tbuckley/cabot-search huggingface dataset:
Gemcitabine, vinorelbine and trastuzumab combination (GemVinT) as second-third line therapy for HER-2 overexpressing metastatic breast cancer (MBC)
Authors: A. Morabito, G. Carillio, P. Bonginelli, S. Amici, R. Longo, R. Sarmiento, M. Fanelli, S. C. Stani, D. Gattuso, G. Gasparini
Journal: Journal of Clinical Oncology (2004)

759 Background: The addition of Trastuzumab (T) to chemotherapy as first-line therapy is associated with significant improvement in response rate (RR), time to progression (TTP) and overall survival (OS), in HER-2 overexpressing MBC. However, the efficacy of T combined with chemotherapy is presently object of evaluation in MBC pretreated with chemotherapy ± T. We evaluated in this phase II study the safety and efficacy of GemVinT as second-third line therapy for HER-2 overexpressing MBC, pretreated with anthracyclines and/or taxanes and/or T. Methods: Eligible patients had HER-2 positive disease (ICH 2+ or 3+), PS ≤ 2, normal LVEF. Pts were treated with weekly T (4 mg/Kg on day 1 and then 2 mg/Kg), in combination with Gem (800 mg/m2) and Vin (25 mg/m2) on days 1 and 8, every 21 days. Pts were re-staged every 3 cycles. Results: 26 pts were enrolled onto the study, median age 58 years (range 41–74), median ECOG PS 0 (range 2–0), median number of metastatic sites 3 (range 1–8), prior first line chemotherapy 90% or second line 10%, prior T treatment (35%). Twenty-three patients are evaluable for toxicity and response. Treatment was well tolerated: grade 4 neutropenia in 2 pts, grade 3 thrombocytopenia in 1 pt, grade 3 anemia in 1 pt and grade 3 asthenia in 2 pts were observed. Nine pts achieved an objective response (1 complete response and 8 partial response: RR of 39.1%): 8/9 of the responsive pts were T-naïve and Herceptest 3+. Noteworthy, four objective responses were observed in patients with brain metastasis. Seven patients had stable disease (30.4%). Median TTP was 6 months (range 2–15), median OS was 9 months (range 5–28). Conclusions: GemVinT is a safe and active regimen in this subgroup of poor prognosis pts. The recruitment is ongoing. No significant financial relationships to disclose.
Early national dissemination of abiraterone and enzalutamide for advanced prostate cancer in Medicare Part D.
Authors: Megan Veresh Caram, Tudor Borza, Hye-Sung Min, Jennifer J. Griggs, David Christopher Miller, Brent K. Hollenbeck, Bhramar Mukherjee, Ted A. Skolarus
Journal: Journal of Clinical Oncology (2017)

35 Background: Abiraterone and enzalutamide are oral medications approved by the Food &amp; Drug Administration in 2011 and 2012 to treat men with advanced castration-resistant prostate cancer. Most men with advanced prostate cancer are over age 65 and thus eligible for Medicare Part D. We conducted a study to better understand the early dissemination of these drugs across the United States using national Medicare Part D data. Methods: We evaluated the number of prescriptions for abiraterone and enzalutamide by provider specialty and hospital referral region (HRR) using Medicare Part D and Dartmouth Atlas data. We categorized HRRs by abiraterone and enzalutamide prescriptions, adjusted for prostate cancer incidence, and examined factors associated with regional variation using multilevel regression models. Results: Among all providers who wrote prescriptions for abiraterone or enzalutamide in 2013 (n=2121), 87.5% were medical oncologists, 3.3% urologists, and 9.2% were listed as other provider specialties. Among those who prescribed either drug, 5% of providers were responsible for 75% of the claims for abiraterone, and 7% were responsible for 75% of the claims for enzalutamide. Some HRRs demonstrated low-prescribing rates despite average medical oncology and urology physician workforce density. Conclusions: The majority of prescriptions written for abiraterone and enzalutamide through Medicare Part D in 2013 were written by a minority of providers with marked regional variation across the United States. Better understanding the early national dissemination of these effective but expensive drugs can help inform strategies to optimize introduction of new, evidence-based advanced prostate cancer treatments.
Pharmacokinetic and pharmacodynamic correlations of flavopiridol in the treatment of chronic lymphocytic leukemia
Authors: M. A. Phelps, D. Wu, J. C. Byrd, T. S. Lin, K. A. Blum, L. Schaaf, A. J. Johnson, A. D. Colevas, M. R. Grever, J. T. Dalton
Journal: Journal of Clinical Oncology (2006)

