of patients were resistant to CpG-B ODN treatment. Here, we investigated the molecular mechanism by which B-CLL cells are sensitive or resistant to CpG-B ODN treatment. Methods: Purified CD19 + CD23 + CD5 + primary B-CLL cells were cultured for 5 days with/without CpG-B ODN (CpG 2006, CpG 685) or rh-IL-10. B-CLL cell apoptosis were determined by viable cell counts, Annexin V/PI and TMRE staining, Western blot and intracellular staining of the activation/cleavage of caspases, PARP, Bax translocation and cytochrome c release, IL-10R1 expression and IL-10 binding by flow cytometry, IL10RA gene deletion by FISH, IL10R1 S138G mutation by Bi-PASA, The tyrosine or serine phosphorylation of STATs by Western blot. Results: Fifteen CpG-sensitive and 11 CpG-resistant primary CLL samples were comparatively studied. B-CLL cells from 15/15 CpG-sensitive samples were induced into apoptosis by either CpG-B ODNs or IL-10 in a treatment time and dose-dependent manner. Both CpG-B ODNs and IL-10 significantly increased pTyr701-STAT1/pTyr705-STAT3 expression and induced apoptosis via the mitochondrial apoptotic pathway in 15 primary B-CLL cells. No IL-10RA gene deletions were detected, 13/15 patients were IL10R1 S138G AA wildtypes and 2/15 patients were AG heterozygotes. In contrast, CpG-B ODNs or IL-10 failed to induce apoptosis in 11/11 CpG-resistant B-CLL cells. Interesting, 2/11 CLL samples had IL10RA genes deletion and 7/11 had IL10R1 S138G GG homozygote mutation. IL10RA gene deletion significantly decreased the IL10R1 expression; both IL10RA gene deletion and mutation significantly decreased the IL-10 binding, abolished or reduced CpG-B ODNs or IL10-induced pTyr701-STAT1/pTyr705-STAT3 expression in B-CLL cells. Conclusion: Deletion and mutation of IL10RA gene on chromosome 11q23 averts CpG-B ODN-induced apoptosis of human B-CLL cells, which may serve as biomarker to predict sensitivity or resistance of CLL to CpG-B ODN treatment.