tbuckley/cabot-search huggingface dataset:
A phase Ia/Ib study of a novel BTK inhibitor, DTRMWXHS-12 (DTRM-12), and combination products, with everolimus and pomalidomide, in pts with CLL or other B-cell lymphomas.
Authors: Jennifer Gill, Wei He, Stephen J. Schuster, Danielle M. Brander, Elizabeth Chatburn, Kaitlin Kennard, Barry Douglas Anderson, Sunita Nasta, Daniel Jeffrey Landsburg, David L. Porter, Ellen Napier, Tanya Latorre, Jakub Svoboda, Victoria Addis, Anthony R. Mato
Journal: Journal of Clinical Oncology (2017)

TPS7570 Background: Synthetic lethality (SL) relies on the chemical inhibition of two aberrant genes to selectively kill malignant cells. SL is now a clinical reality in an era of multiple targeted agents and advanced genetic testing. We investigated small molecule combinations for SL through in vitro and in vivo screening and optimization studies (Table, US patent 20160324878) and demonstrated the potential of SL through best-in-class combinations of targeted agents, immune modulation and low-dose combinations. We hypothesize that BTK and mTOR inhibition combined with an IMiD target multiple key signaling pathways, improve selective cell kill and address acquired drug-resistance. DTRM-555 is an optimized mechanism-based combination of the novel BTK inhibitor DTRM-12, with everolimus (E) and pomalidomide (P). In xenograft tumor models, DTRM-555 has shown superior efficacy over single agents at lower combined doses (1/18 of DTRM-12, 1/6 of E, and 1/6 of P). Methods: We are conducting a phase I, first-in-human multicenter trial exploring DTRM-555 in pts with CLL and B-cell NHL. Phase Ia consists of escalating DTRM-12 monotherapy doses. Phase Ib will explore doublet combination of DTRM-12 plus everolimus, and DTRM-555, the novel triplet combination. Safety is the primary study endpoint. Secondary endpoints include anti-tumor activity and pharmacokinetic studies. Eligible pts are &gt; / = 18 years / ECOG &lt; / = 1 with CLL or B-cell NHL with no available therapies. Treatment is administered for 21 consecutive days of a 28-day cycle, until disease progression or unacceptable toxicity. The trial commenced on 9/27/16. Phase 1a (single subject, 50/100mg respectively) has enrolled 5 pts without DLT and is currently at the 200 mg dose level. Up to 50 pts will be enrolled. Five additional sites are planned to open in the near future across the US. Clinical trial information: NCT02900716. [Table: see text]
Role of FDG-PET/CT and gastrointestinal endoscopy in the staging of diffuse large B-cell lymphoma (DLBCL): Expanded data.
Authors: Tadahiro Honda, Dai Maruyama, Hiroaki Kurihara, Akiko Miyagi Maeshima, Sayako Yuda, Kosuke Toyoda, Nobuhiko Yamauchi, Shinichi Makita, Suguru Fukuhara, Wataru Munakata, Yukio Kobayashi, Hirokazu Taniguchi, Yutaka Saito, Kensei Tobinai
Journal: Journal of Clinical Oncology (2016)

