tbuckley/cabot-search huggingface dataset:
Rovalpituzumab tesirine (Rova-T) as a therapeutic agent for Neuroendocrine Prostate Cancer (NEPC).
Authors: Loredana Puca, Verena Sailer, Kaitlyn Gayvert, Kumiko Isse, Michael Sigouros, David M. Nanus, Scott T. Tagawa, Juan Miguel Mosquera, Laura Saunders, Himisha Beltran
Journal: Journal of Clinical Oncology (2017)

5029 Background: TheNotch ligand Delta like ligand 3 (DLL3) is aberrantly expressed on the cell surface of small cell lung cancer (SCLC), and the DLL3-antibody drug conjugate, Rova-T, has shown promise for patients with SCLC (Rudin et al, Lancet Onc 2017). NEPC is a late stage subtype of castration resistant prostate cancer with limited therapeutic options. Based on clinical and molecular similarities with SCLC, we investigated expression of DLL3 and the use of Rova-T in NEPC. Methods: We evaluated mRNA and/or protein expression of DLL3 in a cohort of 395 patients (535 samples) ranging from benign prostate (BEN), localized prostate adenocarcinoma (PCA), castration resistant adenocarcinoma (CRPC), and NEPC and correlated with pathologic and genomic features. Prostate cancer cell lines and patient-derived organoids were treated with Rova-T (SC16LD6.5) in vitro and in vivo. Results: DLL3 was expressed at the mRNA and/or protein level in 0/143 BEN (0%), 4/266 PCA (1%), 8/76 CRPC (10%), 33/50 NEPC (66%). DLL3 IHC was of higher intensity in NEPC and co-localized with classical NE marker expression (SYP, CGA). DLL3 was amongst the most differentially expressed genes by RNA-seq in NEPC versus CRPC (p = &lt; 0.0001, fold change = 71), correlated with ASCL1 expression (r = 0.88) and RB1 genomic loss (83%), and inversely with AR expression. Although treatment with the Notch inhibitor DAPT suppressed Notch target gene expression in NEPC, DAPT did not have significant effect on cellular proliferation. siRNA knockdown of DLL3 or DAPT did not alter AR signaling or NE markers. Rova-T (SC16LD6.5) was active in DLL3-positive NEPC cell lines with an IC50 of 580pM compared to the control IgG1LD6.5 (IC50 = 6.3nM), whereas CRPC lines were insensitive. Conclusions: DLL3 is a cell surface protein aberrantly expressed in the majority of NEPC and a subset of CRPC, and is not expressed in primary prostate cancer or benign tissues. The DLL3 antibody-drug conjugate Rova-T demonstrates preferential preclinical activity in NEPC compared to prostate adenocarcinoma. These data support further investigation of Rova-T as a potential therapeutic agent for NEPC. A phase I trial with dedicated NEPC arm is currently accruing patients (NCT02709889).
Objective metrics of patient activity: Use of wearable trackers and patient reported outcomes in predicting unexpected healthcare events in cancer patients undergoing highly emetogenic chemotherapy.
