tbuckley/cabot-search huggingface dataset:
A novel phase I trial design featuring a two-dimensional dose-finding algorithm optimizing the dose of gemcitabine and doxorubicin with bortezomib in metastatic urothelial carcinoma (UC).
Authors: Arlene O. Siefker-Radtke, Sijin Wen, Yu Shen, Kristi Stigall, David James McConkey, Randall E. Millikan
Journal: Journal of Clinical Oncology (2013)

4548 Background: Preclinical studies suggested that bortezomib (B) enhanced the activity of gemcitabine and doxorubicin (GA) in UC; thus we sought to define possible combinations of bortezomib with this doublet. We employed a novel phase I trial design systematically exploring doses in 2 dimensions. The method estimates an isotoxic curve allowing not only a combination with approximately equal (with respect to single component MTD) contributions of the two components to be found, but also combinations emphasizing one component or the other. Methods: Since 11/06, 74 patients with previously treated metastatic cancer were enrolled (70 UC, 3 prostate, 1 renal). GA was treated as a single component and given in a fixed ratio to a maximum of 900 and 50 mg/m2, and B to a maximal dose of 1.6 mg/m2 IV, with dosing every 14 days. After determining the MTD along the diagonal, we then decreased the dose of B, increasing GA, and vice versa, exploring doses along an isotoxic curve aiming for ≤ 30% dose limiting toxicity (DLT) in cycle 1. The objective response rate (ORR) includes PR or CR, and excludes SD. Results: The MTD along the diagonal for GAB was 756, 42, and 1.4 mg/m2, respectively. Doses maximizing the GA (900, 50) required reduction of B to 1.2 mg/m2. Likewise, doses maximizing B (1.6) required reduction of GA to 559 and 33 mg/m2. The most common DLT were thrombocytopenia 14%, neutropenic fever 5%, and mucositis 1%. There was minimal activity at the on-diagonal MTD with an ORR 1/10. Of the tolerable doses along the isotoxic curve, the greatest activity was seen when maximizing B (1.5-1.6 mg/m2, ORR 7/12 (58%)). The ORR when maximizing GA was 4/10. The most frequent ≥ G3 toxicities include: thrombocytopenia (26%), neutropenia (26%), anemia (24%), fatigue (8%), and neutropenic fever or infection (12%). Treatment was tolerable in poor renal function; 36 patients (49%) had a GFR &lt; 50 ml/min. Conclusions: The combination of GAB has promising activity at doses maximizing proteosome inhibition, despite relatively low doses of GA. Traditional phase 1 design dosing to the MTD "along the diagonal" would have lead to the incorrect conclusion that there was minimal activity. Clinical trial information: NCT00479128.
A phase I study of amrubicin (AMR) and cyclophosphamide in patients with advanced solid organ malignancies: A trial from the Hoosier Oncology Group.
Authors: S. I. Jalal, J. A. Bufill, G. A. Masters, N. Somaiah, K. Koneru, J. McClean, R. E. Sanborn, J. Wu, Z. Yu, L. H. Einhorn
Journal: Journal of Clinical Oncology (2011)

7082 Background: AMR is a synthetic anthracycline with activity in small cell lung cancer (SCLC). Cyclophosphamide is an alkylating agent commonly combined with anthracyclines in diseases such as breast cancer and lymphoma. We conducted a phase I study to determine the maximum tolerated dose (MTD) of the combination. Methods: Eligible patients (pts) had refractory solid organ malignancies, PS 0-1, and adequate organ function. The primary endpoint was MTD and dose limiting toxicities (DLTs). Secondary endpoint was to assess response. Pts were enrolled in sequential dose escalation cohorts in a standard 3+3 design. Treatment consisted of cyclophosphamide IV at 500mg/m2 on day 1 with escalating doses of AMR IV on days 1-3 (25-40mg/m2 with increments of 5mg/m2 per cohort).Cycles were repeated every 21 days. Results: Eligible and treated pts (n=36) received a median of 4 cycles (range 1-6). Pt characteristics: M: F 47.2%:52.8%, median age 61(range 21-80), PS 0:1 47.2%:52.8%. Eighteen of 36 pts had SCLC. The remaining pts had NSCLC (22%), extrathoracic small cell or neuroendocrine carcinoma (5.56%), and other malignancies (22%). Dose level 2 (cyclophosphamide 500mg/m2, AMR 30mg/m2) was determined to be MTD due to grade 4 thrombocytopenia. Incidence of grade 3-4 neutropenia, anemia, thrombocytopenia and febrile neutropenia at all dose levels was 33.3%, 16.7%, 19.4% and 5.56% respectively. PR, SD and PD rates in the overall study population (n=34) were 20.6% (all in small cell cancers), 38.2% and 41.2% respectively. PR, SD and PD rates in small cell cancer pts were 37%, 26%, and 37% respectively. Of the pts achieving PRs on our study, 4 were platinum sensitive, 3 were refractory. Three of the 7 PRs were of longer duration than observed with first line chemotherapy. Median number of prior therapies in pts with PRs was 3.4 (range 1-6). Median duration of response on our study in pts with PR was 3.4 months. Conclusions: AMR (30mg/m2 x3) and cyclophosphamide (500mg/m2) can be safely combined with significant activity observed in a heavily pretreated SCLC population.
