tbuckley/cabot-search huggingface dataset:
Phase 1 dose escalation of ZW25, a HER2-targeted bispecific antibody, in patients (pts) with HER2-expressing cancers.
Authors: Funda Meric-Bernstam, Muralidhar Beeram, Mariela A. Blum, Diana Felice Hausman, Jeffrey R. Infante, Amita Patnaik, Sarina Anne Piha-Paul, Drew W. Rasco, Gerry Rowse, Jamuna Thimmarayappa, Anthony W. Tolcher, Erika Paige Hamilton
Journal: Journal of Clinical Oncology (2017)

1035 Background: The HER2 receptor is expressed across a range of cancers (ca) although expression and heterogeneity vary greatly within and between tumors. FDA approved HER2-targeted therapies (tx) have shown clinical benefit only in HER2 high (IHC3+ or IHC2+/FISH+) breast and gastric ca. ZW25, built on the Azymetric™ platform which utilizes unique Fc mutations to create IgG1-like bispecific antibodies, binds to the same extracellular domains of HER2 as trastuzumab (T) and pertuzumab (P) with increased binding and internalization compared to T alone. In preclinical studies ZW25 was well tolerated and active in models of HER2 low to high ca. Methods: Eligible pts (HER2 IHC 1-3+, progression after standard of care (SOC) tx, normal LVEF) were enrolled in a 3+3 dose escalation study of ZW25 (5, 10 or 15 mg/kg) IV weekly in 4 week cycles. Assessments included adverse events (AEs), LVEF, tumor response and PK. Results: 9 pts have received ZW25 at 5 (n = 3) or 10 mg/kg (n = 6); 15 mg/kg is ongoing. All pts were HER2 high (breast = 4; gastric/GEJ = 4; adnexal = 1). Prior tx included T in all pts; P and T-DM1 in 4 and lapatinib (L) in 3 of 4 breast pts. The most common AEs (all Gr 1/2) were infusion reaction (IR) (5/9), diarrhea (4/9), and fatigue (3/9), with no DLTs and one related Gr 3 AE of hypophosphatemia. The IRs occurred only with 1st dose and did not recur with prophylactic tx (primarily acetaminophen and diphenhydramine; steroids included for 2 pts). At 5 mg/kg, peak drug levels after C1D1 = ~100 ug/ml, accumulating ~50% higher by dose 4. Best response in 8 pts (1 too early): 2 PR (both breast ca with prior T, P, T-DM1, and L; 10 mg/kg, 55% and 33% target lesion decrease, respectively, after 2 cycles), 1 SD (breast ca, 5 mg/kg, ongoing after 4 cycles), and 5 PD. 5 pts currently active; includes 1 gastric pt (10 mg/kg) with PD (new nodal lesions) and clinical benefit with decrease in target lesions and CEA (33 to 1.5 ng/ml). Conclusions: ZW25 has been well tolerated with promising anti-tumor activity in pts with HER2-expressing ca progressing after SOC therapy. These early signs of activity support the therapeutic potential for bispecific antibodies using the Azymetric platform. Development of ZW25 is ongoing, including in lower HER2-expressing ca. Clinical trial information: NCT02892123.
Preliminary results of a phase I/IIa study of BMS-986156 (glucocorticoid-induced tumor necrosis factor receptor–related gene [GITR] agonist), alone and in combination with nivolumab in pts with advanced solid tumors.
Authors: Lillian L. Siu, Neeltje Steeghs, Tarek Meniawy, Markus Joerger, Jennifer L. Spratlin, Sylvie Rottey, Adnan Nagrial, Adam Cooper, Roland Meier, Xiaowei Guan, Penny Phillips, Gaurav Bajaj, Jochem Gokemeijer, Alan J. Korman, Kyaw Lwin Aung, Matteo S. Carlino
Journal: Journal of Clinical Oncology (2017)