Authors: Alexander S. Martin, Roger Wilson Boles, Luciano Nocera, Anand Kolatkar, Marcella May, Zaki Hasnain, Naoto T. Ueno, Sriram Yennu, Angela Alexander, Aaron Mejia, Ming Li, Frankie A. Cozzens Philips, Paul K. Newton, Joan Broderick, Cyrus Shahabi, Peter Kuhn, Jorge J. Nieva
Journal: Journal of Clinical Oncology (2018)

6519 Background: Functional status and predictors that identify those cancer patients at risk for unplanned hospitalization can have broad implications for the health care system and clinical trials. We evaluated the feasibility of monitoring physical activity (PA) using wearable activity trackers in cancer patients on highly emetogenic chemo as well as potential correlations between PA and unplanned healthcare events (UHE) and ECOG scores. Methods: This study was conducted as a multi-institutional single arm observational clinical trial of 65 patients with solid tumors undergoing highly emetogenic chemo based on Hesketh classification. We measured PA by analyzing daytime hourly metabolic equivalents (1 MET = resting metabolic rate) from 10 AM - 7 PM over 60 days via Microsoft band 2. Patient reported outcome data was collected using smartphone apps. UHE were collected by review of medical records over the 60 days of band wear plus 90 days of clinical follow up. Results: Data was successfully captured from 41 of the 65 activity trackers. Patients were compliant with wearing the activity trackers for > 7 of 9 total hrs on 67.7% of study days. Only 9 out of 41 patients exhibited > 60 hours of non-sedentary activity, defined as > 1.5 METs, over the 60-day band wear period. Mean step counts/day were similar between higher and lower PA groups at 2564 steps/d and 2261 steps/d respectively. 9 patients with > 60 hrs of 1.5 METs had significantly fewer UHE compared to the 32 patients with < 60 hrs of 1.5 METs (p = 0.02). The physician reported ECOG scores had no correlation with PA or UHE. Conclusions: In solid tumor patients undergoing highly emetogenic chemo regimens, activity trackers are feasible and identify those patients with a profile of lower activity that predicts UHE. Incorporation of activity trackers has the potential to identify patients who are at need for interventions to prevent hospitalization and may also predict the subset of patients enrolled in clinical trials who are more likely to record serious adverse events.
A randomized phase 2 trial of veliparib (V), radiotherapy (RT) and temozolomide (TMZ) in patients (pts) with unmethylated MGMT (uMGMT) glioblastoma (GBM): Feasibility and safety outcomes (the VERTU study).
Authors: Mustafa Khasraw, Kerrie Leanne McDonald, Mark Rosenthal, Zarnie Lwin, David M. Ashley, Helen Wheeler, Elizabeth Barnes, Eng-Siew Koh, Matthew C Foote, Michael Buckland, Lauren Fisher, Robyn Leonard, Merryn Hall, Sonia Yip, John Simes
Journal: Journal of Clinical Oncology (2018)

2045 Background: TMZ offers minimal benefit in uMGMT GBM pts. V is synergistic with both RT and TMZ in preclinical models, safe when combined with either RT or TMZ clinically but the triplet (V+RT+TMZ) is poorly tolerated. This study examines a novel approach to patients with uMGMT GBM. Methods: VERTU is a randomized Phase 2 trial comparing Arm A (experimental arm) = RT (60gy/30 fractions) + V (200mg BID) followed by TMZ (150-200mg/m2D 1-5) + V (40mg bid, D 1-7) every 28 days for 6 cycles vs Arm B (Standard of care) = RT (60gy/30 fractions) + TMZ (75mg/m2 daily) followed by TMZ (150-200mg/m2D 1-5) every 28 days for 6 cycles in pts with newly diagnosed uMGMT GBM. The study aims to randomize 120 pts (2:1 to the experimental arm). The primary endpoint is 6 months Progression Free Survival (6PFS) with multiple secondary and tertiary endpoints. Evaluation of feasibility and safety was planned after completion of RT in the first 60 pts (Stage 1). Acceptable feasibility and safety criteria for study continuation was defined as ≥70% of pts on the experimental arm completing ≥70% of the planned treatment with ≤30% of pts having any ≥ Grade (G) 3 Adverse Events (AEs). (ANZCTR #ACTRN12615000407594) Results: 60 pts have been randomized in Stage 1 (Arm A = 39, Arm B = 21). Patient characteristics (age, gender, performance status, and extent of resection) were well matched. All 39 pts in the experimental arm completed at least 80% of the planned V treatment, receiving at least 70% of the full V dose and 80% of the planned RT dose. Eleven pts (28%) in the experimental arm experienced ≥ G3 AEs during concurrent treatment. The commonest severe AEs were seizures observed in 3pt in each arm, 7% in the experimental arm and 15% in the standard treatment arm followed by thrombocytopenia seen in 2 pts in each arm, 5% in the experimental arm and 10% in the standard arm. Conclusions: Stage 1 of VERTU satisfied the predefined feasibility and safety criteria and the study will continue until the accrual target (120pts) is reached (anticipated mid-2018). Efficacy endpoints will be analyzed and reported after completion of accrual. Clinical trial information: 12615000407594.