Usefulness of 18F-FDG PET Associated With a High-Fat, Low-Carbohydrate Preparation for the Detection of a Myocardial-Embedded Metastasis
Authors: Loïc Djaileb, Damien Mandry, Laurent Riou, Pierre-Yves Marie, Antoine Verger
Journal: Clinical Nuclear Medicine (2017)

The detection of left ventricle metastases is highly relevant because of the risk of severe adverse outcomes such as ventricular arrhythmia. We report herein the case of a 68-year-old man who presented with a ventricular tachycardia due to a myocardial metastasis from a renal cell carcinoma. The metastasis was embedded within the left ventricular lateral wall. It was identified on the basis of persistent F-FDG focal uptake following the ingestion of a high-fat, low-carbohydrate preparation.
Estimation of expectedness: How reliable are the predictions for the outcome of standard therapy in randomized phase III studies (RP3) in epithelial ovarian cancer (EOC)?
Authors: V. Castonguay, I. Diaz-Padilla, L. Wang, A. M. Oza
Journal: Journal of Clinical Oncology (2011)

5036 Background: The reliability and anticipated outcome of the standard control (C) arm is an important parameter in the design of RP3s, to calculate sample size, power and study duration. Changing patterns in treatment of EOC patients or in the composition of the study population can lead to discrepancies between expected and actual outcome of the C arm. We compared the expected versus actual outcome of the C arm in RP3s in EOC. Methods: Superiority design RP3s of EOC published or in abstract form from 1/2000 to 12/2010 were reviewed. Trials where the expected outcome of the primary endpoint for the C arm was not explicitly stated and those where the result was not reported were excluded. A trial C estimate was judged as accurate if the outcome of the C arm was 0.75 to 1.25 times predicted. Results: 50 RP3s in EOC were found from 2000 to 2010, 20 were excluded (4 non-inferiority design, 13 expected outcome not reported, 3 no mature data). Thirteen of the 30 trials had survival as a primary endpoint, and 17 had a progression endpoint. Of trials with survival endpoints, 5/13 accurately predicted outcome and 8/13 underestimated outcome. In 8 trials underestimation was such that the C arm outperformed the hypothesized outcome of the experimental arm (actual/expected (A/E) range 1 to 2.65). For trials with progression endpoints, 10/17 were accurate, 4 underestimated outcome, and 3 overestimated it (A/E range 0.52 to 1.57). Studies with survival endpoints underestimated outcome significantly more than those with a progression endpoint (Wilcoxon two-sample test p = 0.0072). Conclusions: The estimation of expected outcome of standard arm in randomized studies is frequently inaccurate. Our analysis shows that overall survival has often been underestimated in recent EOC trials. This has implications for the design of future trials and in interpreting previously published data. Because of this variation, some trials might have been underpowered to show the magnitude of benefit they were designed for. Potential for variation of outcome with standard therapy needs to be factored into the statistical design and sample size calculations for RP3s.