104 Background: BMS-986156 is a fully human IgG1 agonist mAb that binds GITR and promotes T effector cell activation and possible reduction/inactivation of T regulatory cells. Preclinical data show enhanced antitumor T-cell activity with anti-GITR + anti–programmed death-1 (PD-1). Here we describe preliminary dose escalation data from a phase I/IIa study of BMS-986156 ± nivolumab (anti–PD-1 mAb) in pts with advanced solid tumors (NCT02598960). Methods: During dose escalation, pts received BMS-986156 (10–800 mg) or BMS-986156 (30–800 mg) + nivolumab (240 mg) every 2 weeks. Objectives included safety (primary), immunogenicity, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy. Results: As of Dec 12, 2016, 66 pts were treated with BMS-986156 (n = 29) or BMS-986156 + nivolumab (n = 37).No dose-limiting toxicities (DLTs) were reported during dose escalation. The most common treatment-related adverse events reported with BMS-986156/BMS-986156 + nivolumab included pyrexia (21%/30%), chills (10%/16%), and fatigue (14%/14%); events were G1/2 in all pts except for 4 pts (6%) treated with the combination (G3 lipase [n = 1], G3 lung infection [n = 1], G3 fatigue [n = 1], and G3 aspartate aminotransferase with G4 creatine phosphokinase [n = 1; leading to discontinuation of treatment]). Preliminary data indicate that the incidence of immunogenicity to BMS-986156 was low when BMS-986156 ± nivolumab was administered. Preliminary data also indicate that BMS-986156 ± nivolumab exhibits linear PK with dose proportionality after a single dose, and BMS-986156 ± nivolumab is biologically active in PD analyses in peripheral blood. Initial antitumor activity has been observed in several pts treated with the combination; these data will be reported. Conclusions: This is the first report of clinical data with an anti-GITR mAb ± a PD-1 inhibitor.BMS-986156 ± nivolumab was well tolerated, with no DLTs and low immunogenicity. Antitumor activity was observed with BMS-986156 + nivolumab at doses predicted to be biologically active. Further evaluation of this combination in pts with advanced solid tumors is ongoing. Clinical trial information: NCT02598960.
How are enthesitis, dactylitis and nail involvement measured and reported in recent clinical trials of psoriatic arthritis? A systematic literature review
Authors: Sofia Ramiro, Josef S Smolen, Robert Landewé, Désirée van der Heijde, Laure Gossec
Journal: Annals of the Rheumatic Diseases (2017)

While enthesitis, dactylitis and nail involvement are recognised as important outcomes of psoriatic arthritis (PsA) in the core set of domains in PsA,1 2 it is still unclear how these outcomes should best be measured.1 2 We systematically reviewed the instruments and the cut-offs used to report state or improvement, for enthesitis, dactylitis and nail involvement in recent randomised controlled trials (RCTs) in PsA.

A systematic literature review of RCTs on any pharmacological intervention in patients with PsA was conducted to inform the European League Against Rheumatism (EULAR) recommendations for the management of PsA, by searching Medline, Embase and Cochrane datasets for the period 2010–2015.3 4 Only published papers and only results of the placebo-controlled phases were analysed. The presence and type of all outcome measures reflecting enthesitis, …
A phase III trial of neoadjuvant chemotherapy with or without anthracyclines in the presence of dual HER2-blockade for HER2+ breast cancer: The TRAIN-2 study (BOOG 2012-03).
Authors: Mette S. Van Ramshorst, Erik van Werkhoven, Ingrid A. Mandjes, Inge Kemper, Vincent O. Dezentjé, Irma M. Oving, Aafke H. Honkoop, Lidwine W Tick, Agnes W Van de Wouw, Caroline M Mandigers, Jelle Wesseling, Marie-Jeanne Vrancken Peeters, Sabine C. Linn, Gabe S. Sonke
Journal: Journal of Clinical Oncology (2017)