Phase I investigation of lenalidomide plus rituximab and outcomes of lenalidomide maintenance in recurrent CNS lymphoma.
Authors: James L. Rubenstein, Eleanor Fraser, Paul Formaker, James Chi-Chiang Lee, Nianhang Chen, Mallory Kock, Wesley Cheung, Xiaomin Wang, Pamela N. Munster, Bertil Damato
Journal: Journal of Clinical Oncology (2016)

7502 Background: There is an unmet need for effective biological therapies for relapsed CNS lymphoma. Lenalidomide (CC-5013) is active in ABC-type DLBCL. We demonstrated activity of lenalidomide in preclinical models of refractory CNS DLBCL. These observations are the basis for this first trial of an IMiD monotherapy in CNS NHL, and in patients with inadequate responses to lenalidomide, with intravenous plus intraventricular rituximab. (NCT01542918). In an independent cohort, we evaluated lenalidomide maintenance after salvage in relapsed CNS NHL. Methods: The primary objective was to evaluate safety and efficacy of lenalidomide at 10, 20, 30 mg dose levels in refractory CD20+ CNS NHL. Secondary endpoints were to determine: CSF penetration of lenalidomide; feasibility of intraventricular plus intravenous rituximab; TTP of maintenance lenalidomide in an independent cohort of relapsed CNS NHL patients. Results: Thirteen subjects with refractory CNS DLBCL (8 PCNSL, 5 SCNSL; median age 63, range 46-78) were treated on the phase I protocol. 8 achieved > PR with lenalidomide monotherapy: 3 CR’s, 1 PR in brain parenchymal NHL; 2 CR of CSF NHL; 1 CR, 2 PR’s of intraocular NHL. Four maintained CR to lenalidomide > 9 months and two > 1.8 years. An independent cohort of 12 patients with recurrent CNS DLBCL (10 PCNSL, 2 SCNSL; median age 70, range 59-81) received lenalidomide monotherapy (5-10 mg) as maintenance after salvage. With median follow-up of > 18 months, TTP has been impressive: five maintained remissions > 2 years. Among 10 CNS DLBCL patients with multiple CNS relapses that received focal XRT or HD-MTX-rituximab salvage, followed by lenalidomide maintenance, TTP at CR 2-4 was >5 X longer than TTP in these patients after standard induction and consolidation chemotherapy, without lenalidomide. P<0.013; Hazard Ratio 3.75. Trough lenalidomide concentration in ventricular CSF was highest at 20 mg dose. Elevated CSF lactate predicted short PFS (p<0.01). Conclusions: Lenalidomide penetrates ventricular CSF and is active in relapsed CNS DLBCL. We provide the first evidence that maintenance lenalidomide significantly potentiates TTP after salvage in relapsed CNS DLBCL and delays WBRT. Clinical trial information: NCT01542918.
TGF-β and ovarian hormones control endometrial growth by mechanisms that converge on the cyclin-dependent kinase inhibitor, p27Kip1.