Comparison of four models for end-stage liver disease in predicting the survival rate of patients with advanced hepatocellular carcinoma (HCC).
Authors: Zhan-Hong Chen, Xiao-kun Ma, Xing Li, Yingfen Hong, Dong-hao Wu, Min Dong, Qu Lin, Xiang-yuan Wu
Journal: Journal of Clinical Oncology (2015)

251 Background: Prognosis of patients with advanced HCC is very poor, median overall survival varies from 3 to 6 months. Life expectancy more than 3 months is one inclusion criteria for molecular targeted drugs in clinical tirals. There exists four models for end-stage liver disease: 1.) MELD: The model for end-stage Liver disease; 2.) MELD-AS: MELD+4.53×c(Na)+4.46×Ascites [Serum Na: Na&lt;135 mmol/L score 1, otherwise score 0; Ascites: persistent ascites score 1, otherwise score 0]; 3.) iMELD: MELD+(0.3×age)-0.7×c(Na)mmol/L+100; 4.) MESO:[MELD/c(Na)mmol/L]×10.Now we want to compare four models in predicting the survival rate of advanced HCC patients. Methods: From September 2008 to September 2010, a total of 183 patients with advanced HCC who were not amendable to locoregional therapy were analyzed. The median survival was 6.6 months. Data were collected to classify patients according to MELD, MELD-AS, iMELD and MESO at diagnosis.3-month survival and 6-month survival were the end points used in the analysis. Results: When predicting 3-month survival, ROC analysis shows AUC of MELD-AS, MESO, MELD and iMELD is 0.718, 0.691, 0.688 and 0.620. AUC of MELD-AS is significantly higher than that of the other three models (p&lt;0.05 ).Cut-off point of MELD-AS is 9.54 with 76.9% sensitivity and 59.5% specificity.The cut-off point of MESO, MELD and iMELD is 0.44, 6.19 and 23.87. When predicting 6-month survival, ROC analysis shows AUC of MELD-AS, MESO, MELD and iMELD and is 0.574, 0.538, 0.533 and 0.507. AUC of MELD-AS is significantly higher than that of the other three models (p&lt;0.05 ).Cut-off point of MELD-AS is 18.53 with 27.7% sensitivity and 89.1% specificity.The cut-off point of MESO, MELD and iMELD is 1.04, 13.83 and 40.76. MELD-AS, MESO, MELD and iMELD is dichotomized according to the cut-off point generated by ROC analysis when predicting 6-month survival.Log-Rank test shows P value of MELD-AS, MESO, MELD and iMELD is 0.001,0.008,0.02 and 0.0009 respectively. Conclusions: MELD-AS is the best model in prediction of 3-month survival and 6-month survival among the four models for end-stage liver disease analyzed for Chinese advanced HCC patients.
Quality of life (QoL) among patients with renal cell carcinoma (RCC) treated with pazopanib versus sunitinib in the COMPARZ study.
Authors: David Cella, Michelle Denise Hackshaw, Jose Diaz, Chun Huang, Keith C. Deen, Rocco Crescenzo, Robert John Motzer
Journal: Journal of Clinical Oncology (2013)

346 Background: Pazopanib and sunitinib are targeted therapies associated with particular treatment-related side effects that may affect patients’ QoL. COMPARZ was a randomized, open-label, parallel group, phase III study of pazopanib vs. sunitinib in 1,110 subjects with advanced RCC who had not received prior systemic therapy. The study demonstrated pazopanib is non-inferior to sunitinib with respect to progression-free survival. The study also confirmed the differentiated safety profiles of the two drugs. Methods: QoL endpoints were assessed using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), the Functional Assessment of Cancer Therapy-Kidney Symptom Index-19 (FKSI-19), the Cancer Therapy Satisfaction Questionnaire (CTSQ), and a Supplementary Quality of Life Questionnaire (SQLQ). Research to validate the SQLQ is currently ongoing. Each instrument was administered at baseline (except CTSQ) and then day 28 of every cycle. Changes in mean scores over time were analyzed and compared using a repeated measures analysis of covariance. Comparisons were pre-specified at the first 6 months of treatment as this time was expected to be a key interval during which tolerability issues may have occurred. Results: During the first 6 months, treatment differences in change from baseline for 11 of the 14 QoL domains studied were statistically significant (p &lt; 0.05), all of which favored pazopanib. Further analysis up to 12 months of treatment, showed the treatment differences observed for fatigue scores increased over time with pazopanib improving and sunitinib remaining relatively flat. The difference in limitations due to foot soreness between the two treatments also progressively increased with time over 12 months favoring pazopanib. Conclusions: In this study, better patient-reported QoL scores for pazopanib indicate subjects experienced less worsening of fatigue, as well as mouth/throat, hands, and feet soreness, and fewer limitations due to soreness, while on pazopanib compared with sunitinib. The differences observed are likely to be clinically meaningful. The FACIT-F and SQLQ results are also highly consistent with the previously-reported PISCES study.
