tbuckley/cabot-search huggingface dataset:
A phase II study of a modified pegylated liposomal doxorubicin (PLD), bortezomib, and dexamethasone regimen for patients with previously untreated multiple myeloma (MM).
Authors: J. R. Berenson, O. Yellin, C. Chen, R. Patel, A. Bessudo, R. V. Boccia, H. Yang, V. Gupta, J. Hilger, R. A. Swift
Journal: Journal of Clinical Oncology (2010)

8134 Background: PLD and bortezomib (BORT) are FDA-approved for MM patients who have received one prior therapy. We have previously demonstrated in laboratory studies that lower doses of PLD administered more frequently are better tolerated than higher doses given less often. The combination of BORT and dexamethasone (DEX) is effective for previously untreated MM patients. Prior studies by our group have shown that intravenous administration of DEX 40 mg, BORT 1.0 mg/m2 and PLD 5 mg/m2 (DVD) on days 1, 4, 8, and 11 of a 28-day cycle is effective for relapsed/refractory MM patients and well tolerated. Methods: We conducted a single-arm multi-center phase II study for previously untreated MM patients to evaluate the DVD regimen. Patients were treated to a maximum response plus two additional cycles or completed a maximum of eight cycles of therapy without disease progression. Results: Thirty-five patients were enrolled with a median age of 65 years (range, 42-82 years). Thirty and 33 patients are currently evaluable for response and toxicity, respectively. Twenty-five (83%) patients have shown objective responses to the DVD regimen, including 5 (17%) complete responses, 1 (3%) very good partial response, 14 (47%) partial responses, and 5 (17%) minimal responses. Among the other 5 patients, 4 (13%) had stable disease. To date, 5 patients have shown progressive disease after 1-14 months of follow-up. The median number of cycles was 6 (1-8). Seven patients experienced grade 3 adverse events and one patient with a prior history of pulmonary interstitial fibrosis developed a grade 4 toxicity (shortness of breath). The most common grade 3 adverse event was reversible neutropenia (n = 2). To date, only 8 patients (24%) have developed peripheral neuropathy and all were grade 1 except in two patients (grade 2 [n = 1] and grade 3 [n = 1]). Notably, there have been no cases of stomatitis and only 2 cases of hand-foot syndrome (both grade 1). Conclusions: Thus, these results suggest that the DVD regimen using this modified schedule and doses of these drugs is well tolerated and produces high response rates for previously untreated MM patients. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Millennium Centocor Ortho Biotech, Millennium Centocor Ortho Biotech, Millennium
Low-dose metronomic cyclophosphamide/methotrexate (LDCM) and aspirin for patients who fail to achieve pathologic complete response (pCR) after neoadjuvant treatment for stage II-III breast cancer.
Authors: Susan Burdette-Radoux, Chris E. Holmes, Farrah B. Khan, Kim Dittus, Karen M. Wilson, Marie E. Wood
Journal: Journal of Clinical Oncology (2013)

e12000 Background: Patients (pts) who fail to achieve pCR after neoadjuvant chemotherapy have a 20% risk of recurrence at two years. Data for effective postsurgical chemotherapy in this population is lacking. LDCM is an all-oral chemotherapy regimen with anti-angiogenic activity and acceptable toxicity in metastatic breast cancer. Aspirin is associated with a lower risk of breast cancer recurrence in retrospective studies and has anti-angiogenic activity. Here we combine LDCM and aspirin for high risk pts with poor response to neoadjuvant chemotherapy. Methods: Pts with stage II-III HER-2 negative breast cancer who had residual invasive cancer after neoadjuvant chemotherapy were eligible. Pts completed surgery and radiotherapy prior to enrolment and began study treatment within 180 days of surgery. Pts received four 28-day cycles of LDCM (cyclophosphamide 50 mg po daily, and methotrexate 2.5 mg po twice daily on days 1 and 2 each week ). Aspirin 325 mg daily was added on cycles 3 and 4. Pts were evaluated for the primary endpoint of toxicity and safety every 28 days. Secondary endpoint was 2 year relapse free survival. Results: 10 of 13 planned pts were evaluable for toxicity as of Jan 24, 2013. Pathologic stage ranged from T2N0 to T3N3. 70% of tumors were chemoresistant (stable or upstaged at time of surgery). 60% of pts had hormone receptor positive tumors and received concurrent hormonal therapy. Median age was 59 years (range 38-76). All pts completed 4 cycles of study treatment without dose reduction. There were no grade 3 or 4 related toxicities. Worst hematologic toxicity was grade 2 leukopenia. Worst nonhematologic toxicity was grade 2 fatigue; all other related toxicities were grade 1. 9 pts were evaluable for recurrence and none had recurred at a median followup of 13 months (range 7-23). Conclusions: This antiangiogenic regimen is well tolerated in patients at high risk for recurrence after neoadjuvant chemotherapy, resulting in no recurrences at 13 months followup, and suggesting it may be a candidate for future trials in this setting. Subsequent analyses will include longer term followup and biomarkers for angiogenesis. Clinical trial information: NCT01612247.