Authors: Christian Tovar, Shaoqing Chen, Dejan Knezevic, Xiaolan Zhao, Hongmao Sun, Li Chen, David C. Heimbrook, Lyubomir T. Vassilev
Journal: Cancer Research (2006)

5627  The purpose of these studies is to reveal mechanisms involved in normal endometrial growth and endometrial carcinogenesis. Hormones and growth factors regulate endometrial growth. Estrogen (E2) stimulates and progesterone (Pg) inhibits normal endometrial epithelial cell growth in a cyclical manner. Accordingly, unopposed E2 causes most endometrial cancers (ECA) while progesterone is therapeutic. TGF-β inhibits epithelial cell growth by arresting cells in G1 phase of the cell cycle. Although the cyclin-dependent kinase inhibitor (CKI), p27Kip1 (p27), similarly halts the cell cycle by inhibiting cdk2 kinase activity, a direct effect of TGF-β on p27 has not been shown. Using cultures of primary endometrial epithelial cells (EECs), we have shown that TGF-β inhibits EEC growth and directly and dose-dependently increases p27 by preventing its ubiquitin-mediated degradation. As the E3 ligase, skp2, and partner of the SCF complex, cks1, target p27 to the proteasome for degradation, we further show that TGF-β (100 pM) increases and maintains nuclear localization of p27 by decreasing both nuclear and cytoplasmic levels of skp2 and cks1 with a complete decrease of cks1 by 48 hours after treatment. Therefore, a mechanism by which TGF-β inhibits endometrial cell growth is via preventing p27 degradation by effectively decreasing skp2 and cks1. The physiological significance of the inverse relationship between p27 and cks1 is shown in vivo, as the glands of both proliferative phase endometrium and ECA have increased intranuclear cks1 and negligible p27, whereas secretory phase glands have high levels of p27 but little to no cks1. p27 requires phosphorylation at T187 for identification by skp2 and subsequent ubiquitin-mediated degradation. Therefore, we hypothesized that E2 may initiate MAPK-driven phosphorylation of p27. Our results show that E2 (100 nM) treatment of EECs obliterated p27 levels, which was blocked by both the Mek1 inhibitor, PD98509 and the proteasome inhibitor, lactacystin. Therefore, E2 induces MAPK [Erk1]-driven proteasomal degradation of p27. Conversely, medroxyprogesterone (100 nM) induces a 6-fold increase p27 levels over untreated controls. Our results show that TGF-β and ovarian hormones control EEC growth by converging on the regulation of intracellular levels of p27. Since we have shown in previous studies that ECA cells have disrupted TGF-β signaling, we conclude that the pathogenesis of ECA may be related to both, the lack of TGF-β signaling and of Pg, thereby permitting uncontrolled E2-driven proteasomal degradation of p27.
Meningioma: Association of mean and "hot spot" MIB1 with grade.
Authors: Christopher Dardis, Lynn Stuart Ashby, Stephen Coons
Journal: Journal of Clinical Oncology (2018)

2030 Background: The MIB1 labeling index is typically measured by counting cells in the region (‘hot spot’) with the highest proliferative activity. MIB1 is not currently one of the criteria used to classify meningioma as WHO Grade 1 or 2. Here we compare this ‘hot spot’ MIB1 (MIB1hs) with the mean MIB1 (MIB1m) of the whole sample. Methods: Both methods used computer-assisted quantitative analysis on images/optical fields at 400x magnification. MIB1hs was taken by counting a minimum of 1,000 cells in the most proliferative field of the tumor. MIB1m was estimated by taking the mean of 14x fields, from randomly selected regions of the tumor. This was done for meningiomas which underwent resection at our institution in 2009: 108x Grade 1, 32x Grade 2. Results: MIB1hs was more than double that of MIB1m (5.9% vs. 2.7%; two-sided t-test p = 6×10-9). The log of both measures was found to increase in a linear fashion, irrespective of grade. Using recursive partitioning, an optimal ‘cutpoint’ for MIB1 (in terms of Grade) was found to be 1.5% for both methods. As shown in the classification table, the methods were concordant in 100/140 (70%) cases. With these cutpoints, Fisher’s exact test showed a stronger association with Grade for MIB1m vs. MIB1hs (p = 0.04 vs. p = 0.0008). Conclusions: For meningioma, MIB1m shows a significantly greater association with Grade than MIB1hs. The method can be implemented with minimal additional burden to the practicing pathologist. The result appears to be of greater importance clinically. As MIB1 also increases in an exponential manner in breast cancer, schwannoma and low-grade glioma, we propose that this is a general property of the test. MIB1hs MIB1m WHO Grade 1 2 < 1.5% < 1.5% 59 28 ≥ 1.5 % 35 4 ≥ 1.5% ≥ 1.5 % 13 0 < 1.5 % 1 0
Phase II trial of rucaparib (Without ADT) in patients with metastatic hormone-sensitive prostate cancer harboring germline DNA repair gene mutations (TRIUMPH).
