tbuckley/cabot-search huggingface dataset:
Transforming the clinical trial process: The I-SPY 2 trial as a model for improving the efficiency of clinical trials and accelerating the drug-screening process.
Authors: Meredith B. Buxton, Kelsey Natsuhara, Angela DeMichele, Jane Perlmutter, Nola M Hylton, Douglas Yee, Laura van't Veer, William Fraser Symmans, Michael Hogarth, Julia Lyandres, Sarah E Davis, Susan Flynn, Melissa Paoloni, Donald A. Berry, Laura Esserman
Journal: Journal of Clinical Oncology (2014)

TPS2633 Background: The I-SPY 2 TRIAL is a standing, phase 2 trial that screens novel, targeted chemotherapeutic regimens in the neoadjuvant setting for women with stage II/III breast cancer. I-SPY 2 compares the efficacy of novel agents in combination with standard chemotherapy versus standard therapy alone, using pathologic complete response as the primary endpoint. Using an adaptive design, the goal is to identify/graduate regimens that have ≥85% Bayesian predictive probability of success (statistical significance) in a 300-patient biomarker-linked Phase 3 neoadjuvant trial defined by hormone-receptor (HR), HER2 status and MammaPrint. Methods: I-SPY 2 opened to accrual in March 2010, and is currently enrolling at 18 sites in the US, with 2 additional sites opening in 2014 (one in Canada and one in the US). As of January 2014, I-SPY 2 has screened 961 patients, enrolled 541 patients, and 326 patients have completed surgery. Seven novel regimens have entered the trial from 5 different pharmaceutical companies. In 2013, the trial announced the graduation of 2 regimens for two different biomarker signatures – veliparib+carboplatin (HR-/HER2-) and neratinib (HR-/HER2+). The I-SPY 2 TRIAL incorporates many innovative procedures and tools to increase the efficiency of the clinical trial process including: developing a standing trial consortium of academic, industry, governmental and nonprofit partners; involving key stakeholders from the development to implementation to ongoing management phases; democratizing data access; and driving organization efficiencies including testing drugs by class, developing a “Master” IND and protocol to accommodate testing multiple agents, sharing a control arm across multiple treatment arms, focusing on the collection of critical data elements, and utilizing previously and newly developed informatics tools to create an IT bundle to support next generation trials. The I-SPY Program includes a series of linked standing trials (I-SPY 2 and I-SPY 3, a confirmatory phase 3 trial) that may allow for a more efficient process for new chemotherapeutic agents to obtain both accelerated and full FDA approval. Clinical trial information: NCT01042379.
Final analysis of a large, open-label global early access protocol (EAP) with abiraterone acetate (AA) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) progressing after chemotherapy.
Authors: Cora N. Sternberg, Gedske Daugaard, Lajos Geczi, Sebastien J. Hotte, Paul N. Mainwaring, Fred Saad, Ciro Souza, Miah Hiang Tay, Jose Manuel Tello Garrido, Luca Galli, Anil Londhe, Peter De Porre, Dan Atlan, Betty Goon, Emma Lee, Tracy McGowan, Vahid Naini, Mary Beth Todd, Arturo Molina, Daniel J. George
Journal: Journal of Clinical Oncology (2014)

5061 Background: A global EAP was conducted to provide broader access to pts with mCRPC post-chemotherapy and to generate additional clinical efficacy and safety data for AA after registrational study COU-AA-301 had completed enrollment. In COU-AA-301, a phase 3 randomized trial of 1195 pts, AA + prednisone (P) significantly prolonged median overall survival by 4.6 months with a 26% reduction (HR = 0.74 [95% CI, 0.64-0.86]; p < 0.0001) in the risk of death vs placebo + P. Methods: 2314 pts with mCRPC who progressed after a taxane and possibly 1 additional chemotherapy entered an open-label EAP. Pts received AA (1000 mg po/d) + P (5 mg BID) in 28-day cycles. Ongoing pts were to be transitioned to marketed product upon regulatory and marketing approval in individual countries. Efficacy