tbuckley/cabot-search huggingface dataset:
Phase I safety and pharmacokinetic (PK) dose escalation study with SAR245408 (S) polymorph E, a PI3K inhibitor, in patients (pts) with solid tumors or lymphoma.
Authors: Oliver Edgar Bechter, Herlinde Dumez, Jo Costermans, Kevin Punie, Li Liu, Jason Jiang, Jean-François Dedieu, Patrick Schöffski
Journal: Journal of Clinical Oncology (2015)

e13599 Background: S is a potent and selective inhibitor of PI3K class I isoforms. PI3K is implicated in tumor cell proliferation, growth and survival. S polymorph E is a tablet formulation with improved thermodynamic stability compared to polymorph A, which was used in earlier studies. The goal of this trial was to assess the safety and PK of the new formulation. Methods: Pts with solid tumors or lymphoma who were ineligible for standard treatments were included in this open label dose finding phase I study. The primary objective was to assess the safety and tolerability and to assess PK exposure to S with the polymorph E formulation. Exploratory objectives were pharmacodynamics and antitumor activity. S was given orally for two 28 day cycles to cohorts of 3-4 pts each. Inter-patient dose escalation was based on safety and PK data of at least 3 patients exposed to the previous dose level. In case of a dose limiting toxicity (DLT) in Cycle 1, or if further exploration of a dose level was required based on PK data, 3-4 additional patients were included. Results: A total of 18 pts were treated in this trial: 14 with solid tumors and 4 with lymphoma. Six pts received 400 mg/day in Dose Level 1 (DL1) and 12 pts were treated with 600 mg/day (DL2). On DL2, 3 DLTs were observed in 2 pts: 2 events of Grade 3 skin rash and 1 asymptomatic Grade 4 lipase increase. The most frequent adverse events (AE) independently of relationship were constipation, hypertension, nausea, vomiting, decrease in appetite, dry skin, fatigue (including sparse Grade 3/4 AE for constipation, hypertension, vomiting and decrease in appetite). Stable disease was observed in 5 pts. The duration of treatment ranged from 3 weeks to 8 weeks. At steady state, the median tmax was 6.0 h with a mean Cmaxof 135 μg/mL and AUCt of 2690 μg.hr/mL. Exposure at steady state was similar between 400 and 600 mg dose with an accumulation ratio of 4-fold. Conclusions: The polymorph E tablet formulation of S can be given safely at the recommended dose of 600 mg daily, and yields PK steady state exposure comparable to the exposure observed with 600 mg of the polymorph A tablet. Clinical trial information: NCT01943838.
Safety of trastuzumab in HER2-positive primary breast cancer in Japan: Initial safety report for the large-scale cohort study (JBCRG C-01).
Authors: Naohito Yamamoto, Hiroyasu Yamashiro, Hiroji Iwata, Norikazu Masuda, Shoichiro Ohtani, Masato Takahashi, Kosuke Yamazaki, Makoto Kato, Shinji Ohno, Katsumasa Kuroi, Kazuhiko Yamagami, Takashi Morimoto, Yoshie Hasegawa, Toshimi Takano, Takayuki Kadoya, Mitsuchika Hosoda, Hajime Abe, Satoshi Morita, Shinji Yasuno, Masakazu Toi
Journal: Journal of Clinical Oncology (2013)

613 Background: The global randomized trials with trastuzumab (H) shows increased cardiotoxicity in patients (pts) with HER2 positive early breast cancer (BC). Safety in Japanese has not been fully evaluated. We evaluated the safety, especially focused on cardiotoxicity, of H adjuvant (adj) therapy in an observational study in Japan (UMIN000002737). Methods: Pts with histopathologically confirmed HER2 positive invasive BC were registered. Women with stage I-IIIC disease who received H as neo-adj and/or adj therapy were eligible. Mean LVEF at 3, 6, 9 and 18 months (M) was evaluated. The time points represent examination on day 60-120, 150-210, 240-330 and 455-635, respectively. Results: A total of 2024 pts were registered from 56 institutes between July 2009 and June 2011. Data of 1875 pts were collected and finalized by September 