507 Background: Neoadjuvant chemotherapy with dual HER2 blockade boosts pathologic complete response (pCR) rates in HER2+ breast cancer. The optimal chemotherapy backbone in this setting is unknown. We conducted a multicenter phase III trial to study whether anthracyclines would improve outcome compared to a carboplatin-taxane regimen (NCT01996267). Methods: We randomly assigned (1:1) patients with stage II-III HER2+ breast cancer to receive 9 cycles paclitaxel (80mg/m 2 day 1 and 8) and carboplatin (AUC = 6mg/ml·min) (arm A) or 3 cycles 5-fluoruoracil (500mg/m 2 ), epirubicin (90mg/m 2 ), and cyclophosphamide (500mg/m 2 ) followed by 6 cycles paclitaxel and carboplatin (arm B). Both arms received trastuzumab (6mg/kg, loading dose 8mg/kg) and pertuzumab (420mg, loading dose 840mg) concurrent with all chemotherapy cycles, and cycles were repeated every 3 weeks. The primary endpoint was pCR in breast and axilla (ypT0/is,ypN0). Results: 438 patients were included and 418 (arm A 206 vs arm B 212) were evaluable for the primary endpoint. The pCR rate did not differ between arms (arm A 68% [95% CI 61-74] vs arm B 67% [95% CI 60-73], p = 0.75). Hormone receptor (HR) negative tumors had significantly higher pCR rates (87% vs 54%, p &lt; 0.0001), but we found no evidence for treatment-by-HR interaction (p = 0.23). Common adverse events grade ≥3 were neutropenia (arm A 53% vs arm B 57%, p = 0.34), febrile neutropenia (arm A 2% vs arm B 11%, p = 0.0001), and diarrhea (arm A 17% vs arm B 12%, p = 0.14). Neuropathy grade ≥2 was common in both arms (arm A 31% vs arm B 29%, p = 0.83), while left ventricular ejection fraction (LVEF) decline grade ≥2 (defined as ≥10% decline from baseline or LVEF &lt; 50%) was more common in arm B (arm A 18% vs arm B 29%, p = 0.007). Symptomatic left ventricular systolic dysfunction was rare ( &lt; 1%) in both arms. Conclusions: Anthracyclines increase the incidence of febrile neutropenia and grade ≥2 LVEF decline, but do not improve pCR rate in the contemporary neoadjuvant treatment of HER2+ breast cancer with dual HER2 blockade. Therefore, we currently favor a carboplatin-taxane based regimen. Follow-up is required to confirm these results with regard to long-term outcome. Clinical trial information: NCT01996267.
Measures Taken to Prevent Zika Virus Infection During Pregnancy — Puerto Rico, 2016
Authors: Denise V. D’Angelo, Beatriz Salvesen von Essen, Mark J. Lamias, Holly Shulman, Wanda I. Hernandez-Virella, Aspy J. Taraporewalla, Manuel I. Vargas, Leslie Harrison, Sascha R. Ellington, Leslianne Soto, Tanya Williams, Aurea Rodriguez, Carrie K. Shapiro-Mendoza, Brenda Rivera, Shanna Cox, Karen Pazol, Marion E. Rice, Deborah L. Dee, Lisa Romero, Eva Lathrop, Wanda Barfield, Ruben A. Smith, Denise J. Jamieson, Margaret A. Honein, Carmen Deseda, Lee Warner
Journal: MMWR Morbidity and Mortality Weekly Report (2017)

Zika virus infection during pregnancy remains a serious health threat in Puerto Rico. Infection during pregnancy can cause microcephaly, brain abnormalities, and other severe birth defects (1). From January 1, 2016 through March 29, 2017, Puerto Rico reported approximately 3,300 pregnant women with laboratory evidence of possible Zika virus infection (2). There is currently no vaccine or intervention to prevent the adverse effects of Zika virus infection during pregnancy; therefore, prevention has been the focus of public health activities, especially for pregnant women (3). CDC and the Puerto Rico Department of Health analyzed data from the Pregnancy Risk Assessment Monitoring System Zika Postpartum Emergency Response (PRAMS-ZPER) survey conducted from August through December 2016 among Puerto Rico residents with a live birth. Most women (98.1%) reported using at least one measure to avoid mosquitos in their home environment. However, only 45.8% of women reported wearing mosquito repellent daily, and 11.5% reported wearing pants and shirts with long sleeves daily. Approximately one third (38.5%) reported abstaining from sex or using condoms consistently throughout pregnancy. Overall, 76.9% of women reported having been tested for Zika virus by their health care provider during the first or second trimester of pregnancy. These results can be used to assess and refine Zika virus infection prevention messaging and interventions for pregnant women and to reinforce measures to promote prenatal testing for Zika.
The influence of gastric secretion inhibitors on gefitinib therapy in patients with non-small cell lung cancer harboring epidermal growth factor receptor activating mutations.
Authors: Sho Saeki, Jiichiro Sasaki, Junko Morioka, Ryo Sato, Shinya Sakata, Hidenori Ichiyasu, Kazuhiko Fujii, Naoki Saita, Hirotsugu Kohrogi
Journal: Journal of Clinical Oncology (2012)