Assessing the validity of using claims data compared to medical chart reviews for measuring care quality in Japan.
Authors: Nana Nakamoto, Fumiaki Nakamura, Takahiro Higashi, Momoko Iwamoto, Asuka Amano, Masako Hirayasu, Hatsue Higa, Kuniko Asato, Kazuo Aoki, Masato Masuda
Journal: Journal of Clinical Oncology (2014)

264 Background: Health insurance claims data have been used extensively as a less labor-intensive method of collecting data than medical record reviews, which are the preferred source of data collection in most medical studies. Although recent reports have raised questions about its validity of use in measuring care quality, validity of using claims data may differ by health systems and should therefore be assessed by country. We aimed to test the validity of using claims data in Japan by comparing quality performance scores obtained from claims data to those derived from medical record reviews. Methods: We reviewed medical records from Apr 2013 to Apr 2014 of gastric and colorectal cancer patients who were diagnosed in 2011 from 4 cancer care hospitals in Okinawa. We calculated the proportion of patients who received adjuvant chemotherapy for gastric and colorectal cancer using claims data, and compared the results with those obtained from medical record reviews. Chart reviews were performed by certified tumor registrars. We used kappa coefficients to measure the level of agreement between claims data and medical record reviews. Results: Analysis using claims data resulted in 14 Stage II and III gastric cancer patients who had undergone surgery, with 50% receiving adjuvant chemotherapy; whereas medical record reviews resulted in 19 patients, 94.7% of whom either received or had a clinically valid rationale for not undergoing adjuvant therapy. For colorectal patients, claims data resulted in 48.5% of 68 surgical stage III colorectal patients receiving adjuvant therapy, compared to 74.4% of 78 patients using medical record reviews who either received adjuvant therapy or had a valid reason for not undergoing therapy. Agreement between claims data and chart reviews was low (kappa=0.14) for gastric cancer, but fair (kappa =0.37) for colorectal cancer. Conclusions: Our analysis showed that use of claims data may greatly underestimate quality performance measures if they are not compensated by medical record reviews. Claims data alone cannot capture a large proportion of patients who either choose not to, or has a clinically valid reason for not undergoing standard care.
First-in-human study of AMG 208, an oral MET inhibitor, in adult patients (pts) with advanced solid tumors.