12000 Background: Previous clinical trials with 72-hr and 24-hr infusions of flavopiridol were unsuccessful in producing responses in significant numbers of patients (pts). We utilized pharmacokinetic (PK) modeling to develop a 4.5 hr IV infusion strategy with a 30 mg/m 2 loading dose delivered in the first 0.5 hr. and an equal or increased dose delivered over the following 4 hrs to achieve target concentrations of 1.5 to 2.0 μM. This strategy was employed in a phase I study for single agent treatment of CLL. Methods: Plasma samples obtained from pts up to 48 hrs after the start of infusion were extracted and analyzed via LC/MS/MS for parent drug concentration. Non-compartmental analysis was employed in WinNonlin® to analyze flavopiridol plasma concentration vs. time data in 42 patients receiving one or two dosing levels. Patient biographical and response or pharmacodynamic (PD) data, including age, gender, previous treatment, hepatic and renal function, phosphate, albumin and lactate dehydrogenase (LDH) levels, lymph node status, and splenomegaly were collected. In addition, genomic analysis for single nucleotide polymorphisms (SNPs) in flavopiridol metabolizing and transporting enzymes along with correlation of PK, PD and genomic data is underway. Results: Complete PK data has been generated on 41 of the 42 patients treated in cohorts 1 through 3 and is summarized below. 14 of the 42 patients received an escalated dose in cycle 2. As anticipated, the escalated dose achieved concentrations within the targeted window 1.5 to 2.0 μM. This dosing strategy has resulted in response in 45% (19 of 42) of pts treated. Conclusions: PK modeling enabled accurate dose determination for achieving targeted clinical flavopiridol plasma concentrations. Ongoing analysis for correlation of modeled PK parameters with PD and pharmacogenomic data will further enhance our understanding of flavopiridol action in CLL and other malignancies. [Table: see text] No significant financial relationships to disclose.
Energy Balance Modulation Impacts Epigenetic Reprogramming, ERα and ERβ Expression, and Mammary Tumor Development in MMTV-neu Transgenic Mice
Authors: Emily L. Rossi, Sarah M. Dunlap, Laura W. Bowers, Subreen A. Khatib, Steven S. Doerstling, Laura A. Smith, Nikki A. Ford, Darcy Holley, Powel H. Brown, Marcos R. Estecio, Donna F. Kusewitt, Linda A. deGraffenried, Scott J. Bultman, Stephen D. Hursting
Journal: Cancer Research (2017)

Abstract The association between obesity and breast cancer risk and prognosis is well established in estrogen receptor (ER)-positive disease but less clear in HER2-positive disease. Here, we report preclinical evidence suggesting weight maintenance through calorie restriction (CR) may limit risk of HER2-positive breast cancer. In female MMTV-HER2/neu transgenic mice, we found that ERα and ERβ expression, mammary tumorigenesis, and survival are energy balance dependent in association with epigenetic reprogramming. Mice were randomized to receive a CR, overweight-inducing, or diet-induced obesity regimen (n = 27/group). Subsets of mice (n = 4/group/time point) were euthanized after 1, 3, and 5 months to characterize diet-dependent metabolic, transcriptional, and epigenetic perturbations. Remaining mice were followed up to 22 months. Relative to the overweight and diet-induced obesity regimens, CR decreased body weight, adiposity, and serum metabolic hormones as expected and also elicited an increase in mammary ERα and ERβ expression. Increased DNA methylation accompanied this pattern, particularly at CpG dinucleotides located within binding or flanking regions for the transcriptional regulator CCCTC-binding factor of ESR1 and ESR2, consistent with sustained transcriptional activation of ERα and ERβ. Mammary expression of the DNA methylation enzyme DNMT1 was stable in CR mice but increased over time in overweight and diet-induced obesity mice, suggesting CR obviates epigenetic alterations concurrent with chronic excess energy intake. In the survival study, CR elicited a significant suppression in spontaneous mammary tumorigenesis. Overall, our findings suggest a mechanistic rationale to prevent or reverse excess body weight as a strategy to reduce HER2-positive breast cancer risk. Cancer Res; 77(9); 2500–11. ©2017 AACR.
Abdominal pain after surgery
Authors: Zishan Sheikh, Mehtab Ahmad, Arvind Pallan
Journal: BMJ (2017)

