tbuckley/cabot-search huggingface dataset:
Gabrinox: A phase I-II of nab-paclitaxel plus gemcitabine followed by FOLFIRINOX in metastatic pancreatic adenocarcinoma.
Authors: Eric Assenat, Christelle De La Fouchardiere, Caroline Mollevi, Emmanuelle Samalin, Fabienne Portales, Françoise Desseigne, Christophe Carenco, Marie Dupuy, Ernesto Lopez-Martinez, Catherine Fiess, Thibault Mazard, Marc Ychou
Journal: Journal of Clinical Oncology (2016)

e15688 Background: FOLFIRINOX (FFX) and nab-paclitaxel/gemcitabine (AG) showed significant improvement in efficacy compared to gemcitabine alone in metastatic pancreatic cancer (mPC). Alternating AG and FFX may overcome resistance to primary therapy and delay tumor progression. We designed a multicenter phase I-II trial with a new sequential regimen of AG followed by FFX in first-line treatment of mPC. The phase I primary objective was to determine the recommended AG and FFX doses. Primary endpoint was to determine the dose-limiting toxicities (DLTs). The phase II will assess the efficacy of the recommended doses. Methods: AG and FFX were administered sequentially, each AG cycle followed by a FFX cycle. Dose-escalation is shown in the table below. Chemotherapeutic agents were administered according to standard practice, except for Gemcitabine (10 mg/m2/min). Results: From September 2013 to October 2015, 33 mPC patients were included: 7, 6 and 7 patients in levels 1, 2a and 2b, respectively, and 13 in level 3. 31 patients were evaluable for tolerance (2 not evaluable at levels 1 and 2b). Patients’ characteristics at baseline were: male 54.8%, median age 61 years (42-75), ECOG PS 0 (35.5%) or 1 (64.5%). Five DLTs were reported: 1, 2 and 2 in levels 2a, 2b and 3, respectively. All DLTs were grade 4 transient, asymptomatic neutropenia with spontaneous resolution. They occurred at treatment initiation, probably due to the absence of prophylactic GCSF treatment during AG administration. There was no limiting neurotoxicity. Promising efficacy results (response and survival) will be presented at the meeting. Conclusions: This new regimen alternating AG and FFX shows acceptable toxicity and promising efficacy results.The recommended dose (level 3) is being confirmed in a 12 patient-expansion cohort before starting the phase II accrual. Supporter: This project is supported by CELGENE. The authors thank the participating teams. Clinical trial information: NCT01964287.One cycle D1 = D57 AG(mg/m2) D1, D8, D15 FFX(mg/m2) D29, D43 Dose Level Nab- paclitaxel Gemcitabine Oxaliplatin Irinotecan LV 5-FU 1 100 800 70 150 Leucovorin: 200 5-FU bolus: 400 5-FU infusion : 2.400 2 2a 100 800 85 180 2b 125 1.000 70 150 3 125 1.000 85 180
Does therapy-related myelofibrosis exist? Analysis of 1100 myelofibrosis cases from a single institution.
Authors: Lucia Masarova, Prithviraj Bose, Naveen Pemmaraju, Naval Guastad Daver, Kate Newberry, Jorge E. Cortes, Hagop M. Kantarjian, Srdan Verstovsek
Journal: Journal of Clinical Oncology (2016)

e18558 Background: The association between prior other malignancies (OM) and myelofibrosis (MF) as well as the existence of therapy-related myelofibrosis (t-MF) are largely unknown. We aimed to determine the occurrence of MF after a prior OM and its relationship with the therapeutic approach used for the OM. Methods: Fisher’s exact, Mann-Whitney and Kruskal-Wallis tests were used to compare categorical and continuous variables, respectively. Kaplan-Meier analysis and log-rank test were used to compare overall survival. Results: We performed a retrospective chart review of 1100 patients referred to our institution between 1984 and 2013 with a diagnosis of MF. Overall, 121 (11%) patients were found to have OM before MF. Median age at the time of MF diagnosis was 70 years (range, 35-89). Median lag time between OM and MF was 86 months (range, 3-563) and median follow-up from MF diagnosis was 31 months (range, 0.1-213). Twenty-three patients had more than 1 OM. The most common OM were prostate (30%), melanoma (17%), and colorectal carcinoma (10%). Surgery or hormonal manipulation therapy was used in 79 (65%) patients, chemotherapy in 25 (21%) and radiation in 17 (14%). Alkylating agents and topoisomerase II inhibitors were used, either as monotherapy or in combination, in 19 (76%) patients with chemotherapy exposure. OM subtype or primary therapeutic approach had no impact on MF occurrence. No significant differences in clinical parameters (CBC, LDH, transfusion dependence, unfavorable karyotype, major driver mutations) or incidence of AML were seen between patients treated with different primary therapies. Seventy-four percent of patients with OM-MF have died (n = 89) with similar median time to death for all groups: 25 months (range, 2-140). Known causes of death (37% of patients who died) included progression of MF (n = 11), OM (n = 5), multi organ failure (n = 10), and others (n = 7). Estimated median OS from MF was 45 months (range, 0.2-156) and was similar regardless of primary OM approach or subsequent MF therapy. Conclusions: In our experience, t-MF does not appear to exist.
Impact of hospital volume on patterns of care and outcomes in soft tissue sarcoma.
Authors: James Don Murphy, Jennifer Padwal, Zachary David Guss, Kanenori Okamoto, Reith Sarkar
Journal: Journal of Clinical Oncology (2018)