e19057 Background: The Lugano Classification incorporating FDG-PET/CT in the staging and response assessment of lymphomas was published (JCO 2014). We previously reported that there was some non-negligible discrepancy between the clinical stage assessed by FDGPET/CT and that assessed by the conventional evaluation (ESMO Asia 2015). We expanded the number of the patients in addition to the previous study to make our data more reliable. Methods: Patients (pts) who were initially histopathologically diagnosed as having DLBCL at our institution from 2010 to 2014 were included. The clinical stage using FDG-PET/CT was compared to that assessed by the conventional evaluation based on CT, esophagogastroduodenal endoscopy (EGD) and bone marrow (BM) examination. Results: A total of 163 pts were identified as subjects of this retrospective analysis with a median age of 65 years (range; 23-86). 18 pts (11%) resulted in upstaging through conventional evaluation plus FDG-PET/CT; 2 from stage I to II, 5 from I to IV, 2 from II to III, 7 from II to IV, and 2 from III to IV. 3 pts (2%) resulted in downstaging; 1 from stage II to I, and 2 from IV to III. Gastrointestinal tract (GIT) lesions contributed to upstaging most, which accounted for 44% of upstaged pts. However, compared with EGD, FDG-PET/CT seems to be less accurate in detecting gastric lesions. Postulating EGD as standard examination, false-negative rate of FDG-PET/CT in gastric lesions was 31% (Table 1). FDG-PET/CT positive colon lesions in 6 pts were found to be false-positive by colonoscopy as they were adenocarcinoma/adenoma. Bone or BM lesions were more frequently detected by FDG-PET/CT. BM examination detected 17 pts (10%) with BM lesions, while FDG-PET/CT detected 30 pts (24%). However, 3 pts (2%) of BM lesions went undetected by FDG-PET/CT. Conclusions: Our data suggests that FDG-PET/CT cannot completely take the place of conventional staging evaluation for DLBCL mainly because of its low accuracy in detecting GIT lesions, although FDG-PET/CT is useful in the staging of DLBCL. Therefore, we recommend EGD as one of the routine staging procedures of DLBCL. EGD&Biopsy + − FDG-PET/CT + 18 3 − 8 126
Impact of Canadian Cancer Trials Group (CCTG) phase III trials (P3Ts).
Authors: Patricia A. Tang, Joe Pater, Maclean Harvey Thiessen, Richard M. Lee-Ying, Jose Gerard Monzon, Winson Y. Cheung
Journal: Journal of Clinical Oncology (2018)

e18901 Background: P3Ts generate the highest level of evidence at the expense of investment from national agencies and institutional infrastructure. We evaluated the impact of CCTG P3Ts (primary publication) with respect to secondary (2°) publications, citations, citation by guidelines, meta-analyses, and new indications. Methods: Primary (1°) and 2° publications from CCTG led P3Ts (1984-2017) were identified from the CCTG website. Data extraction included: 1° endpoint type and outcome, setting, and 2° endpoints. An endpoint was categorized as positive if results were statistically significant in favor of the experimental arm or if non-inferiority criteria were met. Any 2° publications that used data from ≥ 1 trial were weighted by dividing by the number of trials. Chi square test was used to evaluate factors associated with guideline citation. Results: Characteristics of the 86 P3Ts included: median sample size 302 (range 31- 7576), median journal impact factor 24 (range 0-72) [see table]. The 1° endpoint was positive in 32.6% (n = 28) trials. A 2° endpoint was positive in the absence of a positive 1° endpoint in 17 trials (19.8%). Fifty-four trials (62.8%) generated 2° publications [40 quality of life, 25 correlative, 5 cost, range 0.3-27.3]. The number of citations per 1° publication ranged from 0-3859 (median 72). Guidelines cited 56 trials; this was associated with a positive 1° endpoint (23 positive vs 33 negative trials, p = 0.03), but not larger sample size (≥ median), nor a 1° endpoint of overall survival. There were 9 new chemotherapy indications and 1 delisting. Conclusions: CCTG P3Ts influenced new drug indications, generated numerous 2° publications, and were cited by guidelines and meta-analyses. Although guideline citation was associated with a positive 1° endpoint, many negative trials were also cited. Characteristic Number (n = 86) Percentage Tumor type Breast 16 18.6 Lung 14 16.3 Heme 11 12.8 Other 45 52.3 Setting Curative 38 44.2 Palliative 27 31.4 Supportive Care 18 20.9 Prevention 2 2.3 Other 1 1.2 1° endpoint Overall survival 39 45.3 Overall survival 14 16.3 Response rate 6 7.0 Other 27 31.4 Outcome of 1° endpoint Null 55 64.0 Favor experimental arm 28 32.6 Favor control arm 3 3.5 Citation Any 84 97.7 Meta-analysis or guideline 63 73.3 Guideline 56 65.1
A nationwide analysis of palliative care service utilization in hospitalized metastatic cancer patients.
Authors: Kaushal Parikh, Srikanth Yandrapalli, Arun Kumar, Michael Frankenthaler, Delong Liu
Journal: Journal of Clinical Oncology (2018)