Authors: David S. Hong, Peter J. Rosen, A. Craig Lockhart, Siqing Fu, Filip Janku, Razelle Kurzrock, Rabia Khan, Benny Amore, Isaac Caudillo, Hongjie Deng, Yuying C. Hwang, Robert D. Loberg, Poornima Shubhakar, Stephen Zoog, Darrin M. Beaupre, Peter Lee
Journal: Journal of Clinical Oncology (2013)

41 Background: AMG 208 is a small molecule MET inhibitor that suppresses proliferation and induces apoptosis in human tumor xenografts. This first-in-human study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of AMG 208. We report data from the dose escalation part of the study. Methods: Key eligibility criteria: ≥ 18 yr, advanced solid tumors, ECOG ≤ 2, and evaluable/measurable disease. Using a modified Fibonacci design, 3–9 pts were enrolled into 1 of 7 sequential dose cohorts (25, 50, 100, 150, 200, 300, and 400 mg) of AMG 208. Pts received AMG 208 orally on days 1 and 4–28 once daily. If no dose limiting toxicity (DLT) was seen on days 1–28, pts received AMG 208 once daily starting at day 36 provided pts showed no evident disease progression. In cohorts 1–3, a standard 3+3 design was followed. In cohorts 4–7, a modified 3+3+3 design was followed. Results: As of July 16 2012, 54 pts (25 mg [n=6], 50 mg [n=4], 100 mg [n=4], 150 mg [n=3], 200 mg [n=16], 300 mg [n=10], and 400 mg [n =11]) had received ≥ 1 dose of AMG 208. 67% were men; 19% had prostate cancer (PC). Median (range) age: 61 (39–80) yr. ECOG 0/1: 52%/48%. 6 DLTs were seen: a grade (G) 3 increased AST (200 mg), a G3 thrombocytopenia (200 mg), a G4 acute myocardial infarction (300 mg), a G3 prolonged QT (300 mg), and two G3 hypertensions (400 mg). The maximum tolerated dose was not reached. 83% of pts had tx-related adverse events (AE). Tx-related AE occurring in &gt; 10 pts: fatigue (n=24), nausea (n=18), hypertension (n=12), and diarrhea (n=11). 24% of pts had grade ≥ 3 tx-related AE. AMG 208 was orally bioavailable with a 30–35 hr mean half-life in plasma. Exposure increased linearly with dose; accumulation at day 28 was 2.7-fold across cohorts. Of the 42 pts with available tumor response data for site reads, 1 had complete response on bone scan (PC 300 mg) while 2 had partial responses (PR; PC 400 mg and kidney cancer 200 mg; both had -33% tumor shrinkage), and 29 had stable disease (SD); 1 other PC pt had PR after data cutoff. Of the 35 pts with available tumor response data for central reads, 26 had SD. FLT and biomarker data will be presented. Conclusions: AMG 208 up to 400 mg daily had manageable toxicities and showed evidence of antitumor activity, especially in prostate cancer. Clinical trial information: NCT00813384.
Bioavailability, pharmacodynamic activity, and anti-tumor efficacy of the CD19/CD3-specific BiTE antibody MEDI-538 (MT103) delivered subcutaneously in animal models
Authors: Kathy Mulgrew, David Stewart, Darrin Sabol, Wendy Trigona, Patricia Ryan, Monika Sharma, Ambarish Shah, Marika Mulen, Liang Zhao, Stacy Fuhrmann, Philipp Steiner, Gabriel Robbie, Petra Lutterbuese, Bernd Schlereth, Patrick Baeuerle, Peter Kufer, Peter Kiener, Bahija Jallal, Steven Coats, Scott Hammond
Journal: Cancer Research (2008)

2131  MEDI-538 (MT103) is a bispecific single-chain, T cell-engaging (BiTE) antibody that targets CD19+ B cells and recruits CD3+ cytotoxic T cells to lyse B cells. Ongoing Phase I clinical trials reveal that as a single agent administered by continuous intravenous (IV) infusions, MEDI-538 induces objective clinical responses and clears bone marrow infiltration in heavily pre-treated B cell non-Hodgkin’s lymphoma patients. In an effort to explore alternative routes of administration, we utilized animal models to evaluate the bioavailability, pharmacodynamic effects, and anti-tumor potency of MEDI-538 following subcutaneous (SC) administration. Bioavailability of MEDI-538 was determined following a single IV or SC bolus injection to cynomolgus monkeys and mice. A highly sensitive pharmacokinetic (PK) ELISA assay based on electrochemiluminescence was utilized to measure the amount of MEDI-538 present in each serum sample. Following SC delivery in mice, MEDI-538 concentrations reached a peak at 4-8 hours, exhibited dose-proportionality, and cleared from the blood at a similar rate