Evaluation of cancer trial eligibility criteria (with focus on non-AIDS–defining cancers) for inclusion of persons with HIV infection.
Authors: S. A. Weiss, S. Gajavelli, A. Negassa, J. A. Sparano, M. Haigentz
Journal: Journal of Clinical Oncology (2011)

6092 Background: Non-AIDS-defining cancers (NADC) have become a significant cause of mortality in persons with HIV-infection. In 2008, the Cancer Therapy Evaluation Program (CTEP) set guidelines that HIV-positive individuals “should not be arbitrarily excluded from participation in cancer clinical trials.” The objective of this study is to assess the frequency of and reasons for exclusion of HIV-infected patients (pts) with NADC on clinical trials. Methods: We searched the Clinicaltrials.gov database for open studies of phase I, II, and III cancer clinical trials from 1/1/2009 to 9/20/2010 using lung, head and neck, and hepatocellular carcinoma as our models. We determined the percentage of trials that excluded HIV-infection and noted the justification for exclusion, if listed. The exclusion percentages were sub-divided into trial location (U.S. vs. international) and sponsor (NIH, Industry, or Other). Results: Data from 543 trials was analyzed. 31% of the trials explicitly excluded HIV-positive pts (26% of lung cancer trials, 34% of head and neck cancer trials, and 42% of hepatocellular carcinoma trials). Among study locations, HIV-positive pts were excluded in 37% of U.S. trials and 27% of international trials. Among sponsorship categories, HIV-positive pts were excluded in 45%, 36%, and 21% of NIH, Industry, and Other sponsored trials, respectively. There were no appreciable trends for exclusion among study phases. 85% of the trials that excluded HIV-positive pts did not list a justification on the publically accessible database. Common reasons for exclusion were immune deficiency, risk of neutropenia and infection, and pharmacokinetic interactions of the study drug with antiretrovirals. Review of full protocol documents in active trials at our institution did not show appreciable differences in results. Conclusions: A significant percentage of current cancer clinical trials exclude HIV-positive pts without offering valid scientific justifications, thereby violating CTEP guidelines. Our observational data suggests that there are currently barriers to enrollment of persons with HIV infection that should be addressed by study investigators.
Prospective biomarker validation trial evaluating the prognostic role of the combined expression of phospho-insulin growth factor receptor-1 and matrilysin in <i>KRAS</i> (exon 2) wild-type (WT) metastatic colorectal cancer (mCRC) patients treated with FOLFOX-6 plus panitumumab as first-line therapy [PULSE trial (GEMCAD 09-03)].