2012, and 1800 of them were analyzed for safety. The median follow-up was 35 M. The mean age was 54.5 years. Elderly pts ≥60 years were 32.7%. Treatments after surgery were: concurrent chemotherapy (CT) and H in 20.1%, sequential CT and H in 43.5% and H monotherapy in 35.9%. Adverse events (AEs) associated with H were reported in 350 pts (19.4%) and grade (G) 3/4 AEs in 12 pts (0.7%). G 3/4 cardiotoxicity was reported in 7 pts (dysfunction, 4pts; angina, 1 pt; myocardial infarction, 1 pt and heart failure, 1 pt). The mean LVEF at the baseline was 69.4%. Mean LVEF at 3, 6, 9 and 18M were 66.9%, 66.3%, 65.3% and 66.3%, respectively. Compared to the baseline, LVEF decreased with significant difference at all time points (p&lt;0.0001). LVEF decrease ≥10% occurred in 177 pts (during H treatment,130 and after H treatment, 47). Follow-up data were available in 66 pts: 34 pts recovered to the baseline. Mean time to recover was 262 days. The univariate analysis showed using anthracycline (odds ratio 2.312, p=0.003) was the only risk factor for cardiotoxicity. However, elderly, radiation concurrent/sequential treatment with CT and H had no impact. Conclusions: From our study, we found the AE profiles of H were consistent with previously known AEs. We found using anthracycline was the risk factor for cardiotoxicity at the moment. We should carefully follow pts and watch long-term safety. Clinical trial information: 000002737.
Randomized phase III, multicenter, open-label study comparing TH-302 in combination with doxorubicin versus doxorubicin alone in subjects with locally advanced unresectable or metastatic soft tissue sarcoma.
Authors: Sant P. Chawla, Denise K. Reinke, Sam Saks, Stew Kroll, William D. Tap
Journal: Journal of Clinical Oncology (2012)

TPS10100 Background: A hypoxic microenvironment characterizes solid tumors including soft tissue sarcoma (STS) and is associated with chemotherapy resistance. TH-302, a prodrug of the alkylating agent bromo-isophosphoramide mustard (BR-IPM) is reduced in hypoxic environments, releasing Br-IPM. Combining D with TH-302 should effectively target both the normoxic and hypoxic regions of STS. TH-302 was investigated with full-dose D (75 mg/m 2 ). The regimen was well tolerated, &gt;60% completed 6 cycles. DLTs at higher doses were infection with neutropenia and grade 4 thrombocytopenia. The efficacy was higher than generally reported with single agent D (Sleijfer, The Oncologist, 2005). At MTD (75 mg/m 2 D and 300 mg/m 2 TH-302) best response were 2 (2%) CR, 30 (34%) PR, 43 (48%) SD. Median PFS and OS were 6.7 and 17.5 months, respectively. Based upon these data, a study (NCT01440088) is ongoing to assess the benefit of adding TH-302 to the standard D as first-line therapy of STS. Methods: The randomized (1:1) phase III study of TH-302 (300 mg/m 2 ) with D versus D alone was initiated September 2011. Target goal is 450 patients. TH-302 is administered IV over 30-60 minutes on Days 1 and 8 (21-day cycle). D (75 mg/m 2 , bolus or continuous) is administered Day 1 starting 2-4 hrs after TH-302 when used in combination. Patients receiving TH-302 plus D without progression after 6 cycles may continue on TH-302 alone. Key eligibility criteria: locally advanced unresectable or metastatic STS untreated with chemotherapy (adjuvant allowed), ECOG 0/1, measurable disease (RECIST 1.1) and adequate hematologic, hepatic, renal function. A FDA Special Protocol Agreement was reached on study design and analyses. Primary efficacy endpoint is overall survival (OS) comparison of the combination vs D. The study is designed to detect a 40% improvement in OS with 85% power and one-sided alpha of 2.5%. An interim futility PFS analysis is scheduled after 113 PFS events. Significant improvement in PFS (one-sided p &lt; 0.10) is required to continue. A further analysis for early efficacy stoppage is scheduled after 175 OS events. IDMC will monitor safety and efficacy.