Authors: Mark Christopher Markowski, Hao Wang, Rana Sullivan, Michael Haffner, Angelo M De Marzo, Tamara L. Lotan, Emmanuel S. Antonarakis
Journal: Journal of Clinical Oncology (2018)

TPS5095 Background: The clinical activity of PARPi in patients with homologous recombination DNA-repair mutations and metastatic prostate cancer has now been established. Focusing specifically on patients with a germline mutation in a pre-specified group of DNA-repair genes, we hypothesize that targeted therapy with PARPi should be sufficient to induce a clinical response irrespective of hormonal (castration-sensitive/resistant) status. For men with metastatic hormone sensitive prostate cancer (mHSPC), this trial would also provide an alternative to ADT. Methods: This study is a multi-center, open-label, single arm Phase II trial. Eligible patients are those with mHSPC without prior ADT. All patients must have a documented germline mutation in a homologous recombination DNA-repair gene (BRCA1, BRCA2, ATM, CHEK2, NBN, RAD50, RAD51C, RAD51D, PALB2, MRE11, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM). Patients on trial must be ineligible for or decline standard-of-care hormonal treatment. A mandatory tumor biopsy will be performed prior to therapy. A second, optional tumor biopsy is planned after three months of therapy. Patients will be treated with Rucaparib 600mg po twice daily. Patients will be followed monthly with clinic visits and safety labs with PSA. The primary endpoint is the proportion of patients with a ≥ 50% decrease in PSA from baseline (PSA50 response). A total enrollment of 30 patients is planned to detect an improved PSA50 response rate from 50% to 75% with 90% power (one sided type I error of 0.1). The total number of patients allowed with a non-BRCA1, -BRCA2, or –ATM mutations will be capped at 10. For patients who do not respond to PARPi, we have incorporated safety rules into the study design to take patients off study at first signs of progression. Secondary endpoints include safety, progression-free survival, and objective response. Exploratory analysis will involve biomarker discovery including somatic DNA mutation analysis, RNA expression analysis, and immunohistochemistry for DNA damage markers. Clinical trial information: NCT03413995.
The impact of body mass index on the risk of early progression of smoldering multiple myeloma to symptomatic myeloma.
Authors: Wilson I. Gonsalves, S. Vincent Rajkumar, Angela Dispenzieri, Martha Lacy, Francis Buadi, David Dingli, Ronald S. Go, Prashant Kapoor, Suzanne R. Hayman, John Anthony Lust, Nelson Leung, Stephen J. Russell, Steven R. Zeldenrust, Yi Lin, Yi Lisa Hwa, Taxiarchis Kourelis, Robert A. Kyle, Morie A. Gertz, Shaji Kumar
Journal: Journal of Clinical Oncology (2017)

8032 Background: Human adipocytes can contribute directly to the in vitro growth and progression of multiple myeloma (MM) cell lines. Clinically, an elevated body mass index (BMI) has been associated with an increased risk of MGUS and a shorter time to progression (TTP) of MGUS to MM. However, the impact of BMI on the risk of early progression to MM from a more advanced plasma cell disorder such as smoldering MM (SMM) remains unknown. Methods: This study included patients (pts) with a known or new diagnosis of SMM evaluated at the Mayo Clinic, Rochester from January 2000-December 2010. Pts were classified based on their BMI as: normal (&lt; 25) and elevated (&gt;/= 25) BMI. Progression to symptomatic MM was defined by the development of hypercalcemia, renal insufficiency, anemia or lytic bone lesions. Results: There were 306 pts with a diagnosis of SMM who were included in this analysis. The median follow up was 106 months. There were 203 (66%) pts who progressed to symptomatic MM at last follow up. The median BMI of the group was 27.5 (Range: 17.2 – 56.4). There were 228 (75%) pts with an elevated BMI. There were 76 (28%) pts who had myeloma defining events (MDEs) such as a serum free light chain ratio &gt; 100 or &gt; 60% clonal bone marrow plasma cells at initial evaluation. MDEs were present in 17% and 33% of pts with a normal and elevated BMI respectively (P = 0.011). The median TTP of SMM to MM in pts with a normal and elevated BMI was 64 and 36 months respectively (P = 0.0006). The 2-year progression rate of SMM to symptomatic MM in pts with a normal and elevated BMI was 16% and 42% respectively (P &lt; 0.0001). Upon limiting the analysis to only SMM pts without MDEs at initial evaluation (N =187), the 2-year progression rate to symptomatic MM with a normal and elevated BMI was 15% and 33% respectively (P = 0.013). In a multivariable model, only elevated BMI (P = 0.004) and increasing clonal bone marrow plasma cells (P = 0.001) was statistically significant in predicting for a 2-year progression to MM. Conclusions: SMM pts with an elevated BMI appear to have a higher risk of early progression to MM than those with a normal BMI. This study provides evidence of a potentially modifiable risk factor for the progression of SMM to MM and warrants confirmation in larger studies.