measures, collected to guide treatment decisions, were prostate-specific antigen progression (PSAP) and clinical progression (CP). Safety assessments included treatment-emergent adverse events (AEs). The final results are presented. Results: Pts were enrolled from 253 sites in 23 countries in Europe (51%), N. America (23%), Asia-Pacific (20%), and Latin America (6%). Baseline pt characteristics were similar to COU-AA-301, with median age 70 years (range 44-98) and bone metastases present in 91%. Median therapy duration was 4.9 months (74% received ≥ 4 cycles). Median time to PSAP (683 events) and CP (721 events) was 8.5 months (95% CI, 8.3-9.7) and 12.7 months (95% CI, 11.8-13.8), respectively. Median time to PSAP was identical to the AA + P arm of COU-AA-301 (ie, 8.5 months; CP not measured). No new safety signals were detected. Grade 3/4 AEs of special interest were infrequent: any liver function test abnormalities (8.0%), hypertension (4.3%), cardiac disorders (2.2%), hypokalemia (1.2%), fluid retention/edema (1.0%). Discontinuations due to AEs or death were 7.4% each. Conclusions: These final EAP results demonstrate that the clinical safety and efficacy of AA + P are reproducible across a broader global distribution of sites than COU-AA-301, and reveal no additional safety concerns. Clinical trial information: NCT01217697.
Correction: Vaccine Efficacy in Senescent Mice Challenged with Recombinant SARS-CoV Bearing Epidemic and Zoonotic Spike Variants
Authors: Damon Deming, Timothy Sheahan, Mark Heise, Boyd Yount, Nancy Davis, Amy Sims, Mehul Suthar, Jack Harkema, Alan Whitmore, Raymond Pickles, Ande West, Eric Donaldson, Kristopher Curtis, Robert Johnston, Ralph Baric
Journal: PLoS Medicine (2007)
Systematic evaluation of risk factors for acquired heart disease in sarcoma survivors.
Authors: Laurence H. Baker, Venkatesh Locharla Murthy, Richard Lawrence Weinberg, Nina Pagadala Bobowski
Journal: Journal of Clinical Oncology (2017)

127 Background: Sarcoma survivors are at high risk for severe heart disease at a young age. The study objective is to evaluate risk factors for cardiac disease in sarcoma survivors receiving more than 300 mg/m2 of Doxorubicin. Left ventricular ejection fraction is a routinely used test but is not predictive. It is imperative to determine which modifiable cardiovascular risk factors increase cardiac risk. Methods: Our unique Sarcoma Survivorship Clinic was established to evaluate high risk sarcoma patients for the long-term and late effects of cancer and its treatment. Each patient regularly electronically completes NIH’s PROMIS questionnaires developed for this clinic. Family medical history is reviewed. Chemotherapy doses are abstracted from original medical records. Data collected includes: blood pressure, lipid profile, high-sensitivity C-reactive protein (hs-CRP), basic metabolic panel, chemistries, renal and pulmonary function, echocardiography. We will compare standardized cardiac risk assessments with mediastinal calcification and epicardial fat on serial chest CT scans. All patients signed an informed consent. Results: The 24 patient cohort had a cumulative dose of &gt; 300 mg/m2 of Doxorubicin. No patient had chest radiation. All patients had normal left ejection fractions (median= 60%). Eight patients (33%) had an elevated hs-CRP (&gt;3) and 10 patients (42%) had elevated blood pressure. Framingham risk may underestimate risk in this relatively young population and other metrics may be required. Conclusions: Our findings suggest high risk sarcoma survivors' follow-up management requires a comprehensive approach to establish the patient's overall cardiac risk profile. Symptoms may be discounted and/or attributed to other causes, leading to delayed and/or inappropriate treatment of cardiovascular disease. We must improve our knowledge of the long-term cardiac risk associated with surviving a bone or soft tissue sarcoma to effectively counsel survivors and offer effective intervention strategies to prevent or minimize the impact of adverse late effects.