Simultaneous detection of multiple key genes in Chinese non-small cell lung cancer was feasible in clinical practice.
Authors: Hua-Jun Chen, Jian Su, Hong-Hong Yan, Jin-Ji Yang, Xu-Chao Zhang, Zhi-Hong Chen, Yi-Long Wu
Journal: Journal of Clinical Oncology (2014)

e19149 Background: The identification of genetic mutational profiles is significant in personalized management of non-small cell lung cancer (NSCLC). Previous techniques are limited to analyzing only a single or a few mutations together. The study was to investigate the feasibility of simultaneously rapid detection of several key genes in a Chinese cohort. Methods: A multiplexed PCR-based assay (SnapShot) and GeneScan were integrated to genotype hotspots across over 9 key genes with pertinence to current or potential targeted therapy in NSCLC. Clinicalpathologic features, distribution frequency of individual gene and mutation overlap were reviewed. Results: Totally 45 treatment-naïve and 44 treated NSCLC patients with eligible tumor specimens were enrolled into the study. Eighty-four percent of the cohort was with adenocarcinoma, and 54% of patients were smokers. EGFR, KRAS, NRAS, PTEN, BRAF, PIK3CA, MEK1, HER2 and BIM were simultaneously analyzed in a platform. Forty-three percent of patients were classified as wild type in the analysis. Fifty-seven percent of the cohort harbored mutated genes. EGFR was the most prevalent mutated gene, and its rate reached 42% in the cohort; rare mutations were found in 9.0% of the enrolled patients. Four patients with BIM_DEL were male, adenocarcinoma, and no response to erlotinib treatment. None of patients were found to harbor BRAF, PTEN, or MEK1 mutation. Sixty-four percent of patients with adenocarcinoma were detected gene mutations. None mutated genes were detected in nine patients with squamous cell carcinoma. Three patients had overlap of mutations: EGFR_L858R/BIM_DEL, KRAS_G12R/EGFR_L858R, and NRAS_Q61R/EGFR_L858R. Conclusions: Simultaneous detection of several targeted genes by multiplexed molecular testing was feasible in clinical practice. More studies are warranted to establish its utility as more targeted therapies are developed.
Late relapse in soft tissue sarcoma: Prognostic factors for recurrence after 3 years.
Authors: Karim Boudadi, Lili Zhao, Elizabeth J. Davis, Scott Schuetze, Laurence H. Baker, Rashmi Chugh
Journal: Journal of Clinical Oncology (2014)

10570 Background: In patients (pts) with localized soft tissue sarcoma (STS), 80% of relapses occur within the first 2 years (yrs) after definitive resection. However, relapse after 3 yrs is not uncommon, and limited data exists to identify higher risk pts. While the possibility of late relapse suggests prolonged surveillance, we performed a retrospective study to identify prognostic factors for relapse > 3 yrs that may help guide long-term follow-up (f/u). Methods: A cancer center-based registry identified adult STS pts seen from 1999-2010 at University of Michigan. Pts with resected localized STS with >3 yrs of f/u and who remained disease free > 3 yrs were eligible. The primary endpoint was time-to-relapse, defined from resection to disease relapse. Pts were censored at last f/u if they remained disease free. The Kaplan-Meier method was used to estimate survival functions, and Cox proportional hazard model identified prognostic factors of relapse. Results: Of 750 pts with resected localized STS, 232 remained disease free > 3yrs. 37 pts relapsed, 18 (8%) locally, 15 (6%) distantly, and 4 (2%) with both, with a median f/u of 5.1 yrs (3.0-13.8). The relapse-free survival rates at 4, 5, and 6 yrs were 92%, 88%, and 81%, respectively. On multivariate analysis, thoracic location (HR=109.2, 95% CI 4.3-278.3, p=0.005), head/neck location (HR=109, 95% CI 5.7-209.5, p=0.002), size > 10 cm (HR=10.1, 95% CI 0.9-102.6, p=0.05) and positive margins (HR=28.9, 95% CI 5.8-144.1, p<0.0001) were associated with higher risk of relapse > 3 yrs. Grade, histology, or chemotherapy did not correlate with relapse in this selected group. For local relapse only, thoracic location, positive margins, and no radiotherapy were associated with increased risk, while positive margins was the sole factor for distant relapse. Conclusions: In our series, disease relapse after 3 yrs occurred in 16% of localized STS pts. Tumor size > 10 cm, thoracic or head/neck location and positive margins conferred an increased risk. For pts with high risk STS, standard practice is decreased intensity of surveillance beyond 2-3 yrs. Given the incidence of late relapse, continued f/u is important; strategies to minimize radiation exposure to pts during surveillance will be critical moving forward.
Improving durable power of attorney completion rates within an academic cancer center.
Authors: Joshua Murray Wilfong, Kunal C. Kadakia, Sumana Devata, Vedran Radojcic, Leonel Fernando Hernandez-Aya, Philip S. Boonstra, Benjamin Scheier, Maria Silveira, Francis P. Worden
Journal: Journal of Clinical Oncology (2015)

e17672 Background: Documentation of patient’s advance directives (AD) is one important quality metric based on the Quality Oncology Practice Initiative. Many institutions do not have a standardized method to address AD. We performed a pilot project with the goal of developing a structured process to improve durable power of attorney of health care (DPOA-HC) completion rates. We hypothesized that integrating a scalable process focusing on patient education and physician-patient discussion would improve DPOA-HC completion rates. Methods: The pilot occurred within the University of Michigan Comprehensive Cancer Center from January-April 2014. At check-in, all patients were given a questionnaire asking whether they had a DPOA-HC form. If the response was “no” or “uncertain,” an educational pamphlet (EP) and a state-approved DPOA-HC form was placed into the chart, which were then distributed to the patient by the oncologist. The investigators designed the EP. The process was repeated at all subsequent visits within the study period. The primary outcome measure was new DPOA-HC completion rate in eligible patients compared to a historical cohort from 2013. Eligible patients for this analysis included those seen at least twice during the studied periods. Logistic regression was applied to predict the probability that an eligible patient would complete a DPOA-HC during the time periods analyzed. Post-intervention, participating oncologists were surveyed. Results: A total of 768 (intervention cohort) and 745 (historical cohort) patient charts were analyzed. Baseline DPOA-HC completion rates and number of visits were similar in both cohorts (14.1 vs. 14.7% and median of 3, respectively). The intervention cohort was associated with a significant increase in DPOA-HC completion rate (11.1 vs. 3.9%, OR 3.06; p = < 0.0001 95% CI 1.99-4.84). The post-intervention survey revealed no significant perceived negative effect on duration of visits. Conclusions: A process for systematically inquiring about, educating, and soliciting DPOA-HC can increase completion rates without increasing oncologist perception of workflow. Similar interventions should be tested to improve completion rates for other kinds of advance directives.
The in vivo efficacy of docetaxel and cabazitaxel in a cell-line based xenograft of castration-resistant prostate cancer (CRPC) previously treated with enzalutamide.