A 24 year old woman presented with acute upper right abdominal pain radiating to the ipsilateral shoulder tip. She had undergone a laparoscopic cholecystectomy four days earlier without immediate complication. There was no other history of previous surgery. Initial observations showed she was tachycardic with normal blood pressure and low grade pyrexia. On examination she was tender in the epigastrium and upper right quadrant, with no signs of peritonism. There were no other notable examination findings. Her blood tests showed mildly raised liver transaminases and raised inflammatory markers, including a C reactive protein of greater than 200 mg/L. Urinalysis was unremarkable. A magnetic resonance pancreatocholangiogram was obtained for further evaluation (fig 1⇓). This showed an area of abnormal T2 hyperintense (bright) signal above the right lobe of the liver that was tracking under the right hepatic margin. Fig 1 T2 weighted coronal slice from magnetic resonance pancreatocholangiogram showing high signal around the liver, similar to the gastric contents (*)
AGRO100: The translation from lab to clinic of a tumor-targeted nucleic acid aptamer
Authors: K. M. Barnhart, D. A. Laber, P. J. Bates, J. O. Trent, D. M. Miller
Journal: Journal of Clinical Oncology (2004)

3126 Background: AGRO100 is nucleic acid aptamer that binds to nucleolin, a protein found within the nucleus in all cells, but uniquely expressed on the surface of tumor cells. Such expression is not tumor type specific. Binding of AGRO100 to the tumor surface nucleolin leads to internalization and a robust, anti-proliferative response. These early discovery studies have been combined with pharmacokinetic, toxicologic, and animal anti-tumor efficacy studies to validate the potential of both this drug and target prior to clinical testing. Methods: AGRO100 was injected i.v. in single or multiple doses, or as a continuous infusion, in rats, and pharmacokinetics in serum were measured via HPLC. Toxicity testing consisted of acute and continuous dosing in rats and dogs, followed by full necropsy, histopathology, clinical chemistry, and hematology analysis. Genotoxicity testing was performed in both mammalian chromosome aberration and bacterial reverse mutagenesis analysis. Anti-tumor efficacy studies were conducted in human xenograft tumor-containing nude mice, with both delay in tumor growth and survival measured as end-points. Results: All forms of AGRO100 administration lead to measurable serum circulating levels of drug that were dose dependent and lasted up to four hours post-administration. Acute dosing of up to 100 mg/kg or continuous infusion of up to 10 mg/kg/day lead to no drug-related toxicity in any system or organ. Genotoxicity of AGRO100 was negative compared to actual and historical controls. AGRO100 delayed the growth of SK-MES xenografts in a dose-dependent manner (day 15 post-treatment, 5 mg/kg = 41% tumor growth inhibition, 10 mg/kg = 56%). In an A2780 model of ovarian cancer, treatment with AGRO100 lead to a greater than 50% increase in survival time compared to vehicle or mock-treated animals. Conclusions: AGRO100 is effective, bioavailable, and safe enough to proceed with testing in human cancer patients in a Phase I trial. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aptamera, Inc. Aptamera Aptamera
Phase I dose escalation study of TG02 in patients with advanced hematologic malignancies.
Authors: Gail J. Roboz, Hanna Jean Khoury, Jamile M. Shammo, Mary Syto, Francis Burrows, Sara L. Zaknoen, Elias Jabbour
Journal: Journal of Clinical Oncology (2012)