e18059 Background: Gefitinib is orally available, selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor used in patients with non-small cell lung cancer (NSCLC), especially harboring EGFR activating mutations. Pharmacokinetic study revealed absorption of gefitinib was affected by the gastric pH. However, cancer patients in advanced stage are frequently administered gastric secretion inhibitors, such as proton pump inhibitors (PPIs) and H2 blockers (H2Bs) for various reasons. We hypothesized that gastric secretion inhibitors might suppress the efficacy of gefitinib therapy in NSCLC patients with EGFR activating mutations. The purpose of this study is to investigate the influence of PPIs/H2Bs on the efficacy of gefitinib therapy in the patients with NSCLC harboring EGFR activating mutations. Methods: From Apr 2004 to Aug 2011, we retrospectively analyzed the correlation between administration of PPIs/H2Bs and efficacy of gefitinib therapy in the patients with NSCLC harboring EGFR mutations. Results: Forty-three patients with EGFR mutations received gefitinib therapy in our hospital. 65.1% (28/43) patients administered PPIs/H2Bs simultaneously. Patients who received PPIs/H2Bs (PPIs/H2Bs group) had similar response rate compared with patients who didn’t receive PPIs/H2Bs (non-PPIs/H2Bs group) (77.8% vs 73.3%, p=1.00). Median progression free survival was 291 days in PPIs/H2Bs group and 353 days in non-PPIs/H2Bs group ( HR 1.23, Log-rank trest, p=0.578), respectively. Median overall survival was 718 days in PPIs/H2Bs group and not reached in non-PPIs/H2Bs group ( HR 1.53, Log-rank trest, p=0.403), respectively. Conclusions: Gastric secretion inhibitors didn’t affect the efficacy of gefitinib treatment in patients with NSCLC harboring EGFR activating mutations.
Concurrent use of capecitabine with radiation therapy and survival in breast cancer (BC) after neoadjuvant chemotherapy.
Authors: Ying Liu, Benjamin Peter Catanese, Christine Chin, Shing Lee, Serena Zhan, Kevin Kalinsky, Eileen Connolly
Journal: Journal of Clinical Oncology (2017)