Authors: Juan Maurel, Carlos Fernandez-Martos, Marta Martin-Richard, Vicente Alonso, Jose Carlos Mendez, Antonia Salud, Carles Pericay, Jorge Aparicio, Javier Gallego, Alberto Carmona, Enrique Casado, Hermini Manzano, Carlos Horndler, Michele Rubini, Miriam Cuatrecasas, Xabier Garcia-Albeniz, Jaime Feliu
Journal: Journal of Clinical Oncology (2016)

583 Background: Matrilysin can activate phospho-insulin growth factor receptor-1 (pIGF-1R) through IGFBP-3 degradation, releasing IGF-1. Matrilysin per se has shown poor prognosis in mCRC and the co-expression of matrilysin and pIGF-1R (double positivity, DP) correlates with poor prognosis in WT KRAS refractory patients (pts) treated with anti-EGFR in retrospective analyses. We performed a prospective clinical trial in WT KRAS (exon 2) pts, treated with FOLFOX plus panitumumab in first-line therapy to validate those findings. Methods: Positive cases were defined by immunohistochemistry as those with moderate or strong intensity (++/+++) and &gt; 70% expression for both matrilysin and p-IGF-1R (antibody anti-pY1316). The primary end-point was progression-free survival (PFS). Seventy-eight pts and 56 events were required to have an 80% power to detect a difference in median PFS of 6 months (two-sided p&lt; 0.05). Results: We screened 196 mCRC pts in 24 centers between Nov/2010 and Apr/2013 and 78 pts met inclusion criteria (42 non-DP and 36 DP). Median follow-up was 23 months. There were no differences in baseline characteristics [age, sex, liver metastases, lactate dehydrogenase (LDH) levels, performance status and BRAF mutational status] between both groups. There were no differences in the number of FOLFOX-6 and panitumumab cycles received. Cutaneous toxicity was more frequent in DP pts (p = 0.035). Response rate was 80.5% in non-DP and 72.2% in DP patients (p = 0.37). Median PFS (95% CI) was 7.4 months (95%CI 5.2-13.3) in non-DP and 9.6 months (95% CI 6.7-17.5, p = 0.15) in DP patients. Median overall survival was 19.8 months (11.5-26.3) in non-DP pts and 39.1 months (26-NE, p = 0.071) in DP pts. Adjusted HR for PFS was 0.68 (95% CI 0.41-1.12). Adjusted analysis for OS was 0.50 (95% CI 0.27-0.90). Conclusions: We found that co-expression of matrilysin and pIGF-1R is a novel strong prognostic biomarker of survival benefit in mCRC KRAS WT pts treated in first-line with FOLFOX-6 plus panitumumab. Clinical trial information: NCT01288339.
IDH2 Mutations Have An Unfavorable Impact in Elderly Patients with Acute Myeloid Leukemia
Authors: Shunichro Yamaguchi, Eisaku Iwanaga, Kenji Tokunaga, Tomoko Nanri, Hitoshi Suzushima, Taizo Shimomura, Hiroaki Mitsuya, Norio Asou
Journal: Blood (2011)
BIOSHARE multicenter neoadjuvant phase 2 study: Results of pre-operative sorafenib in patients with resectable hepatocellular carcinoma (HCC)—From GERCOR IRC.
Authors: Mohamed Bouattour, Laetitia Fartoux, Olivier Rosmorduc, Olivier Scatton, Eric Vibert, Charlotte Costentin, Olivier Soubrane, Maxime Ronot, Muriel Magali Granier, Armand De Gramont, Jacques Belghiti, Valerie Paradis, Dominique Wendum, Annemilai Tijeras-Raballand, Alexandra Hadengue, David Brusquant, Benoist Chibaudel, Eric Raymond, Sandrine J. Faivre
Journal: Journal of Clinical Oncology (2016)

252 Background: This open-label, multicenter, phase II study aimed at investigating the activity of sorafenib including radiological, pathological and biological changes in tumor from patients with resectable HCC. Methods: Preoperative administration of sorafenib 400 mg bid for 4 weeks was followed by surgery. Primary endpoints were antitumor activity and histological changes on paired tumor samples and plasma biomarkers between baseline and post sorafenib. Secondary endpoints were safety, R0 surgery and post-surgical complications. Results: Among 30 patients enrolled, 28 were evaluable for safety. Neoadjuvant sorafenib was not feasible in 3 patients (early limiting toxicities). Twenty-five patients (21 men; median age: 61.5 years) were evaluable for the primary endpoints. Baseline median tumor size was 37 mm and 21 patients (84%) had a single lesion. Median duration and dosing of sorafenib were 28 days and 793 mg/day respectively. Overall, the safety profile of preoperative sorafenib was good. According to RECIST criteria, all patients showed stable disease. Among 19 patients evaluated according to mRECIST and Choi criteria, objective responses were observed for 6 (32%) and 10 (53%) patients respectively. All evaluable patients went on liver resection and no unexpected complication occurred. R0 tumor resection was achieved in 22 patients (88%). Surgical specimen showed macrovascular and microvascular invasion in 12% and 48%, respectively. Intratumor necrosis was observed in 17 (68%) surgical specimen with necrosis ≥ 50% in 24 % of cases. Blood biomarkers analysis showed a trend toward increased angiogenesis biomarkers (VEGF-A, VEGF-C and PlGF) after sorafenib treatment. Biomarkers from pre- and post-treatment tissue will be presented during the meeting. Conclusions: Neoadjuvant sorafenib displays a favorable toxicity profile and yields significant activity in patients with resectable HCC. BIOSHARE trial also allows exploration of drug effects on tumor biology. Clinical trial information: NCT01182272.