e23550 Background: Given the rarity and nuance of soft-tissue sarcoma management, current clinical guidelines call for treatment at experienced treatment facilities. However, the actual impact of sarcoma expertise on oncologic outcomes is unclear. This study evaluates the impact of institutional treatment volume on outcomes among patients with soft-tissue sarcoma. Methods: We identified 14,255 patients within the National Cancer Database who underwent resection for stage I-III extremity or retroperitoneal soft-tissue sarcoma between 2004 and 2015. Differences in patterns of care and outcomes were compared between high volume and low volume treatment centers. Outcomes included patterns of chemotherapy and radiation therapy, surgical margin status, and overall survival. Multivariable logistic and Cox regression models were used to determine the impact of treatment center volume while controlling for potential confounders. Results: Patients treated at high volume centers had lower rates of positive surgical margins (odds ratio [OR] 0.68; 95% CI 0.61-0.75; p < 0.0001), increased use of chemotherapy (OR 1.33; 95% CI 1.18-1.5; p < 0.0001), and increased use of neoadjuvant radiation (OR 1.94; 95% CI 1.72-2.2; p < 0.0001). Patients treated at high volume centers had an 8% decreased risk of death compared to those treated at low volume centers (hazard ratio [HR] 0.92; 95% CI 0.85-0.99; p = 0.045). The association between high volume centers and outcomes differed by treatment center type, with high volume academic institutions showing the strongest improvement in survival (HR 0.89; 95% CI 0.81-0.97; p = 0.004), and high volume community centers showing decreased survival (HR 1.9; 95% CI 1.3-2.9; p = 0.004). Conclusions: This study demonstrates different patterns of care and improved outcomes for soft-tissue sarcoma patients treated at high volume treatment centers. Though patient selection bias could influence these associations, overall these findings affirm the suggested benefits of receiving care at experienced treatment centers.
Short course pembrolizumab in complete responders with advanced non-small cell lung cancer.
Authors: Daniel Boon Yeow Chan
Journal: Journal of Clinical Oncology (2017)

e20537 Background: Pembrolizumab has been available in Singapore since October 2014 for clinical use. All clinical trial protocols of Pembrolizumab in patients with advanced non-small cell lung cancer (NSCLC) require a 2 year period of treatment in responders, even in complete responders. It is not known if shorter treatment durations in complete responders can afford reasonable progression free interval (PFS). Such abbreviated treatment in complete responders would result in significant cost savings and lesser side effects. Methods: A single physician practising at a single private medical oncology center in Singapore collated consecutive cases of advanced NSCLC seen by him and treated with Pembrolizumab from October 2014 till December 2016. All were smokers except for 2 patients. All patients were biopsy and imaging proven to have advanced NSCLC. 46 patients were treated with Pembrolizumab 2mg/kg body weight 3 weekly and observed with sequential imaging every 3-6 months with the first assessment scan after Cycle 4. All complete responders by imaging stopped treatment after 4 cycles of Pembrolizumab by mutual consent. PD-L1 IHC testing by DAKO 22C3 was not done on any of the patients’ tumours as the test has only been available in Singapore since December 2016. Results: Cut-off date for analysis of data was 1 Feb 2017. 4 out of 46 patients (9%) achieved a complete metabolic response on FDG PET by irRC and/or CT scans by RECIST 1.1. All 4 patients with complete response (CR) (except Patient #3) were smokers. All 4 patients remain in CR with ECOG Performance Status (PS) 0 without any further treatment. Conclusions: Real world clinical usage of Pembrolizumab in advanced NSCLC can afford long PFS in complete responders in spite of abbreviated treatment of 4 cycles. Clinical trials should be designed to address this issue due to its impact on health care costs. [Table: see text]
The impact of CMV reactivation on HSCT outcomes in children with malignancies: A 13 years single center experience.
Authors: Francesco Baccelli, Alessandro Di Gangi, Sayla Bernasconi, Gabriella Casazza, Claudio Favre, Mariacristina Menconi
Journal: Journal of Clinical Oncology (2018)