as compared to IV administration of drug (t1/2 of 2-4 hours). Dose optimization studies showed that varying the dose concentration or volume for a given dose level did not effect the concentration of MEDI-538 in the serum after SC administration. Bioavailability of MEDI-538 delivered via a single SC dose in the mouse was 20-30% based on the mean area under the curve (AUC). In similar studies, PK parameters and bioavailability in cynomologus monkeys was comparable to that measured in mice. MEDI-538 also provided anti-tumor efficacy following SC administration in NOD/SCID mice that were engrafted with human B cell tumor cells mixed with human PBMC and that were capable of demonstrating human T cell-mediated killing of tumor cells. Pharmacodynamic effects were observed following SC administration of a hybrid mouse surrogate form of MEDI-538 (anti-human CD19 x anti-mouse CD3) to immunocompetent human CD19 transgenic knock-in mice. Treatment caused a rapid reduction in B cells and an increase in activated T cells in the spleen as measured by flow cytometry. These results demonstrated that SC delivery of MEDI-538 yielded comparable PK characteristics in multiple animal models, provided sufficient systemic levels for efficacy against tumor challenge in xenograft mouse models, and depleted B cells in an immunocompetent mouse model. Taken together, our data support the SC route of administration as an alternative method for delivery of MEDI-538.
Relevance of MUC1 mucin variable number of tandem repeats polymorphism in Helicobacter pylori adhesion to gastric epithelial cells
Authors: Natalia Costa, Nuno Mendes, Nuno Marcos, Paula Paulo, Tom Caffrey, Michael Hollingsworth, Filipe Santos-Silva
Journal: Cancer Research (2007)

622  The aim of this work is to evaluate the impact of the MUC1 mucin Variable Number of Tandem Repeats (VNTR) polymorphism in the adhesion of Helicobacter pylori to gastric cells.  The Gram negative bacterium H. pylori is involved in the pathogenesis of several gastrointestinal diseases, ultimately leading to gastric carcinogenesis. The attachment of H. pylori to gastric epithelial cells is mediated by the interaction between bacterial adhesins and LPS, and the gastric cell membrane glycolipids and glycoproteins. MUC1 is a membrane glycoprotein that protects epithelial surfaces and has also been recently identified as an H. pylori-binding target. MUC1 shows a highly glycosylated polymorphic VNTR domain, that may be involved in the binding of the bacteria. However, the relevance of MUC1 VNTR variability for H. pylori adhesion to gastric cells remains to be clarified.  We used a gastric carcinoma cell line model, GP202, established from a signet ring cell gastric carcinoma that constitutively expresses MUC1. This cell line was stably transfected with FLAG epitope-tagged MUC1 constructs with 0, 3, 9 and 42 Tandem Repeat units (respectively GP202-MUC1 deleted-TR, GP202-MUC1 3TR, GP202-MUC1 9TR and GP202-MUC1 42TR). Two H. pylori strains were used in this study: the pathogenic strain 26695 (vacA s1/m1, cagPAI+) and the non-pathogenic strain Tx30a (vacA s2/m2, cagPAI-). An ELISA-based adhesion assay was performed to evaluate the bacterial binding to the different transfectants and parental cell line, using the anti-H. pylori monoclonal antibody MAB922.  Adhesion of the pathogenic strain 26695 to gastric cells was higher than the adhesion of the non-pathogenic strain Tx30a in all the transfectants and parental cell line, which may contribute to the previously described pathogenicity of the 26695 strain. There was also a correlation between the increased number of Tandem Repeats and the increased adhesion for both strains. This may be due to the fact that MUC1 with larger Tandem Repeat regions contains more potential binding sites, thus enhancing bacterial adhesion. Moreover, differences in VNTR length lead to glycosylation changes in MUC1, which may also contribute to the altered adhesion observed.  	This work shows that MUC1 VNTR polymorphism may play an important role in Helicobacter pylori colonization of the gastric mucosa.  Supported by FCT (POCI/SAU-IMI/56895/2004).
Activity of gemcitabine/5-FU combination in refractory esophagogastric (EG) cancer.