6577 Background: TG02 is a novel multikinase inhibitor with a unique spectrum of activity, targeting both the cell cycle regulatory cyclin-dependent kinases (CDKs) 1 and 2 and the transcriptional regulators CDKs 7 and 9. TG02 also inhibits the emerging oncogenic MAPK ERK5 and the DNA damage response mediator CDK5. TG02 kills primary blasts from a variety of hematologic cancers and is curative in the MV4-11 model of FLT3-mutant AML. Methods: This is a first-in-man,single arm, open label, phase I dose escalation trial. The primary endpoints are dose-limiting toxicity (DLT), maximally tolerated dose (MTD ) and recommended phase 2 dose (RP2D). Patients (pts) ≥ 18 years with advanced hematological malignancies or newly diagnosed AML pts ≥ 65 years unfit for intensive therapy were enrolled onto daily (A) and intermittent (B, 5 days on 2 days off X 2 weeks) schedules. Pts had acceptable organ function and ECOG PS 1-2. Definition of DLT was G3-4 AST or ALT ≥7 days, G4 AST or ALT, G4 hyperbilirubinemia, any other NCI CTC G3-4 events not due to underlying disease. Dose levels on arm A were 10mg to 70mg and 15mg-150 mg on arm B. Results: Forty-five pts have received at least one dose of study drug. Median age was 66 years (range, 37-87) and 80% were ECOG 0-1. Disease types enrolled included: AML (80%), high-risk MDS (22%), and CML-BC (3%). The median number of previous regimens was 3 (range, 1-12). The MTD on arm A was defined at 50 mg daily based on 2 DLTs at the 70mg dose level (G4 hyperbilirubinemia, G4 fatigue). Enrollment to arm B has competed dose levels 15 (N=3), 30 (N=3), 50 (N=3), 70 (N=3), 100mg (N=3), and enrollment at 150mg is ongoing without DLT to date. Common drug related adverse events were nausea (42%), vomiting (23%), fatigue (18%), decreased appetite (15%), constipation and diarrhea (13% each). Preliminary PK demonstrated dose proportional increases in exposure and a T 1/2 , supporting once daily dosing. Conclusions: The MTD for TG02 has been determined for the daily schedule at 50mg. Enrollment continues on the intermittent schedule. Schedules of every other day and week on/week off dosing will also be evaluated.
A first-in-human phase I study of the oral Notch inhibitor LY900009 in patients with advanced cancer.
Authors: Shubham Pant, Suzanne Fields Jones, Carla Kurkjian, Jeffrey R. Infante, Kathleen N. Moore, Howard A. Burris, D. Scott McMeekin, Jonathan D. Kursar, Maciej Zamek-Gliszczynski, Emma Jones, Eunice Yuen, Edward Michael Chan, Johanna C. Bendell
Journal: Journal of Clinical Oncology (2012)