Breast cancer: Draining lymph node of vaccination site targeted by adjuvant GM-CSF in an autologous vaccine
Authors: E. Garcia-Giralt, E. Lasalvia-Prisco, S. Cucchi, M. Aghazarian, J. Larrañaga, M. Brent, D. Walton
Journal: Journal of Clinical Oncology (2007)

13506 Background: We have reported the sensitization against Tumor Associated Antigens (TAA) and the tumor antiprogressive effect of Autologous Thermostable Hemoderivative-Cancer Vaccine (ATH-CV) in breast cancer patients (E. Garcia-Giralt et al ASCO, 2006). Systemic immune response elicited by TAA is started by a locoregional immune response at the microenvironment constituted by the antigens source and the draining lymph node. The antigens source can be a tumor or a vaccination site and respectively, the draining lymph node is the sentinel lymph node (SLN) or the Sentinel Immunized Node (SIN). Tolerogenic or protective locoregional immune response is decisional because it starts a corresponding systemic immune response, tolerogenic or protective. GM-CSF is a conditioner of SLN and SIN, switching the locoregional immune responses from tolerogenic to protective (ML Disis et al Blood, 1996; AJ Cochran et al Nat Rev Immunology, 2006). Therefore, to optimize the ATH-CV antitumoral effect, we have explored GM-CSF as a locoregional adjuvant. Methods: Thirty six M1 breast cancer patients, ER+,HER 2-, hormone and chemotherapy resistant, performance status = 2, and CA 15–3 rising level, were included in this prospective, IRB-approved phase I/II trial. Patients were 3-group (G) randomized (12 each), submitted to different treatments: G1, no additional oncology treatment; G2, ATH-CV; G3, ATH-CV plus GM-CSF at vaccination site 150 μg/day, 5 days. Statistic assessment (Student’s t-test) was performed at the 30-day end point: ATH sensitization by Delayed Type Hypersensibility test (DTH) and Lymphocyte Proliferative Assay (LPA); PSA serum level and immunophenotyping of lymph node cells in biopsies of SIN scintigraphy-localized. Results: Significant differences (p&lt;0.05): DTH test &gt; 5 mm: G1, 0/12; G2, 3/12 and G3, 6/12. LPA &gt; 2.0: G1, 0/12; G2, 4/12 and G3, 7/12. Immunophenotyping: MHC-II+CD83+ (Mature Dendritic Cells):G3&gt;G2&gt;G1. 30 days CA 15–3 increase: G1&gt;G2&gt;G3. No relevant toxicities were evidenced. Conclusions: In advanced breast cancer, ATH-CV sensitization and tumor antiprogressive effect were potentiated by GM-CSF as local adjuvant. Increase of SIN mature dendritic cells is suggested as mechanism of action. No significant financial relationships to disclose.
Early onset hypothyroidism as a predictor for progression-free survival (PFS) and overall survival (OS) benefit in patients with advanced renal cell carcinoma treated with first-line sunitinib.