Authors: Elizabeth Won, David H. Ilson, Joanne F. Chou, Marinela Capanu
Journal: Journal of Clinical Oncology (2014)

147 Background: Systemic chemotherapy has been demonstrated to improve survival and palliate symptoms in metastatic EG cancer. 2 nd line (or more) chemotherapy with best supportive care also improves progression free and overall survival. Single-agent gemcitabine did not show activity in EG cancers (Ann Oncol 11:1161, 2000). Addition of gemcitabine to 5-fluorouracil (5FU) has shown modest activity (Oncology 69:130, 2005). To determine the efficacy and tolerability of gemcitabine with 5FU, we reviewed our experience in patients (pts) with metastatic or advanced EG cancers treated with this regimen. Methods: Retrospective review of MSKCC database for pts with metastatic EG cancer treated with gemcitabine/5FU (or capecitabine) between 1/1/2000 - 12/31/2012. Gemcitabine given at 600-1000mg/m2 day1, day 8 of q21 day cycle or 600-1000mg/m2 q2 weeks. 5FU given at 600-1000m2/m2 IV/48 hrs, with bolus 5FU/Leucovorin (200-400mg/m2 IV) on day 1. Capecitabine most commonly given as 1500-4000mg flat dose daily, in two divided doses, 7 days on/7 days off. Results: Of 146 pts, median age was 60; KPS 70 (50-90); 84% adenocarcinoma, 6% squamous (SCC). Sites of disease: 45% liver; 22% bone, 21% peritoneum. 112(77%) had ≥ 2 sites of disease. Pts were heavily pretreated: 42(29%) 2 prior lines of treatment (tx) for metastatic disease, 37(25%) 3 lines of tx, and 7(5%) 4+ lines of tx. Prior tx: 5FU/platinum (37%); Taxanes (56%); Irinotecan (44%). With gemcitabine, 49(34%) received 5FU and 97(66%) received capecitabine. In 144 evaluable pts, partial response rate was 7%, and stable disease was seen in 33%. Median PFS 1.84 months (95% CI,1.38-2.04) and for adenocarcinoma 2.0 months (95%CI,1.2-2.2) vs 1.2 months (95%CI: 0.9-1.51) for SCC (p =0.068). In the PR group, median PFS was 5.0 months (range 3.7-16.3 mo). Grade 3 toxicity was seen in 19 (13%); 1 pt had Grade 4 toxicity. 3(2%) discontinued treatment due to toxicity. Conclusions: Combination gemcitabine/5FU or capecitabine in metastatic EG cancer may have some limited activity and is well tolerated in a previously treated population. This regimen may be an appropriate palliative option for patients with an intact performance status who have progressed on other regimens. Research supported by Foundation 14.
A phase Ib/IIa study of combination therapy with gemcitabine and Atu027 in patients with locally advanced or metastatic pancreatic adenocarcinoma.