3008 Background: Notch signaling plays a critical role during stem cell self-renewal and is deregulated in multiple human cancers. The Notch pathway may be activated inappropriately by receptor mutation and overexpression as well as aberrant signals from the tumor microenvironment. LY900009 is a selective small-molecule inhibitor of gamma secretase, the enzyme that cleaves and thereby activates Notch receptors. Methods: Dose escalation was performed in cohorts of 3 patients (pts) using a modified continual reassessment method. LY900009 was taken orally thrice weekly (every MWF) during a 28-day cycle. Safety, pharmacokinetic, pharmacodynamic, and clinical endpoints were evaluated. Results: 22 patients received LY900009 across 6 dose levels: 2mg (3pts), 4mg (4pts), 8mg (3pts), 15mg (3pts), 30mg (6pts), and 60mg (3pts). The most common treatment emergent adverse events possibly related to LY900009 across all grades included diarrhea (27%), vomiting (23%), nausea (18%), fatigue (23%), anorexia (23%), hypophosphatemia (14%), and rash (18%). Dose-limiting toxicities of fatigue/N/V (G3) and diarrhea (G3) were seen in 2 patients, respectively, treated at 60mg. The maximum tolerated dose (MTD) was tentatively identified at 30mg. After a single dose, mean Cmax increased from 4 to 158 ng/ml and mean AUC 0-t(last) increased from 14 to 1160 ng-hr/ml. Both Cmax and AUC 0-t(last) increased in a dose-dependent manner. Elimination half-life of LY900009 was approximately 2-3 hrs. LY900009 inhibited plasma levels of amyloid-β peptide (a downstream product of gamma secretase) in a dose-dependent manner with 80-90% inhibition observed in the 30 and 60mg cohorts. In the 15mg cohort, one patient had colonic biopsy that showed markedly increased glandular mucin consistent with pharmacologic inhibition of the Notch pathway. Two patients (10%) with leiomyosarcoma and ovarian cancer received 4 cycles of therapy. Conclusions: LY900009 demonstrates acceptable safety and pharmacokinetics in patients with advanced cancer. Pharmacodynamic endpoints show pathway inhibition at tolerable doses. One more cohort at 45mg is ongoing to refine the MTD and will be followed by an expansion cohort for patients with ovarian cancer.
Immunocytochemistry staining for ER and PR in circulating tumor cells as compared to primary tumor or metastatic biopsy.
Authors: Farideh Z. Bischoff, Tony J Pircher, Tam Pham, Karina Wong, Eligie Villarin, Kevin Kalinsky, Julie Ann Mayer
Journal: Journal of Clinical Oncology (2012)

584 Background: Hormone receptor (estrogen receptor [ER] and progesterone receptor [PR]) status in all breast cancer patients is recommended for selection of treatment options. However, the analytical sensitivity of immunohistochemistry (IHC) in detecting low levels of ER/PR is often poor and is likely due to methodological variation. Because biopsy is not often feasible in all patients with recurrent and/or metastatic breast disease, circulating tumor cells (CTCs) offer an attractive alternative source of tumor tissue for determining ER/PR status and can be monitored more readily to enable a more effective course of treatment. Methods: Twenty mL of peripheral blood was collected prospectively from 15 patients diagnosed with late stage metastatic/recurrent breast cancer. CTCs were isolated using the microfluidic OncoCEE platform. A cocktail of antibodies was utilized for CTC capture and detection with an expanded anti-cytokeratin (CK) cocktail mixture and anti-CD45. ER/PR protein expression was assessed by immunocytochemistry (ICC) on the cells captured within the microchannels and compared to IHC performed on the primary tumor or metastatic biopsy. Results: CK+/CD45-/DAPI+ cells were located and assessed for ER/PR ICC. Among the 15 cases, a high concordance (13/15; 87%) in ER/PR status between IHC and ICC results was observed. Two cases were found to be discordant where one was positive by IHC and negative on the CTCs, and the other was negative by IHC and positive on the CTCs. However, both cases that were discordant had low numbers of detected CTCs. Conclusions: There is significant heterogeneity between ER/PR protein expression in CTCs and primary tumor/metastatic biopsy, and this status may change over time due to therapy. ER/PR ICC on CTCs from peripheral blood using the OncoCEE platform is shown to be feasible with high concordance (87%) in ER/PR status between primary tumor/metastatic biopsy (by IHC) and CTCs (by ICC). The significance of heterogeneity at the ER/PR protein level in CTCs ascertaining to the prognosis and predictive response to anti-estrogen therapy needs further evaluation in larger prospective clinical trials.
Phase I/II trial of IV topotecan (TOPO) in combination with whole brain radiation therapy (WBXRT)
Authors: M. A. Spear, A. Mirmiran, E. McClay
Journal: Journal of Clinical Oncology (2004)

