tbuckley/cabot-search huggingface dataset:
Phase I dose escalation study of bortezomib in combination with lenalidomide in patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML).
Authors: Philip C. Amrein, Eyal C. Attar, Amir Tahmasb Fathi, Steven L McAfee, Martha Wadleigh, Daniel J. DeAngelo, David P. Steensma, Julia Foster, Richard M. Stone, Donna S. Neuberg, Karen K. Ballen
Journal: Journal of Clinical Oncology (2012)

6621 Background: Both bortezomib (Bz) and lenalidomide have clinical activity in patients with MDS and AML. We conducted a phase I dose escalation study to determine the maximal tolerated dose (MTD) of Bz in combination with lenalidomide. Methods: Patients with MDS (IPSS score ≥ 0.5 or therapy-related) received Bz by IV bolus on Days 1, 4, 8, and 11 and lenalidomide 10 mg/day PO on Days 1-21 in 28 day cycles for up to 9 cycles. Three doses of Bz were tested (0.7, 1.0, or 1.3 mg/m 2 ). Cohorts consisted of 3-6 patients; the dose of Bz was escalated if there were &lt; 2 dose limiting toxicities (DLTs). Growth factor support and transfusions were permitted. Dose limiting toxicities (DLTs) were assessed during the first cycle and were defined as severe neutropenia (absolute neutrophil count ≤ 250/ul), thrombocytopenia (platelet count &lt; 10,000/ul), grade ≥ 2 neurotoxicity, or other grade ≥ 3 non-hematologic toxicity. Following determination of the MTD, enrollment opened to patients with relapsed and refractory AML and those with untreated high risk disease for whom induction therapy was not indicated. Responses were assessed by IWG 2006 criteria for MDS and IWG 2003 criteria for AML. Results: 23 patients (14 men) were enrolled; one patient was inevaluable due to disease progression prior to starting protocol therapy. The median age was 73 years (range 54-87). There was 1 DLT observed, neutropenia, in 6 patients treated with 1.0 mg/m 2 Bz and no DLTs at 0.7 or 1.3 mg/m 2 . The median number of cycles was 2 (range 2-9). Grade ≥ 3 toxicities possibly attributable to the treatment at any dose level were: anemia (2), thrombocytopenia (10), leukopenia (3), infection (1), rash (2), dyspnea (1), dizziness (1), hypotension (1), pneumonia (2) and neuropathy (1). Among the 14 patients with MDS, 1 patient with RARS experienced a CR and 2 with RAEB-2 experienced marrow CR (mCR). Among the 8 patients with AML, there was 1 CR. Conclusions: The maximal tested dose of Bz (1.3 mg/m 2 ) in combination with lenalidomide is safe. Responses were seen in MDS and high risk AML. Future testing of this regimen is planned.
Novel combination of toll-like receptor (TLR)-7 agonist imiquimod and local radiotherapy in the treatment of breast cancer chest wall recurrences or skin metastases.