Authors: Alvaro Pinto, Maria Garrido, Patricia Cruz, David Lopez, Francisco Zambrana, Cristina Aguayo, Jaime Feliu, Enrique Espinosa
Journal: Journal of Clinical Oncology (2014)

e15564 Background: Renal cell carcinoma is a heterogeneous disease; about 20% of the patients will show progression of the disease as their best response, while 25% will be long-term responders. Nowadays, the identification of potential predictive factors for these drugs is an unmet medical need. Methods: Data from patients with advanced renal cell carcinoma treated with first-line sunitinib were collected from four university hospitals in Spain. Patients with baseline thyroid dysfunction were excluded. We obtained information regarding clinical and pathological issues, as well as toxicities and clinical course of the disease. Hypothyroidism was defined as a level of TSH > 10 mUI/l in the first 12 weeks of therapy. Results: A total of 86 patients were analyzed, with a median age of 59.5 years (range 30–78). Clinical and pathological characteristics of the patients are summarized in the Table. In the univariate analysis, there was a better progression-free survival (PFS) in the group of patients with hypothyroidism (19 vs 8 months, p=0.007); this was also true for OS (39 vs 15 months, p=0.01). Hypothyroidism was confirmed as an independent prognostic factor in the multivariate analysis, together with MSKCC prognostic group and nephrectomy. ECOG performance status and histology (clear cell/non-clear cell) were not significant for survival in the multivariate analysis. Conclusions: In our group of patients, the occurrence of hypothyroidism was strongly associated with a better outcome, with improvement both in PFS and OS. This association was confirmed in the multivariate analysis. These data support that hypothyroidism could be used as an early predictive factor of outcome for patients treated with first-line sunitinib. Characteristics of the patients. ECOG 0 1 2 35 (40.6%) 47 (54.7%) 4 (4.7%) Nephrectomy Yes No 61 (70.9%) 25 (29.1%) MSKCC group Good Intermediate Poor 23 (26.7%) 60 (69.8%) 3 (3.5%) Histology Clear cell Non-clear cell 76 (88.4%) 10 (11.6%) Second-line None TKI mTOR Other Still in 1st line 15 (17.4%) 27 (31.4%) 26 (30.2%) 1 (1.2%) 17 (19.8%)
Outcomes with sorafenib (SOR) followed by regorafenib (REG) or placebo (PBO) for hepatocellular carcinoma (HCC): Results of the international, randomized phase 3 RESORCE trial.
Authors: Richard S. Finn, Philippe Merle, Alessandro Granito, Yi-Hsiang Huang, Gyorgy Bodoky, Marc Pracht, Osamu Yokosuka, Olivier Rosmorduc, René Gerolami, Chiara Caparello, Roniel Cabrera, Charissa Chang, Weijing Sun, Guohong Han, Marie-Aude Le Berre, Annette Baumhauer, Gerold Meinhardt, Jordi Bruix
Journal: Journal of Clinical Oncology (2017)

344 Background: SOR is standard first-line systemic treatment for HCC unsuitable for locoregional therapy. RESORCE showed that REG improves overall survival (OS) in patients who progressed during SOR treatment (HR 0.63, 95% CI 0.50, 0.79; P &lt; 0.001). This exploratory analysis describes outcomes for the sequence of SOR followed by REG. Methods: 573 patients were randomized 2:1 to receive REG 160 mg/day (d), 3 wks on/1 wk off or PBO. Data on prior SOR treatment and radiologic progression were prospectively collected. Efficacy and safety were evaluated by the last SOR dose. Time from the start of SOR to death was assessed. Results: Baseline characteristics were balanced. Times from the start of SOR to progression on SOR and times from progression on SOR to start of study drug were similar (Table). When analyzed based on last SOR dose 800 mg/d vs &lt; 800 mg/d, rates of all grade treatment-emergent adverse events (TEAEs) on study were similar (REG: 100% vs 100%; PBO: 92% vs 93%). TEAE grades 3/4/5 by last SOR dose 800 mg/d vs &lt; 800 mg/d were 52/11/15% vs 61/10/12%, respectively, with REG and 30/8/24% vs 32/7/14% with PBO. HRs (95% CI) REG/PBO for OS by last SOR dose were similar: 0.67 (0.51, 0.87) for 800 mg/d and 0.68 (0.48, 0.97) for &lt; 800 mg/d. Median OS (95% CI) from the start of SOR was 26.0 months (22.6, 28.1) for REG and 19.2 months (16.3, 22.8) for PBO. Clinical trial information: NCT01774344. Conclusions: This exploratory subgroup analysis by prior SOR dose demonstrates a consistent survival benefit for REG. In addition, the safety profile of REG was not remarkably different when analyzed by the last SOR dose.[Table: see text]
The phase I study of concurrent chemoradiotherapy using a combination of gemcitabine and nab-paclitaxel for unresectable locally advanced pancreatic cancer: Update.