1553 Background: Durable intracranial control of brain metastases remains an issue subsequent to WBXRT. Topotecan (TOPO) crosses the blood-brain barrier and has been shown to exhibit synergistic cytotoxicity with XRT. We thus conducted a phase I/II trial to determine the toxicities and estimate efficacy TOPO and WBXRT. Methods: Eligible patients had radiologically detectable evidence of brain metastases. Patients received 30 Gy WBXRT given in 10 fractions. TOPO was administered as a 30 min. IV infusion within 60 min prior to XRT. In phase I, patients were treated in groups of 3 at each TOPO dose level. The dose of TOPO started at 0.4 mg/m2/day and was escalated in increments of 0.1 mg/m2/day. A total of 9 patients were studied at UCSD and the outcomes of these patients reported below. Results: The dose-limiting toxicity proved to be Grade IV neutropenia at 0.6 mg/m2. Thus, 0.5 m/m2 came to be established as the MTD and was used in the phase II portion of the trial. Two of the 9 patients experienced grade IV (22%), and 1 each had Grade III (11%), Grade II (11%), and Grade I (11%) neutropenia. 2 patients experienced Grade IV (22%),1 had Grade III (11%), and 2 experienced Grade I (22%) thrombocytopenia. 5 patient sdemonstrated Grade I elevated liver enzymes (56%), and 1 had Grade II (11%). Other observed toxicities included nausea, vomiting, constipation, and skin rash. Alopecia and radiation dermatitis (Grade I) were seen within the expected time frame and severity as for WBXRT alone. Only Grade I neurologic events were observed in 2 patients (22%) (headache and weakness). 1/9 patients showed a response to treatment, and that was partial (OR 11%). 3 had Stable Disease (33%), and 4 experienced Progressive Disease (44%). Median Progression-Free Survival was 60 days; Median Overall Survival was 102 days. Conclusions: TOPO concomitant to WBXRT is tolerable. This regimen has the additional advantage of providing systemic treatment while whole brain radiation is in progress. Although response and survival outcomes in this small study are not higher than expected from historical controls, efficacy was not a primary end point, and thus larger studies would be useful investigate this issue. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline
Biomarkers of Cytokine Release Syndrome and Neurotoxicity after CD19 CAR-T Cells and Mitigation of Toxicity By Cell Dose
Authors: Cameron J Turtle, Kevin A Hay, Gust Juliane, Laila-Aicha Hanafi, Daniel Li, Colette Chaney, Shelly Heimfeld, Stanley R Riddell, David G. Maloney
Journal: Blood (2016)
Preliminary data of GOIM 2107 study: Multicenter phase II study of sequential hormonotherapy with anastrozole/exemestane in metastatic breast disease
Authors: R. V. Iaffaioli, R. Formato, A. Tortoriello, A. Pisano, S. Del Prete, S. Cigolari, V. Pisconti, L. Manzione, F. Giotta
Journal: Journal of Clinical Oncology (2004)

820 Background: The present study was designed to evaluate the overall response as primary endpoint, TTP, clinical benefit, toxicity and overall survival as secondary end-point. Methods: We enrolled patients with advanced breast cancer or primary tumour or locally advanced not resectable, with positive or unknown ER/PgR, with interrupted TMX treatment and physiological, pharmacological, radiotherapeutic or surgical menopause. Treatment: Anastrozole 1 mg/die up to progression, followed by exemestane, 25 mg/die up to 2nd progression. Recruitment time: 12 months. Patient characteristics: 103 pts were recruited, median age 64 (range 30–93) with bone metastases (52), skin (11), lymphonodes (18), lung (18), liver (18), soft tissue (20), pleural effusion (5), and PS 0 (58%), PS 1 (35%), PS 2 (17%) and 42 months median DFS. Results: 94 valuable pts; CR 9 (9.6%), PR 20 (21.27 %), MOR 29 (30.87%), NC 23 (24.47%), clinical benefit 52 (55.34%), TTP range 6–24 months, median time follow-up 18.6 months. In 38 pts treated in second line with Exemestane were evidenced 3 PR (7.9%) and 15 NC (39.47%). Conclusions: These actual data are comparable with literature results. Preliminary data regarding MRD, clinical benefit and TTP seem very promising. The next update will be performed at the February 2004. No significant financial relationships to disclose.