10572 Background: After the introduction of pre-emptive therapy, the incidence of CMV disease dramatically decreased in HSCT recipients, while indirect effects of CMV infection (CMVI) are still under investigation. Methods: We retrospectively analyzed children ( < 18 years) who underwent first allogeneic HSCT for malignancies at our institution between 01/2003 and 12/2016. CMVI was defined as the presence of pp65 or DNA in any body fluid. Patients were classified according to their CMVI status. 5-years probabilities of OS, DFS, GVHD-free relapse-free survival (GRFS) and infections were estimated using Kaplan-Meier method and log-rank test. Cumulative incidence and Gray’s test were used to assess differences in relapse, NRM, aGVHD grades 2-4, extensive cGVHD (e-cGVHD), neutrophils and platelets engraftment. Cox regression was performed to identify possible correlations. Major endpoints are reported in Table 1 with standard errors (SE). Results: 92 HSCT were included (CMVI+ N = 40). Groups were homogeneous for age, sex, diagnosis, donors, HSC source and graft composition with the exception of lower median cellularity in UCBU. No significant differences were reported for OS, DFS, infections, GRFS, relapse, NRM, and both neutrophils and platelets engraftment (p > 0.05). The mean day of CMVI diagnosis was 39.6 (28.2-51.0). Although statistically non-significant aGVHD grade 2-4 was higher in CMVI+, suggesting a possible association. Noticeable, aGVHD has often preceded CMVI (N = 7 vs N = 1). In contrast, e-cGVHD was less frequent in CMVI+ patients. Remarkably, infections were slightly higher in the early period in CMVI+. Conclusions: Despite variations in HSCT procedures and the limited sample size, pre-emptive therapy determined a dramatical decrease in CMV indirect effects. Moreover, aGVHD is a possible risk factor for CMVI but not vice versa. However, further evidences are needed to enlighten the role of CMV in the modern era of pediatric HSCT. Endpoints (SE) CMVI+ CMVI- p OS 70.0 (.07) 64.5 (.07) ns DFS 59.9 (.08) 64.1 (.07) Relapse 25.1 (.07) 24.2 (.06) NRM 5.0 (.04) 4.1 (.03) aGVHD 20.0 (.06) 9.6 (.04) e-cGVHD 6.3 (.04) 13.1 (.07) GRFS 35.0 (.08) 46.4 (.07) Infections 58.3 (.09) 47.8 (.08)
Methodological Issues in Studying PAHSA Biology: Masking PAHSA Effects
Authors: Ismail Syed, Jennifer Lee, Odile D. Peroni, Mark M. Yore, Pedro M. Moraes-Vieira, Anna Santoro, Kerry Wellenstein, Ulf Smith, Timothy E. McGraw, Alan Saghatelian, Barbara B. Kahn
Journal: Cell Metabolism (2018)
An orally available tubulin inhibitor, VERU-111, to overcome paclitaxel resistance and to suppress breast cancer tumor growth and metastasis.
Authors: Shanshan Deng, Raisa I Krutilina, Qinghui Wang, Tiffany N. Seagroves, Duane D. Miller, Wei Li
Journal: Journal of Clinical Oncology (2018)