e12117 Background: Capecitabine has been studied as a radiosensitizer in rectal cancer, but its role in BC is unclear. Our study seeks to examine the association of concurrent capecitabine/radiation therapy (RT) on survival in women with BC and residual disease after neoadjuvant chemotherapy (NAC). Methods: In a retrospective study of women with stage I-III BC who received Adriamycin/Taxane-based NAC from 2010-2016, we identified 21 women administered concurrent capecitabine/RT. To assess differences in survival, we selected a clinical control cohort (n = 64) based on criteria used to select patients for capecitabine/RT including pathological stage II/III disease and non-HER2+ tumor subtype. We also created a matched cohort (2:1), matching on tumor subtype, pathological stage, and age ( &lt; 50 or 50+ years). Differences in progression-free survival (PFS), using STEEP criteria, and overall survival (OS), using all-cause mortality, between those who received capecitabine/RT and controls were assessed. Results: Of the 21 women who received capecitabine/RT, the majority were 50+ years (n = 12), pathological stage III (n = 15), and hormone receptor positive/HER2 negative BC (n = 20). Compared with clinical controls, women who received capecitabine/RT had larger disease (p = 0.041) and a higher pathological stage (p = 0.067), but there were no other differences. In those receiving capecitabine/RT, there were 9 recurrences (3 local, 6 distant) compared with 14 recurrences (4 local, 10 distant) in the clinical controls and 10 recurrences (all distant) in the matched controls. In multivariate models, capecitabine/RT was associated with worse PFS (HR 3.04 95% CI 1.24-7.43 p = 0.015) and OS (HR 4.29 95% CI 1.45- 12.6 p = 0.008), after adjusting for clinical size and pathologic stage. In the 2:1 matched cohort, capecitabine/RT was also associated with worse PFS (HR 2.96 95% CI 1.20-7.29 p = 0.018) and OS (HR 5.61 95% CI 1.76-17.9 p = 0.004). Conclusions: Capecitabine/RT after NAC is associated with worse PFS and OS using two control populations, suggesting capecitabine/RT should be discouraged in BC.
Evaluation of RAD1901, a novel investigational, selective estrogen receptor degrader (SERD), for the treatment of ER-positive (ER+) advanced breast cancer.
Authors: Aditya Bardia, Peter Kabos, Richard Elledge, Dannie Wang, Jinshan Shen, Fiona Garner, Alison O'Neill, Virginia G. Kaklamani
Journal: Journal of Clinical Oncology (2017)

1014 Background: The treatment of advanced ER+ breast cancer remains a clinical challenge with the majority of patients eventually progressing due to resistance to endocrine therapy. RAD1901 is a novel, nonsteroidal, oral SERD that has demonstrated dose dependent degradation of ER, and ER regulated genes in preclinical studies. In multiple in vivo patient derived xenograft models of breast cancer, including those harboring ESR1 mutations, RAD1901 demonstrated significant antitumor activity. Methods: In a phase-1 Study RAD1901-005 (ClinicalTrials.gov ID: NCT02338349), patients with advanced ER+ breast cancer were enrolled in dose escalation cohorts, followed by a safety expansion cohort. Key inclusion criteria include postmenopausal women aged 18 years or older, with advanced ER+, HER2- breast cancer, who have received ≤ 2 prior chemotherapy regimens in the metastatic setting and &gt; 6 months of prior endocrine therapy. ESR1 mutation status was determined from circulating tumor DNA (ctDNA) samples. Clinical outcomes were evaluated based on RECIST v1.1 criteria. Results: As of January 25, 2017, total of 39 patients were enrolled at the 400 mg qd dose. Patients were heavily pre-treated (median lines of prior therapy = 3), with 38% and 41% having previously received fulvestrant and palbociclib/CDK4/6 inhibitor, respectively. RAD1901 was generally well-tolerated, with the most common adverse events being low grade nausea (Grade 3/4 = 0%) and dyspepsia (Grade 3/4 = 0%). ESR1 mutations, including D538G, Y537S/N/C, L536H/P/R, S436P and E380Q, were detected at baseline in 44% of patients and dynamic changes in the allele frequency of ESR1 mutations were observed in response to treatment. Confirmed partial responses were observed in patients with ESR1 mutations, and those who had previously received fulvestrant and palbociclib. Conclusions: RAD1901 has demonstrated evidence of single agent activity, with confirmed partial responses in heavily pre-treated patients with advanced ER+ breast cancer, including those with ESR1 mutations, warranting additional clinical development. Clinical trial information: NCT02338349.
SOLE (Study of Letrozole Extension): A phase III randomized clinical trial of continuous vs intermittent letrozole in postmenopausal women who have received 4-6 years of adjuvant endocrine therapy for lymph node-positive, early breast cancer (BC).
Authors: Marco Colleoni, Weixiu Luo, Per Karlsson, Jacqueline H. Chirgwin, Stefan Paul Aebi, Guy Heinrich Maria Jerusalem, Patrick Neven, Erika Hitre, Marie-Pascale Graas, Edda Simoncini, Claus Kamby, Alastair Mark Thompson, Sibylle Loibl, Joaquín Gavilá, Katsumasa Kuroi, Michael Gnant, Manuela Rabaglio-Poretti, Meredith M. Regan, Alan S. Coates, Aron Goldhirsch
Journal: Journal of Clinical Oncology (2017)