Authors: Maxwell Dale Janosky, Sandra Demaria, Yelena Novik, Ruth Oratz, Amy Tiersten, Judith D Goldberg, Ena Wang, Francesco Marincola, Silvia Formenti, Sylvia Adams
Journal: Journal of Clinical Oncology (2013)

TPS3122 Background: To assess the local and systemic effects of the novel combination of local radiotherapy (RT) with imiquimod (IMQ) applied topically to breast cancer metastatic to skin, and measure immunologic correlates (clinicaltrials.gov NCT01421017). Breast cancer is the 2nd most common tumor to metastasize to the skin. Current therapies for unresectable skin lesions are rarely curative. Patients ultimately die of visceral metastases, necessitating more effective therapies. IMQ, a synthetic TLR-7 agonist has profound effects on the tumor immune microenvironment and can lead to regression of cutaneous breast cancer metastases (Adams, Clin Ca Res, 2012). The trial was designed based on accumulated data supporting the synergy of combined RT/immunotherapy (Formenti, JNCI, 2013), and pre-clinical data demonstrating the synergy of topical IMQ and local RT in a mouse model of mammary adenocarcinoma which ulcerates through the skin, and mimics a chest wall recurrence. In the mouse model, the combination was superior with complete regressions of the treated tumors, responses at untreated sites and improved survival (Dewan, Clin Ca Res, 2012). Methods: Eligibility: patients with biopsy-confirmed breast cancer, measurable disease and skin metastases, ECOG PS 0-2 and adequate organ/marrow function. RT is delivered to 1 area of skin metastases in 5 fractions of 6 Gy (days 1, 3, 5, 8, 10). IMQ cream is applied topically 5 nights/week for 8 weeks, beginning on day 1. Following a brief phase I portion to allow dose optimization in the event of unanticipated adverse events (3-3 design), the phase II study evaluates efficacy with 25 additional patients planned. Primary endpoint is the response rate in untreated distant metastases, assessed by immune-related response criteria. The local tumor responses and safety of the combination will also be determined; tumor biopsies will be studied for immune-mediated rejection signatures and peripheral lymphocytes for antigen-specific T and B cell responses. To date, 10 patients have been enrolled. The phase I portion has been successfully completed with 6 patients without DLT. Phase II enrollment has begun. Clinical trial information: NCT01421017.
Enhancing accurate prediction of survival outcomes and aiding decision making in malignant pleural mesothelioma (MPM) using a three-item index from the LCSS-meso PRO measure: Results from a randomized 444 patient (pt) prospective trial.
Authors: James Thomas Symanowski, Richard J. Gralla, Patricia J Hollen
Journal: Journal of Clinical Oncology (2014)

7588 Background: Accurate prediction of survival of patient groups is required for appropriate trial design, while attention to the effect of treatment on PROs can help guide individual patient management. No pt reported factor is routinely used for these purposes, as performance status (PS) is not pt rated; nor is PS change known to guide accurately treatment changes. Methods: This study analyzes data from the prospective MPM EMPHACIS study comparing pemetrexed + cisplatin with cisplatin in 444 pts. LCSS-meso was given to all pts. An index of the 3 global LCSS items (symptom distress, activity level, quality of life) was correlated with survival outcomes. Results: Baseline and 6 week LCSS results and survival data were available for 83% of pts. Survival results were analyzed for differences for those scoring less than or greater than the median for each LCSS symptom and global factor. Unlike individual symptoms which are found only in subsets of pts, the 3 LCSS pt reported global items each apply to all pts. Median survival differences above (positive factor) or below (negative factor) medians for each global item varied by < 6 months. An index was created using the number of negative factors, 0 to 3, based on scoring less than the median for each of these 3 factors; see the Table. A landmark survival analysis was done comparing survival of those with a total LCSS 3-item score at 6 weeks which had fallen by > 20% since baseline vs all other pts. Median survivals = 7.8 months vs 13.3 months (HR 1.91, p <.001). Conclusions: This 3-item index, based entirely on PROs, has strong predictive properties. It can help improve trial design and analysis. For all patients, a fall by > 20% in the total 3-item score after just 2 cycles of chemotherapy allows rapid, convenient and inexpensive identification of a large group of patients (28%) with poorer survival on their current chemotherapy, which can assist in clinical decision making. # of negative PRO factors % of pts (N = 444) Median survival: mos. Survival: 1 year HR* 0 35% 14.6 61% 0.371 (p<.001) 1,2 33% 10.8 45% 0.616 (p<.001) 3 32% 7.4 26% - - *Reference group is 3 negative PRO factors.
First-in-human study of FLX925, an orally administered FLT3/CDK4/CDK6 inhibitor, in subjects with relapsed or refractory acute myeloid leukemia (AML).