e13110 Background: Triple negative breast cancer (TNBC) is highly aggressive that has poor prognosis due to the development of drug resistance. In this study, we evaluated the preclinical efficacy of the potent tubulin inhibitor, VERU-111, in treating TNBC in mouse xenograft models. Methods: We first conducted in vitro studies to evaluate the anticancer potency and induction of apoptosis of VERU-111 in TNBC cells (MDA-MB-468 and MDA-MB-231). We then determined the efficacy of VERU-111 in MDA-MB-231 cell xenografts into NSG mice. Primary tumor size and body weight of the mice were monitored during the treatment. After 33 days treatment, when the tumor size in the vehicle group reached 1000 mm3, tumors and major organs were collected for histological analysis. Efficacy was also tested in a tail vein injection mouse model and all major organs were collected at 23 days. The degree of tumor necrosis and metastatic burden were determined by H&E staining and cell proliferation, apoptosis and angiogenesis were measured after immunostaining. Results: VERU-111 showed remarkable anticancer activities against two TNBC cell lines with IC50 values of 8 and 23 nM, efficiently inhibited the cancer cell colony formation and suppressed cell migration and invasion. It also strongly induced apoptosis in TNBC cells in vitro. In vivo, orally administered VERU-111 inhibited TNBC xenograft tumor growth in a dose-dependent manner (80% tumor growth inhibition at 12.5 mg/kg) with similar efficacies to that of paclitaxel and without acute toxicity. In addition, orally administered VERU-111 significantly reduced metastasis of TNBC in an experimental metastasis model. Finally, VERU-111 effectively suppressed tumor growth and metastasis in a strong paclitaxel-resistant TNBC tumor model. Conclusions: Collectively, these preclinical studies strongly suggest that VERU-111 is a potent inhibitor of the growth and metastasis of TNBC in vitro and in vivo. Orally administered VERU-111 also effectively circumvents paclitaxel resistance. VERU-111 is a promising new generation of tubulin inhibitor for the treatment of drug resistant TNBC. A Phase 1/2 clinical trial of VERU-111 will begin later this year.
Association of decrease of left ventricular ejection fraction with overall survival benefit in trastuzumab treated metastatic esogastric cancer patients.
Authors: Jerome Martin-Babau, Yves Eusen, Laurent Doucet, Helene Simon, Elisabeth Gaye, Laura Deiana, Laurent Corcos, Cedric Le Marechal, Jean-Philippe Metges
Journal: Journal of Clinical Oncology (2016)

e15514 Background: Trastuzumab is used in Her2 positive metastatic esogastric cancers along with chemotherapy. Cardiotoxicity (CT) of trastuzumab has been described in Her2 positive breast cancers and occurs with asymptomatic lowering of Left Ventricular Ejection Fraction (LVEF) in up to 10% of cases. We wanted to evaluate the impact of CT on esogastric cancer patient's outcomes. Methods: This monocentric retrospective study measured the incidence of symptomatic and asymptomatic CT in patients treated for metastatic esogastric cancers and its impact between October 2009 to January 2016. Patients should receive trastuzumab with chemotherapy for treatment of Her2 positive metastatic esogastric cancer as a 1st lign treatment. We compared outcomes of patients with CT to the other patients. Results: 27 patients received trastuzumab along with chemotherapy during the period of study. Median age was 62.3 years, sex ratio 21 M/6 W. Between the enrollment echocardiogram and the 3rd month evaluation 8 patients (29%) developped a CT : - either asymptomatic (n = 6) with a decrease of 5% of LVEF or more - or symptomatic (n = 2) : one cardiac failure and one myocardial infarction - no related death. There was no difference in the number of cycles of trastuzumab (p = 0.10). Cardiovascular comorbidities and cardiac irradiation during previous radiotherapy treament did not appear as a predictive factor of CT (p = 1). Progression Free survival of patients was not statistically modified by the occuring of CT even if we noted a trend to better outcome of the patients presenting an asymptomatic LVEF lowering (9 months versus 4.62 months ; p = 0.0845). Overall survival (OS) was improved in patients with CT (23 months) compared to the others (7.7 months) (p = 0.0349). Conclusions: This study shows a statistical improvement of OS for patients with mild cardiotoxicity of trastuzumab. The incidence of asymptomatic cardiotoxicity seems to be higher in esogastric patients than breast cancer patients. Cardiovascular comorbidities didn’t appear as predictive factors of trastuzumab induced CT. Further investigations are required to confirm these results.
A phase II study evaluating efficacy of zoledronic acid in prevention of aromatase inhibitor (AI)-associated musculoskeletal symptoms: The ZAP trial.
Authors: Cesar Augusto Santa-Maria, Aditya Bardia, Amanda Blackford, Roisin M. Connolly, John H. Fetting, Stacie Jeter, Robert Stephen Miller, Anne T Nguyen, Katie Quinlan, Shannon Slater, Claire Frances Snyder, Antonio C. Wolff, Jane Zorzi, N. Lynn Henry, Vered Stearns
Journal: Journal of Clinical Oncology (2014)