503 Background: In animal models of hormone receptor positive (HR+) breast cancer, acquired resistance to continued letrozole was shown to be reversed by estrogen-induced apoptosis. Sensitization to reintroduction of estrogen withdrawal by letrozole was hypothesized to improve treatment outcome. SOLE tested the hypothesis that 3 mos treatment-free intervals during extended adjuvant therapy will improve disease-free survival (DFS). Methods: SOLE enrolled 4884 postmenopausal women with HR+ lymph node-positive BC who had completed 4-6 yrs of adjuvant endocrine therapy (19% SERM, 43% AI, 38% both; stratification factor). Pts were randomly assigned to an additional 5 yrs continuous letrozole (2.5 mg daily; n = 2441) vs 5 yrs intermittent letrozole (taken for the first 9 mos of yrs 1-4, and 12 mos in yr 5; n = 2443). The primary endpoint was DFS (randomization until invasive local, regional, distant recurrence or contralateral BC; 2nd malignancy; death). Final analysis was at 665 DFS events, after 2 interim analyses. SOLE required 4800 pts for 80% power to detect a 20% DFS hazard reduction with 2-sided α = 0.05 using a stratified log rank test. Analysis is by intention-to-treat. Results: At 60 mos median follow-up, 5 yr DFS from randomization was 85.8% vs 87.5% for patients assigned intermittent vs continuous letrozole (HR = 1.08; 95% CI 0.93-1.26; P = 0.31). Similar outcome was observed for breast cancer-free interval (HR = 0.98; 95% CI 0.81-1.19), distant recurrence-free interval (HR = 0.88; 95% CI 0.71-1.09), and overall survival (HR = 0.85; 95% CI 0.68-1.07). AEs of grade &gt; 3 were reported for 43.5% vs 41.6% of pts assigned intermittent vs continuous letrozole. Overall 24% pts discontinued letrozole early in both groups. Conclusions: Among postmenopausal women with HR+ BC, extended intermittent letrozole did not improve DFS vs continuous letrozole. The similar observed outcomes and incidence of AEs provides clinically relevant information on the intermittent administration of extended letrozole for patients who could benefit from temporary treatment breaks. Clinical trial information: NCT00553410.
Skp2 regulates G2/M progression in a p53-dependent manner
Authors: Hu Rong, Andrew Aplin
Journal: Cancer Research (2008)

4227  Targeted proteasomal degradation mediated by E3 ubiquitin ligases controls cell cycle progression. Alterations in E3 ubiquitin ligase activities are thought to contribute to malignant cell proliferation. Skp2 is the F-box component of an E3 ubiquitin ligase complex that targets p27Kip1 and cyclin E1 to the proteasome. In human melanoma, Skp2 is highly expressed, regulated by mutant B-RAF, and required for cell growth. Here, we show that Skp2 depletion in melanoma cells resulted in a G2 cell cycle arrest. G2/M regulator genes including cyclin B1, cyclin-dependent kinase 1 (CDK1), and cyclin A were down-regulated in Skp2 knockdown cells. Surprisingly, co-knockdown of p27Kip1 with Skp2 in melanoma cells failed to reverse G2 accumulation induced by Skp2 knockdown and co-knockdown of cyclin E1 with Skp2 only elicited a partial effect. Rather, control of G2 arrest and regulatory genes was strongly dependent on p53 expression, which is frequently wild-type in melanoma. Finally, inducible expression of nuclear localized cyclin B1 in Skp2 depleted cells was able to restore the cell cycle profile. These data indicate that Skp2 may overcome p53-dependent cell cycle checkpoints in melanoma cells and raises the possibility of Skp2 acting in a manner independent of p27Kip1 accumulation.