Authors: Naval Guastad Daver, Marina Konopleva, Holbrook Edwin Kohrt, Jordan Scott Fridman, Dan Johnson, Juan C. Jaen, Hagop M. Kantarjian, Jorge E. Cortes
Journal: Journal of Clinical Oncology (2015)

TPS7098 Background: Acquired mutations in oncogenic kinases remains an obstacle between valid therapeutic hypotheses and meaningful patient benefit. The inhibition of FLT3 can be efficacious in AML patients, particularly in FLT3-ITD mutated cancers. However, relapse is common and frequently associated with the acquisition of secondary resistance mutations in FLT3. FLX925 is a next-generation kinase inhibitor that was prospectively designed to address or avoid common mechanisms of resistance to earlier FLT3 inhibitors, with its unique binding mode and potent activity against CDK4/CDK6 (Keegan et al, Mol Cancer Ther, 2014). FLX925 retains its cellular potency against clinically relevant secondary resistance mutations in FLT3 that occur with quizartinib or sorafenib treatment. In addition, FLX925 potently inhibits CDK4/CDK6, central components of the cell cycle machinery. This unique profile may reduce the emergence of resistant clones and extend the therapeutic potential of FLX925 to other malignancies dependent on these pathways (e.g., MCL). These data suggest the unique profile of FLX925 makes it an ideal inhibitor for the treatment of cancers driven by FLT3 signaling, such as AML. Methods: This open label, sequential-group, dose escalation and cohort expansion study includes adult patients diagnosed with relapsed or refractory AML. Eligible patients need to have failed prior induction therapy or relapsed within 12 months of prior therapy. During cohort expansion, at the RP2D, patients will be enrolled into 3 cohorts: subjects with a FLT3 ITD or kinase domain mutation with (Cohort A) or without (Cohort B) prior FLT3 inhibitor treatment, or patients without a FLT3 mutation at screening (Cohort C). The primary objectives of the study are to characterize the safety and tolerability of twice-daily, oral FLX925. Key secondary objectives are to evaluate the pharmacokinetic (PK) profile, pharmacodynamics (PD) effects, and the magnitude and duration of antitumor activity with FLX925, using standard criteria. A Simon 2-stage mini-max approach will be used to test the null hypothesis based on the CRc rate. This trial (NCT02335814) is currently enrolling patients. Clinical trial information: NCT02335814.
Changes in renal function following treatment for ovarian cancer.
Authors: Matthew James Butler, Azadeh Stark, Lester Kirchner, Radhika Gogoi, Joseph B Leader, Meredith W Lewis, Franco Muggia
Journal: Journal of Clinical Oncology (2013)

5581 Background: Among women treated for Epithelial Ovarian Cancer (EOC), new or worsening renal dysfunction has been observed but not systematically studied. We conducted a retrospective cohort study to estimate the rate of decline in renal function following a diagnosis of EOC, compared with the rate of decline among the same patients prior to diagnosis. Methods: We study a historical cohort of women diagnosed with EOC between 1/1/2000 and 12/31/2011, who received health care services within a large community medical center. Data were retrieved from institutional electronic records. We develop a Generalized Estimating Equations (GEE) model to quantify changes in estimated glomerular filtration rate (eGFR) over time, with the date of EOC diagnosis as the reference point (time zero). All analyses were conducted using SAS version 9.2 (SAS Institute Inc., Carey, NC). Results: The cohort is comprised of of 323 women. At diagnosis, the mean age was 63.4 (± 13.5) years and the mean eGFR was 81.0 (± 22.7). There were 74 (22.9%) patients carrying a diagnosis of hypertension, 25 (7.7%) with diabetes, and 73 (22.6%) who were clinical obese. Prior to EOC diagnosis the decline in mean monthly eGFR was not significant (- 0.052, 95% CI -0.11-0.009, p = 0.092), after controlling for age, obesity, hypertension, and diabetes. This monthly decline increased by almost 4-fold (p = 0.0007) subsequent to EOC diagnosis. To discern the potential effect of chemotherapy on renal function, we conducted a secondary analysis on the 120 women for whom detailed chemotherapeutic data is available. For women who received standard first-line chemotherapy (paclitaxel and carboplatin) the rate of eGFR decline increased 10-fold (-0.025 vs. -0.25, p = .0066) relative to their baseline rate of decline. For those who received other regimens, the increase was 11.4 times (-0.025 vs. -0.286, p =.0011); this was not significantly higher than those receiving the standard regimen (p = 0.72). Conclusions: This ongoing study suggests that women treated for EOC suffer an accelerated rate of renal function decline, independent of major comorbid conditions, that is therefore attributable to the disease and/or its treatment.