Authors: Tatsuya Ioka, Kazuhiro Katayama, Ryoji Takada, Kazuyoshi Ohkawa, Hidenori Takahashi, Teruki Teshima
Journal: Journal of Clinical Oncology (2017)

462 Background: Gemcitabine (GEM) plus nab-paclitaxel (nP) are one of the standard of care for metastatic pancreatic cancer, but it is still controversial about the value in non-metastatic patients. Purpose: The primary objective of this study is to assess the toxicity of concurrent chemoradiotherapy (CRT) with a combination of GEM and nP for unresectable locally advanced pancreatic cancer (UR-LAPC). Methods: Chemotherapy-naive patients with histologically or cytologically proven UR-LAPC were enrolled to this trial. The patients received GEM and nP intravenously over 30 min. respectively on days 1, 8 and 15 every 28 days. Cycles were repeated every 28 days during radiotherapy. Patients were scheduled to receive GEM (mg/msq/week) and nP (mg/msq/day) at six dose levels: 600/50 (level 1), 600/75 (level 2), 600/100 (level 3), 800/100 (level 4), 1,000/100(level 5) and 1,000/125(level 6). Radiation therapy was delivered through four fields as a total dose of 50.4 Gy in 28 fractions over 5.5 weeks, and no prophylactic nodal irradiation was given. Dose-limiting toxicity (DLT) was defined as grade 4 hematological toxicity, grade 3 non-hematological toxicity and &gt;14 days delay of treatment. Every patients were evaluated for response with RECIST criteria. Results: Twenty one patients were enrolled in this study between 12/2013 and 05/2015. Treatment was well tolerated; Every 21 patients completed radiotherapy of 50.4 Gy. Our recommended dose was level 3, Gem 600mg/ nP 100mg. Nine patients experienced DLT. The response rate was 67% (CR 0, PR 14, SD 6 and PD 1). Median OS was 23.8 months (95%CI: 17.0, -) and median PFS was 9.0 months (95%CI: 4.8, 11.9). Conclusions: The CRT with a combination of GEM and nP can be delivered almost safely for UR-LAPC. Clinical trial information: UMIN000012254.
Detection of circulating tumor cells (CTC) using a non-EpCAM-based, high-definition, single-cell assay in advanced hepatocellular carcinoma (HCC) for patients enrolled on phase I and II trials of sorafenib plus temsirolimus.
Authors: Robin Kate Kelley, Mariam Rodriguez Lee, Jimmy Hwang, John Dozier Gordan, Halla Sayed Nimeiri, Andrea Grace Bocobo, Sheetal Mehta Kircher, Advaita Kanakamedala, Mary Frances Mulcahy, Al Bowen Benson, Peter Kuhn, Alan P. Venook
Journal: Journal of Clinical Oncology (2017)

311 Background: Noninvasive biomarkers are needed for diagnosis, prognosis, and molecular profiling of HCC due to scarcity of tumor tissue and heterogeneous tumor biology. CTC are detectable in metastatic HCC using methods which enrich for expression of the cell adhesion molecule, EpCAM. Because a subset of HCC does not express EpCAM, however, non-EpCAM enrichment methods are needed for CTC studies in HCC. Methods: This CTC cohort was derived from patients enrolled on multicenter phase 1 and 2 trials of the combination of sorafenib plus temsirolimus in advanced HCC (NCT01008917, NCT01687673) with approval and funding from the National Comprehensive Cancer Network (NCCN) Oncology Research Program. Eligibility required histologic diagnosis of incurable HCC with no prior systemic therapy. All patients in the cohort were treated at the recommended phase 2 dose of sorafenib 200 mg PO BID and temsirolimus 10 mg IV weekly. Whole blood samples were collected at baseline and on treatment. CTC were enumerated and analyzed cytomorphologically using a high-definition, single cell assay without EpCAM enrichment