Authors: Robert J. van Soest, Ellen S. de Morrée, Corrina M.A. de Ridder, Herman Burger, Erik A.C. Wiemer, Ron H.J. Mathijssen, Wytske M. van Weerden, Ronald De Wit
Journal: Journal of Clinical Oncology (2014)

5046 Background: With the rapid evolvement of treatment options for metastatic CRPC, it has become of critical importance to determine the optimal sequencing of therapies. We recently reported in vitro cross-resistance between the taxanes docetaxel and cabazitaxel, and the AR targeting agents abiraterone and enzalutamide (Eur J Cancer 2013;49(18):3821-30). In the present study, we investigated the efficacy of docetaxel and cabazitaxel in an in vivo model of CRPC previously treated with enzalutamide. Methods: The enzalutamide-resistant prostate cancer cell line PC346Enza was derived by continuous culturing of PC346C cells in the presence of enzalutamide (1 µM). PC346Enza cells were subcutaneously inoculated in nude mice. Castrated mice were treated with a single intraperitoneal dose of docetaxel 33 mg/kg, cabazitaxel 33 mg/kg, or placebo when a tumor volume of 300 mm3 was reached. Uncastrated male mice received oral enzalutamide 60 mg/kg daily or placebo. Mean tumor volumes at the time of analysis were calculated after 46 and 25 days of follow-up and compared using an unpaired 2 sample t-test. Results: Cabazitaxel demonstrated a greater antitumor effect as compared to docetaxel in the PC346Enza xenograft. Mean tumor volumes after 46 days of treatment were 61 mm3 (95% CI 24-98) for cabazitaxel versus 258 mm3 (95% CI 95-421) for docetaxel (p=0.01). The mean tumor volume of the placebo treated mice was 743 mm3(95% CI 345-1142). Although the PC346Enza cell line demonstrated complete resistance to enzalutamide in vitro, xenografts still responded to high dose enzalutamide in vivo (60mg/kg). Conclusions: Our in vivo data demonstrated that cabazitaxel was more effective as compared to docetaxel in a model of CRPC previously treated with enzalutamide. Our current findings provide the rationale for a clinical study investigating the efficacy of cabazitaxel versus docetaxel, given as first-line chemotherapy in patients previously treated with enzalutamide. These data and are concordant with clinical studies demonstrating that cabazitaxel retains activity as second-line chemotherapy, even after prior AR-targeted treatment in metastatic CRPC.
A randomized open-label phase II study evaluating antitumor activity of the survivin antisense oligonucleotide LY2181308 (LY) in combination with docetaxel (DO) for second-line treatment of patients with non-small cell lung cancer (NSCLC) using change in tumor size (CTS).
Authors: Denis Charles Talbot, Fiona Helen Blackhall, Dariusz Kowalski, Rodryg Ramlau, Gerold Bepler, Francesco Grossi, Christian A. Lerchenmuller, Mary Colleen Pinder, Jorg Mezger, Sarah Danson, Sophie Callies, Valerie Andre, Mayukh Das, Michael M. F. Lahn, Ronald B. Natale
Journal: Journal of Clinical Oncology (2013)

8051^ Background: Resistance to chemotherapy in progressive NSCLC is associated with overexpression of antiapoptotic proteins including survivin. Down-regulation of survivin can sensitize NSCLC to DO in vitro and in xenograft studies. On the basis of preclinical/phase I results we examined antitumor activity of DO+LY compared with DO alone. Methods: Key eligibility criteria: ECOG PS 0-1, stage IIIB/IV NSCLC all histologies, progression after first-line platinum regimen. Patients randomized (N=180) 2:1 to receive DO+LY (LY 750 mg IV loading ×3, Q1W maintenance) or DO alone (75 mg/m 2 D1Q3W) until progression/toxicities. Antitumor activity was compared using CTS from baseline to end of cycle (C) 2 in each arm. This analysis, which uses tumor measurements as a continuous variable rather than a categorical endpoint based on RECIST, increases statistical efficiency and enables early assessment of clinical benefit. Secondary objectives included assessment of toxicity, PK, PFS and OS. Results: 114 patients received study drug and were included in the analyses. Baseline patient demographics were similar. No statistically significant difference in mean CTS ratio at C2 or in PFS was observed between the 2 arms: CTS was 1.07 with LY+DO (SD, 0.28) and 1.04 with DO (SD, 0.28); median PFS was 2.83 mo (95% CI, 1.84–3.65) with LY+DO and 3.35 mo (95% CI, 2.69–4.57) with DO (log-rank p=0.191). However, Cox regression revealed CTS to be a statistically significant factor for PFS: decreased CTS was associated with increased PFS (HR 0.45; 95% CI, 0.30–0.68, p=0.0001). Median OS was 7.9 mo (90% CI, 6.6–9.7) with LY+DO and 8.8 mo (90% CI, 5.7–13.8) with DO (log-rank p=0.481). There were no differences in toxicities or other secondary parameters. Incidence of grade III/IV toxicities was similar in both arms and was consistent with the known profile of LY+DO as was the PK profile. Conclusions: Addition of LY to DO did not improve the antitumor activity of DO. CTS appears to be a useful endpoint in phase II studies and should be considered further as an endpoint for early decision-making. Clinical trial information: NCT01107444.