Triple-negative breast cancer: Neoangiogenesis and hormonogenesis in tumor and surrounding tissues.
Authors: Yuliana Sergeyevna Shatova, Elena Mikhaylovna Frantsiyants, Valeria Bandovkina, Yulia A. Pogorelova, Ludmila Petrovna Kuchkina, Lyudmila Gennadiyevna Sergostyants, Marina Ilyinichna Vereskunova
Journal: Journal of Clinical Oncology (2015)

e12089 Background: Triple-negative breast cancer (TNBC) is characterized by the absence of receptors for estrogen, progesterone or HER2, aggressive clinical course and poor response to standard therapy and is mainly observed in young women. In TNBC pathogenesis there is a high probability of genotoxic variant of hormonal cancerogenesis, when estrogens and their metabolites 16-OHE1 can have a direct DNA damaging effect. The purpose of this study was to analyze some characteristics of estrogen metabolism in tumor and perifocal zone in patients of different reproductive status with TNBC. Methods: 15 menopausal patients (mean age 72±3.4 years), 15 premenopausal patients (mean age 52.1±2.7 years) and 15 young patients with normal reproductive function of the ovaries (mean age 35.6±3.2 years) were examined. Levels of estradiol (E2), estrone (E1), 2-hydroxyestrogen (2-OHE) and 16-hydroxyestrone (16-OHE1) were detected by the ELISA method in tumor and perifocal zone, E1/E2 ratio was calculated. The values in healthy breast tissue obtained during breast reduction surgery served as the control. Results: E1/E2 increase by 2.5-6.5 times was found in perifocal zone of TNBC patients in comparison with the ratio in intact tissues. In older women, E1/E2 in tumor was higher than in perifocal zone, while in women of reproductive and premenopausal age differences between tumor and perifocal zone were not detected. 2-OHE formation both in tumor and perifocal zone decreased by 1.5-1.9 times with the “aggressive” 16-OHE1 increased by 1.5 times, in comparison with intact breast tissue. Conclusions: Prevalence of E1 and 16-OHE1 over E2 and 2-OHE was detected in tumor and perifocal zone of TNBC patients. Similarity between estrogen metabolism in tumor and in perifocal zone of young TNBC patients may be the evidence of vanishing of metabolic borders and more aggressive clinical course of the disease.
A randomized, double-blind phase II trial of exemestane plus MM-121 (a monoclonal antibody targeting ErbB3) or placebo in postmenopausal women with locally advanced or metastatic ER+/PR+, HER2-negative breast cancer.