Authors: Beate Schultheis, Dirk Strumberg, Jan Kuhlmann, Martin Wolf, Karin Link, Thomas Seufferlein, Joerg Kaufmann, Frank Gebhardt, Nico Bruyniks, Uwe Pelzer
Journal: Journal of Clinical Oncology (2016)

385 Background: Atu027 is a liposomally formulated short interfering RNA with anti-metastatic activity, which silences expression of protein kinase N3 (PKN3) in the vascular endothelium. PKN3 acts as a Rho effector downstream of PI3K. This trial was designed to assess safety, pharmacokinetics and efficacy of Atu027 in combination with gemcitabine in advanced pancreatic carcinoma (APC). Methods: 23 patients (pts) with APC stage 3 or 4 were enrolled and randomly assigned to different Atu027 dosing schedules (arm 1: 0.253mg/kg once weekly, n = 11; arm 2: 0.253mg/kg twice-weekly, n = 12) but identical gemcitabine regimen. Response was evaluated according to RECIST 1.1. Quality of life was assessed with EORTC questionnaire QLQ-C30. Results: Combination therapy with Atu027 and gemcitabine was given up to 7.8 months until progression. Grade 3 adverse events (AEs) were reported by 9/11 pts (82%) in arm 1 and 11/12 pts (92%) in arm 2. Grade 4 AEs were reported by two pts in each arm. Interestingly, there was a difference in median progression free survival (mPFS) between the two treatment arms. Arm 1 showed an mPFS of 1.8 [95%CI: 0.4-5.5] months vs. 5.3 [95%CI: 1.5-6.0] months in arm 2, p= 0.399. In a post-hoc analysis of metastatic disease only, the difference in mPFS between the two arms reached statistical significance (1.6 [95%CI:0.4-2.1] vs 2.9 [95%CI:1.0-7.3] months, n = 9 vs 10, p= 0.025). Disease control during treatment was achieved in 4/11 (36%) pts in arm 1 and in 7/12 (58%) pts in arm 2. New lesions occurred in all (6/6) pts in arm 1 who had at least one RECIST re-evaluation but only 5/10 pts (50%) in arm 2. In quality of life analysis, pts in the once-weekly arm showed a stable global health status while pts in the twice-weekly arm reported an improvement (0-100 score change from baseline: -2.3 vs +21.6 after one cycle, N = 7 vs 7). Conclusions: Combination of Atu027 with gemcitabine for the treatment of APC is safe and was well tolerated. Despite the small patient number, there is a clear signal that twice-weekly Atu027 dosing might be superior to the once-weekly regimen. These results suggest efficacy of Atu027 and warrant further investigation with Atu027 added to standard of care in APC. Clinical trial information: NCT01808638.
A Phase 2 Study of Prolonged Carfilzomib Therapy in Patients with Multiple Myeloma Previously Enrolled in Carfilzomib Clinical Trials.
Authors: David S. Siegel, Michael Wang, Thomas G Martin, Jeffrey R. Infante, Jonathan L. Kaufman, Kanya Ranjangam, Mei Huang, Elizabeth Bilotti, Ravi Vij
Journal: Blood (2012)
Colorectal cancer in African American and Caucasian patients: A comparison of an urban, university hospital with the National Cancer Institute SEER database.
Authors: E. P. Mitchell, A. Topham, R. Singla, S. Maron, J. Schoenfeld, F. Guiles, S. Goldstein, P. R. Anne, G. Isenberg, P. J. Maxwell, J. Palazzo
Journal: Journal of Clinical Oncology (2011)

3631 Background: African Americans (AA) have a higher incidence and lower survival from colon and rectal cancer than Caucasian Americans (C). Disparities among AA and C have been attributed to multiple factors, including later stage at diagnosis, a higher proportion of poor histopathologic features, inadequate and unequal treatment, and socioeconomic factors. The multidisciplinary management setting provides similarity in management and treatment planning. The objective of this study was to assess pathologic features and survival of CRC in AA and C pts using a large institutional database and comparing national population-based data. Methods: We compiled data from 4,654 patients with colon and rectal cancer treated at Thomas Jefferson University Hospital from 1988-2010 and used Surveillance Epidemiology and End Results registry data from 1988-2004 to compare survival rates. Independent variables included age, racial background, site of primary tumor, differentiation, stage at presentation, recurrence-free survival, and overall survival rates for colon and rectal cancer and for each stage of the disease. We compared survival rates, using statistical modeling to account for disease characteristics between the two groups. Results: At diagnosis, AA pts presented with more advanced stage of disease, were more likely to have proximal disease (p<0.0001), had worse overall 5-year survival, and worse survival stage-by-stage than C pts. The odds ratio for risk of nodal involvement was greater for AA than C pts with lower T-tumors. AA pts were more likely to have less differentiated colon tumors, but more well-differentiated rectal tumors, younger age, and worse survival stage-by-stage than C pts. Although C pts were more likely to have rectal cancer (p<0.0001), they were less likely to have stage IV disease at presentation. Conclusions: AA pts with CRC are more likely to present at a younger age, with later stage, more proximal tumors, have higher nodal involvement with lower T-lesions, and less well differentiated tumors than C. Additional studies on biological features and molecular markers are ongoing and will be presented.