and blinded to clinical outcomes. Results: The CTC cohort was comprised of 36 patients (phase 1 n = 9, phase 2 n = 27). Characteristics: male 89%; white 64%, Asian/PI 28%, black 6%; HBsAg+ 31%, HCV+ 44%; Child Pugh A 92%, B7 8%; BCLC C 83%; tumor vascular invasion 47%; median AFP 74 ng/mL. Median OS from start of treatment was 392 days (95% CI: 214, 569). CTC ≥ 1/mL were detectable at baseline in 23/36 (64%) overall (95% CI: 47%, 80%), with similar findings in the phase 1 (56%) and phase 2 (67%) subsets. There was no significant relationship between baseline CTC values ≥ 1, 2, or 5/mL and overall survival (OS) on univariate analysis. Analyses of CTC relationship to clinical characteristics and time to progression, changes on treatment, and multivariable analysis for relationship to OS will be presented. Conclusions: CTC were detected in over 60% of patients in this advanced HCC clinical trial cohort using a non-EpCAM, high-definition single cell assay, suggesting future potential for noninvasive molecular profiling of HCC.
Pharmacokinetic and pharmacodynamic analysis of preoperative therapy with dabrafenib alone and in combination with trametinib in patients with BRAF mutation–positive melanoma with metastases to the brain (BRV116521).
Authors: Michael A. Davies, Hussein Tawbi, Daniele Ouellet, Alexander J. F. Lazar, Jeffrey S Weinberg, Lisa H. Butterfield, Ronald L. Hamilton, Nduka Amankulor, Johnathan A. Engh, Brindha Shivalingham, Richard Kefford, Richard A Scolyer, Syed Mahmood, Lauren Elizabeth Richards-Peterson, Suzanne Swann, Michael C. Arbushites, Georgina V. Long, John M. Kirkwood
Journal: Journal of Clinical Oncology (2014)

TPS9112 Background: Dabrafenib (D) has clinical activity in patients (pts) with BRAF V600E/K mutation–positive melanoma brain metastases (MBM). The combination of D and trametinib (T) has increased activity in pts with BRAFV600E/K mutation–positive melanoma with extracranial metastases (ECM). It is not known whether the activity of D in MBM pts is due to blood-brain barrier penetration of the D parent compound or 1 (or more) of its active metabolites. In addition, the relationships between drug levels (parent compound and metabolites) achieved in MBM, and (1) peripheral exposure and (2) target inhibition in plasma and ECM are unknown. Methods: This international, open-label study will enroll up to 30 evaluable pts with stage IV BRAFV600E/K metastatic melanoma with untreated, resectable MBM (1-4 cm) and accessible ECM. Pts will be treated with D 150 mg twice daily (BID) for 7-14 days (cohort A, n=15) or D 150 mg BID + T 2 mg once daily for 7-14 days (cohort B, n=15), followed by resection of intracranial lesion(s) and biopsy or resection of accessible ECM(s). Blood (mandatory) and cerebrospinal fluid (CSF; optional) will also be collected on the day of surgery. If clinically indicated, pts in both cohorts will be treated with D + T starting 72 hours postsurgery until disease progression. MBM and ECM tumor tissue will be studied for levels of D (parent and metabolites) and T; expression and activation of pharmacodynamic markers and oncogenic signaling networks (protein, mRNA); DNA mutations and methylation; and immune cell infiltrates. Plasma and CSF will be studied for pharmacokinetics (PK). Blood will also be studied for circulating immune cells and cytokines. The primary objective is to assess PK in MBM, ECM and peripheral blood. Safety and efficacy will also be evaluated. The trial is currently open for accrual in the United States and Australia. Clinical trial information: NCT01978236.