Authors: Michaela Jane Higgins, Catherine Doyle, Stefan Paepke, Analia Azaro, Miguel Martin, Vladimir Semiglazov, Iya Smirnova, Dmitriy Krasnozhon, Alexey Manikhas, Wael A. Harb, Lawrence C. Panasci, Joseph Pearlberg, Gavin MacBeath, Rachel Nering, Paul E. Goss, Kathy Miller
Journal: Journal of Clinical Oncology (2014)

587 Background: Ligand-driven ErbB3 signaling has been implicated as a mechanism of resistance to conventional therapies across multiple malignancies, including endocrine resistant metastatic breast cancer (mBC). Here we present results of a trial evaluating MM-121 (M) or placebo (P) in combination with exemestane in postmenopausal women with ER/PR+ HER2-negative mBC. Methods: This study enrolled women with locally advanced or mBC who had failed adjuvant therapy or progressed in the metastatic setting. The primary endpoint was progression free survival (PFS) and the study was powered to detect a HR of < 0.5. Secondary and exploratory analyses included overall survival (OS), safety, and analyses of a pre-specified set of mechanistically-linked biomarkers ((BM), heregulin, betacellulin, EGFR, ErbB2, and ErbB3) in archived tissues. Results: 115 randomized and treated patients (56 (M), 59 (P)) were included in safety and efficacy analyses. Baseline demographics and disease characteristics were balanced. At the time of the analysis, 92 (80%) patients (78.6% (M), 81.4% (P)) had discontinued treatment, mainly due to progressive disease (66.1% (M), 76.3% (P)). PFS was analyzed after 84 events (38 (M), 46 (P)). The median PFS was 15.9 weeks (M) vs. 10.7 weeks (P), with a stratified hazard ratio (HR) of 0.772 (95% CI [0.496- 1.201]), p=0.249). OS data were immature at the time of the primary analysis (29 events: 11 (M), 18 (P)), with a stratified HR of 0.436 (95% CI [0.197 – 0.966]). In patients positive for two of the pre-specified BMs (31%: 17 of the 55 patients with BM data), the HR for PFS was 0.32 (95% CI [0.10-1.00]). Common adverse events (AEs, >20%) of any grade and causality (M vs. P), were diarrhea (50% vs. 23.7%), nausea (28.6% vs. 23.7%), fatigue (23.2 % vs. 23.7%), and arthralgia (17.9% vs. 20.3%). Conclusions: The addition of MM-121 to exemestane did not significantly prolong PFS in the unselected population, although the HR appears to favor the MM-121 arm. The biomarker findings were consistent with preclinical hypotheses, as well as an independently conducted Phase 2 study in platinum resistant ovarian cancer. Clinical trial information: NCT01151046.
Abstract 401: Shortening of Action Potential Duration With Increased Work in Contracting Rabbit Heart
Authors: Kara E Garrott, Anastasia Wengrowski, Hanyu Zhang, Jack Rogers, Matthew Kay
Journal: Circulation Research (2015)

Studying heart function in contracting hearts at higher workloads provides crucial knowledge of cardiac performance in high-stress situations. Ratiometric optical mapping of fully loaded hearts is a novel method to study electrical activity while replicating in vivo energy consumption. We predict that an imbalance between energy supply and demand during increased work and hypoxia will manifest in shortened action potential duration (APD), especially in the more physiologically-relevant bi-ventricular (BiV) working heart. Rabbit hearts were perfused with oxygenated Krebs-Henseleit solution in unloaded Langendorff and fully-loaded BiV mode. Epicardial action potentials (APs) were measured using optical mapping of Di-4-ANEPPS. Excitation ratiometry using 450 and 505 nm illumination on alternate camera frames together with motion tracking removed motion artifact. Aortic pressure, left atrial preload, and LVDP was measured. A range of workloads were studied by pacing at 330, 220, and 170 ms cycle length (CL). Gradual hypoxia was induced by bubbling with N2 gas. In Langendorff mode, the APD was 137.67±4.29 ms, 113.44±7.89 ms, and 106.44±0.44 ms at CL of 330ms, 220ms, and 170ms, respectively, while in BiV mode, the APD was 106.56±13.03 ms, 78.00±2.33 ms, and 69.33±0.77 ms. Aortic pressure dropped from NSR in BiV hearts by 1.26% at 330ms, 4.11% at 220ms, and 11.65% at 170ms CL. Shortening of APD, independent of restitution, with increasing HR indicates an imbalance of energy supply and demand with greater workload. KATP channels are implicated. This novel method of optical mapping reveals important implications of electrophysiological changes during high-stress situations.