Contribution of estrogen and progesterone receptor status of carcinoma in situ to risk of subsequent development of invasive cancer and disease specific survival
Authors: M. J. Martin, S. G. Chong, M. MacLochlainn-Row, N. Enright, A. Alaudin, D. S. Kamel, A. M. Ibrahim
Journal: Journal of Clinical Oncology (2008)

593 Background: The estimated risk of developing an invasive breast cancer following a diagnosis of carcinoma in situ (CIS) varies widely, ranging from 14% - 60%. Numerous factors, such as histology, grade, surgical margins, and patient age have been implicated in the risk of developing invasive disease. Given the role of receptor status in the prognosis of invasive breast cancer, this study investigated the contribution of estrogen (ER) and progesterone (PR) receptor status to the subsequent risk of developing invasive cancer, and disease-specific survival. Methods: Using data from the Surveillance Epidemiology and End Results (SEER) database, 17,264 patients were identified with a known ER / PR status. Of these, 1,539 had invasive breast cancer diagnosed at or before the time of CIS diagnosis. Kaplan-Meier analysis and Cox proportional hazards regression modelling were used in the remaining 15,725 patients to assess risk of developing invasive breast cancer, and disease specific survival at 5 and 10 years by receptor status. Results: Results from Kaplan-Meier analysis and Cox proportional hazards regression modelling are given in the table below. Conclusions: The ER / PR status of CIS does not appear to be statistically significantly associated with the subsequent risk of developing invasive breast cancer. In those who do develop invasive breast cancer, the ER / PR status is statistically significantly associated with disease-specific survival rates. Given the clonality observed between CIS and synchronous, adjacent invasive cancers, this observed effect on disease-specific survival likely reflects the ER / PR status of the subsequent invasive cancer. Kaplan-Meier Analysis and Cox Proportional Hazards Regression Modelling Kaplan-Meier Analysis ER-positive, PR-positive ER-positive, PR-negative ER-negative, PR-positive ER-negative, PR-negative P Invasive Breast Cancer at 5 Years 3.95% 4.65% 3.81% 4.18% 0.8762 Invasive Breast Cancer at 10 Years 6.69% 7.39% 4.91% 6.38% 0.6642 Disease-Specific Survival at 5 Years 99.86% 99.46% 99.57% 99.41% 0.0229 Disease-Specific Survival at 10 Years 99.48% 98.35% 99.57% 98.48% 0.0356 Cox proportional hazards regression modelling ER-positive, PR-positive ER-positive, PR-negative ER-negative, PR-positive ER-negative, PR-negative Invasive Breast Cancer at 5 Years (95% CI) 1.000 0.997 (0.720–1.381) 0.760 (0.388–1.492) 1.041 (0.788–1.374) Invasive Breast Cancer at 10 Years (95% CI) 1.000 1.045 (0.786–1.389) 0.683 (0.381–1.227) 0.967 (0.756–1.236) Disease-Specific Survival at 5 Years (95% CI) 1.000 5.927 (1.068–32.874) 7.093 (0.596–84.477) 4.323 (0.972–19.24) Disease-Specific Survival at 10 Years (95% CI) 1.000 3.138 (1.283–7.676) 1.062 (0.137–8.206) 2.164 (0.989–4.736) No significant financial relationships to disclose.