A biopsy-based molecular diagnostic test for prediction of aggressive prostate cancer despite variability in pathology assessment.
Authors: Jeffry P. Simko, Matthew R. Cooperberg, Janet E. Cowan, June M. Chan, Imelda Tenggara, Athanasios C. Tsiatis, Nan Zhang, Tara Maddala, H. Jeffrey Lawrence, Peter Carroll, Mark Lee
Journal: Journal of Clinical Oncology (2014)

5082 Background: The 17-gene Genomic Prostate Score, GPS (Genomic Health, Inc., Redwood City, CA), has been analytically (Knezevic et al. BMC Genomics 2013) and clinically validated as a biopsy-based predictor of adverse pathology at radical prostatectomy (RP) (Cooperberg et al. AUA 2013). In the clinical study, central review of biopsy and RP pathology was performed by a single expert uropathologist (JS). Given inter-observer variability of pathologic interpretations, we assessed the ability of GPS to predict adverse pathology at RP based on the original diagnostic reads. Methods: RP patients treated at UCSF from 1997-2011 for clinical low or low-intermediate risk PCa (biopsy Gleason score [GS] 3+3, or 3+4 with ≤ 3 (or 33%) positive cores; PSA ≤ 20; clinical stage ≤ T2) were eligible for the study. The original biopsy GS, RP GS and pathologic T stage reflected diagnoses rendered by > 15 different UCSF pathologists. GPS, using a 100-unit scale, was assessed by qRT-PCR of mRNA from microdissected biopsy tumor tissue. Adverse pathology at RP was defined as major pattern 4 or any pattern 5 and/or pT3 stage. Univariate and multivariable logistic regression models were used. Results: Of 395 patients, 295 (75%) had biopsy GS 6 disease based on original pathology review and 301 (76%) based on central review with 24% discordance. GPS was predictive of adverse pathology defined by central RP review after adjusting for either central biopsy GS (GPS OR/20 units=1.93, 95% CI: 1.30-2.88, p=0.001, GS OR=1.94, 95% CI: 1.17-3.21, p=0.011) or original biopsy GS (GPS OR/20 units=1.98, 95% CI: 1.33-2.93, p <0.001, GS OR=1.82, 95% CI: 1.11-2.98, p=0.019). At RP, 123 (31%) and 66 (17%) patients had adverse pathology based on central review and original review, respectively. Discordance for RP GS was 26% and for pT stage 14%. In univariate models, GPS was a significant predictor of adverse pathology at RP as assessed by central (p < 0.001) or original (p < 0.001) pathology review. Conclusions: The observed discordances between separate pathology assessments of grade and stage are consistent with previous studies. GPS is a robust predictor of adverse pathology despite differences in Gleason scoring and pathologic stage assessment.