A phase I/II study of the combination of temozolomide (TM) and pazopanib (PZ) in advanced pancreatic neuroendocrine tumors (PNETs) (NCT01465659).
Authors: Manali A. Bhave, Sheetal Mehta Kircher, Aparna Kalyan, Jordan Berlin, Mary Frances Mulcahy, Steven J. Cohen, Crystal S. Denlinger, E. Gabriela Chiorean, Vaibhav Sahai, Mark Zalupski, Alfred Rademaker, Al Bowen Benson, Halla Nimeiri
Journal: Journal of Clinical Oncology (2018)

4096 Background: PNETs are distinguished by increased vascularity and benefit from anti-angiogenic therapies. PZ is a tyrosine kinase inhibitor (TKI) of VEGFR-1-3, PDGFR-α, -β, and c-Kit with single agent activity in PNET (overall response rate (ORR) 22%, median PFS of 14 mo and median OS of 25mo). TM is an oral alkylating agent also with known single agent activity in well-differentiated NETs (PFS of 7 mo). The rationale for the combination of TM and VEGF TKI is based on preclinical synergism through alteration of the tumor microenvironment by VEGF TKI to enhance the activity of TM. Methods: This is an open-label phase I/II study to determine the maximum tolerated dose (MTD), safety profile, ORR and pharmacokinetics (PK) of TM and PZ in patients (pts) with advanced well-differentiated PNETs who received 1-4 prior therapies. In a 28-day cycle, TM was given days 1-7 and 15-21 with PZ 400 mg once daily continuously. Dose escalation cohorts of TM: (-2) 75 mg/m2, (-1) 100 mg/m2, and (1) 150 mg/m2. PK analysis was performed for 6 pts at MTD. The phase II portion at MTD is ongoing. Results: 28 pts with advanced well-differentiated PNETs were enrolled in phase I between Feb 2013 and Jan 2016 (16 at cohort -2, 5 at cohort -1, and 7 at cohort 1). 2 pts were not evaluable for any endpoint. There were 5 dose-limiting toxicities (DLTs): hepatic dysfunction (2), thrombocytopenia (2) and neutropenia (1). The MTD was at dose level -2, TM 75 mg/m2 and PZ 400 mg. The most common treatment-emergent adverse events were hepatic toxicity (16%), nausea (5%) and fatigue (5%). Best ORR was PR in 5 pts (25%) and SD in 9 pts (45%). At a median follow-up of 18.5 mo, the median PFS was 12.1 mo (95% CI, 5.7-25.1) and median OS was 36.2 mo (95% CI, 21.4-56.4). Conclusions: The combination of TM and PZ was tolerable at a dose level of -2 with hepatic toxicity and myelosuppression as the DLTs. The ORR was 25% with disease control rate of 70% in patients with previously treated advanced well-differentiated PNETs. The phase II component of the study is ongoing. Clinical trial information: NCT01465659.