9615 Background: Aromatase inhibitor-associated musculoskeletal symptoms (AIMSS) contribute to significant morbidity and therapy discontinuation. Retrospective data suggest that bisphosphonates may reduce the prevalence of AIMSS. Methods: We conducted a single-arm prospective clinical trial in postmenopausal women with stage 0-III breast cancer scheduled to initiate adjuvant AI, designated ZAP. Eligible women received intravenous zoledronic acid 4 mg (ZA) at baseline and 6 months, and started letrozole 2.5 mg daily 1-2 weeks afterwards. We compared the percentage of women who developed AIMSS over 12 months to historical controls not taking bisphosphonates from the Exemestane and Letrozole Pharmacogenetics (ELPh) trial (NCT00263913). AIMSS were defined as an increase of 0.22 from a scale of 0-3 in the Health Assessment Questionnaire Disability Index (HAQ-DI) and/or 2.0 cm in the Visual Analog Scale (VAS). AIMSS were assessed at 1, 3, 6, and 12 months and compared between studies with a logistic regression model adjusting for patient age, body mass index, race, prior chemotherapy, and prior tamoxifen use. We also evaluated the probability of AI discontinuation or change to another endocrine therapy by 1 year using a Kaplan Meier approach. Results: From 2011 to 2013, 59 women enrolled in ZAP. All (100%) and 52 (88%) women received baseline and 6 month ZA, respectively. 435 of 502 women from ELPh were eligible as historical controls. Both cohorts had similar characteristics, except more women in ELPh received prior tamoxifen. Twenty-two (37%) and 267 (61%) women on ZAP and ELPh, respectively, reported AIMSS during the first year (p<0.001). Five (8%) and 67 (15%) women on ZAP and ELPh discontinued AI or changed endocrine therapy (p=0.24). The cumulative probability of discontinuing AI or changing endocrine therapy was 9% for ZAP and 21% for ELPh (log rank p=0.05). Conclusions: Compared to historical controls, ZA prophylaxis in the adjuvant setting is associated with reduced AIMSS and decreased probability of AI discontinuation or change. A prospective randomized control trial is required to confirm these findings. Clinical trial information: NCT01194440.
NCI 9922: Phase 2 study of ibrutinib in treatment-refractory distant metastatic cutaneous melanoma (DMCM).
Authors: Stergios J. Moschos, Zeynep Eroglu, Elizabeth Mary Gaughan, Theresa Michelle Medina, Peng Wang, Elizabeth Claire Dees, Leanne Cartee, Christy Arrowood, Craig Carson, Nancy E Thomas, David W. Ollila, Nana Nikolaishvilli-Feinberg, S. Percy Ivy, Pamela Jo Harris, Herbert Hurwitz
Journal: Journal of Clinical Oncology (2017)

TPS9592 Background: We have previously shown that the IL-2 inducible kinase (ITK) is highly expressed in primary melanomas compared with nevi due to promoter hypomethylation (Conway PCMR 2011). We have also shown using 2-color immunofluorescence (2CIF) that ITK protein expression is increased even more in metastatic compared to primary melanomas (S100+) and that molecular targeting (shRNA) or pharmacologic inhibition of ITK (BI 10N) in various melanoma cell lines, various melanoma xenografts and an immunocompetent melanoma mouse model suppresses cell proliferation and retards tumor growth without inducing cell death (Carson CCR 2015). We have also shown by intracellular stain of peripheral blood mononuclear cells (PBMC) that ITK is expressed in PBMC obtained from patients (pts) treated with MAPK or CTLA-4 inhibitors. Other groups have shown that ITK and BTK are expressed in Th2 cells, myeloid-derived suppressor cells, and tumor-associated macrophages. We have also shown that ibrutinib suppresses proliferation of various melanoma cell lines in low nM concentrations depending on tumoral expression of ITK. We hypothesize that targeting DMCM with ibrutinib alone will induce antitumor responses and/or prolong survival if DMCM expresses high levels of melanoma-associated ITK by 2CIF (S100/ITK). Methods: This is an open-label, single-arm, multicenter, phase II study of DMCM refractory to or ineligible for PD-1 and MAPK inhibitors. Ibrutinib will be dosed at 840 mg p.o. qd. The null hypothesis is that an ineffective drug will confer a 5% response rate (RR) and 18% 6-month PFS (6m PFS), whereas ibrutinib will confer &gt; = 20% RR and &gt; = 35% 6m PFS (KEYNOTE-002). This trial accrues in two stages; if either the RR and/or 6m PFS endpoint are met after 18 patients, then 14 additional pts will be accrued for a total of 32. The Simon’s design will reject the null hypothesis if &gt; = 4 responses are observed or &gt; = 9 pts have PFS better than 6 months out of 32 patients. All pts are required to have baseline tumor tissue available for analysis of ITK expression by 2CIF. Immune monitoring will be performed on PBMC collected at baseline and various time points during treatment. Trial is currently recruiting pts (NCT02581930). Clinical trial information: NCT02581930.