<i>ATM</i> Deficiency Is Associated with Sensitivity to PARP1- and ATR Inhibitors in Lung Adenocarcinoma
Authors: Anna Schmitt, Gero Knittel, Daniela Welcker, Tsun-Po Yang, Julie George, Michael Nowak, Uschi Leeser, Reinhard Büttner, Sven Perner, Martin Peifer, Hans Christian Reinhardt
Journal: Cancer Research (2017)

Defects in maintaining genome integrity are a hallmark of cancer. The DNA damage response kinase ATM is frequently mutated in human cancer, but the significance of these events to chemotherapeutic efficacy has not been examined deeply in whole organism models. Here we demonstrate that bi-allelic Atm deletion in mouse models of Kras-mutant lung adenocarcinoma does not affect cisplatin responses. In marked contrast, Atm-deficient tumors displayed an enhanced response to the topoisomerase-II poison etoposide. Moreover, Atm-deficient cells and tumors were sensitive to the PARP inhibitor olaparib. This actionable molecular addiction to functional PARP1 signaling was preserved in models that were proficient or deficient in p53, resembling standard or high-risk genetic constellations, respectively. Atm deficiency also markedly enhanced sensitivity to the ATR inhibitor VE-822. Taken together, our results provide a functional rationale to profile human tumors for disabling ATM mutations, particularly given their impact on PARP1 and ATR inhibitors. Cancer Res; 77(11); 3040-56. ©2017 AACR.
Continuing single-agent capecitabin as maintenance therapy after induction of XELOX (or FOLFOX) in first-line treatment of metastatic colorectal cancer.
Authors: Rui-hua Xu, Yu-hong Li, Huiyan Luo, Wei Wang, Zhiqiang Wang, Xia Yuan, Fenghua Wang, Dong-sheng Zhang, Dong Ma, Da Ren Lin, Jun Jia, Xiao-hua Hu, Jie Wen Peng
Journal: Journal of Clinical Oncology (2015)

3580 Background: Colorectal cancer (CRC) is one of the most common malignant tumors. All advanced CRC will progress after first-line treatment. Therefore, it is emergent to seek an efficient and low toxic maintaining regimen to prolong progression free survival (PFS). Some clinical researches demonstrated that maintaining treatment followed first-line treating could extend PFS. Our previous non-randomized small sample study indicated that patients receiving first-line treatment of XELOX followed by capecitabine as maintaining therapy had significantly prolonged median time to progression (TTP). Therefore, we plan to initiate the first randomized study to evaluate the efficacy and safety of maintenance therapy with capecitabine following induction of (XELOX) or (FOLFOX) versus observation until progression in first-line therapy in metastatic CRC. Methods: This is a multi-center, randomized phase III study. Patients who received 18-22 weeks chemotherapy with XELOX or FOLFOX and achieved objective response or stable disease were randomized 1:1 to received maintenance therapy of capecitabine (1,000 mg/m2 twice a day from days 1–14, every 3 weeks) or only observation until disease progression. The primary endpoint was PFS, which was defined as the interval between initial treatment and the first documentation of disease progression or death. Results: The intent-to-treat population comprised 275 patients (capecitabine maintenance, n= 136; observation, n=139); there were no significant differences in baseline characteristics. The median follow-up was 29.0 months (range, 0–62.5 months). Median PFS in capecitabine maintenance group was significantly longer than the observation group (11.0 months [95% confidence interval (CI) 9.45 to 12.5m] versus. 8.0months, [95%CI 7.2m to 8.8m]; p < 0.001). The most common grade 3 or 4 toxicities in capecitabine maintenance versus observation were neutropenia, hand–foot syndrome, and mucositis. Conclusions: Maintenance therapy with capecitabine single agent following induction of XELOX or FOLFOX improved the outcome in patients with mCRC, as compared with the observation group. Clinical trial information: NCT02027363.