6602 Background: ASCO guidelines recommend palliative care consultation (PC) to patients with advanced cancer to improve quality of life and overall survival. However, limited data are available on contemporary trends in PC utilization in hospitalized metastatic cancer patients. Methods: We used the 2005-2014 Unites States National Inpatient Sample to identify all hospitalizations in adult patients with a primary or secondary discharge diagnosis of lung, prostate, breast, or colorectal cancers, with documented metastasis. Multivariable logistic regression models accounting for the complex survey design were used to analyze associations of PC with various cancer related complications, comorbidities, and patient and hospital demographics. Results: Of the 3,040,740 cases included in the study, 289,600 (9.5%) had PC. Median ages of patients with prostate, lung, colorectal, and breast cancers were 76, 67, 65, and 61 years, respectively. There was a 550% increase in PC utilization between 2005 and 2014 (2.7% to 17.5%; P < 0.001). While the utilization rate was highest with metastatic lung cancer (3% in 2005 to 20.2% in 2014; P < 0.001), increase in utilization was highest for colon cancer (577%; 2.2% in 2005 to 14.9% in 2014; P < 0.001). Overall, cancer related pain (adjusted Odds ratio (aOR) 2.35, 95% confidence interval (CI) 2.26-2.45; P < 0.05) and failure to thrive (aOR 2.19, 95% CI 2.09-2.29; P < 0.05) were strongly associated with PC referrals. Age > 65 years (aOR 1.56, 95% CI 1.46-1.67; P < 0.05), respiratory failure (aOR 2.10,95% CI 2.03-2.16; P < 0.05), and sepsis (aOR 1.12, 95% CI 1.078-1.16; P < 0.05) were also independently associated with PC. PC was more likely to be utilized in teaching hospitals (aOR 1.25, 95% CI 1.16-1.34; P < 0.05), large-sized hospitals (aOR 1.25, 95% CI 1.13-1.37; P < 0.05), and west coast hospitals (aOR 1.31, 95% CI 1.17-1.47; P < 0.05). Conclusions: Despite a significant rise between 2005 and 2014, palliative care services are still underutilized for hospitalized advanced cancer patients in the United States. Cancer related pain and failure to thrive were strongly associated with PC utilization. Regional and hospital based variations exist in PC utilization in patients with metastatic tumors.
TCT-680 Trends and predictors of early readmission in STEMI patients undergoing multivessel percutaneous coronary intervention
Authors: Byomesh Tripathi, Varun Kumar, Varunsiri Atti, Srikanth Yandrapalli, Deepak Asti, Nikhil Nalluri, Praveen Vemula, Saurav Chatterjee
Journal: Journal of the American College of Cardiology (2018)
Phase II multicenter, single arm, open label study of nivolumab (NIVO) in combination with ipilimumab (IPI) as first line in adult patients (pts) with metastatic uveal melanoma (MUM): GEM1402 NCT02626962.
Authors: Josep M. Piulats, Luis De La Cruz-Merino, Maria Teresa Curiel Garcia, Alfonso Berrocal, Lorenzo Alonso-Carrión, Enrique Espinosa, Rafael López Castro, Delvys Rodriguez-Abreu, Pablo Luna Fra, Salvador Martin-Algarra
Journal: Journal of Clinical Oncology (2017)

9533 Background: Uveal melanoma is the most common primary intraocular malignant tumor in adults. Overall Survival (OS) at 5 years(y) is 62% due high incidence of liver metastasis, fatal within 4-9 months(m) from diagnosis. No standard treatment exists for MUM. NIVO+IPI combination has shown efficacy in metastatic cutaneous melanoma. However, MUM pts were excluded in these trials. Methods: GEM1402 is a phase-2 trial evaluating NIVO+IPI in untreated adult pts with MUM; is being conducted in 10 centers in Spain, leading by the Spanish Melanoma Group. Eligible pts had histologically-confirmed MUM, ECOG-PS 0/1, and no prior systemic treatment for MUM. Treatment consisted in NIVO (1mg/kg, iv, q3 weeks [wk]) and 4 doses of IPI (3mg/kg iv q3wk) followed by NIVO (3mg/kg q2wk) until progressive disease (PD), toxicity or withdrawal. Primary endpoint is OS and secondary progression free survival (PFS), Overall Response Rate (ORR) (per RECIST 1.1) and safety. Radiologic evaluations q6wk. Interim analysis (n = 19) was planned per protocol to assess safety and ORR. Intention to treat analysis includes pts with PD at first radiological evaluation. Safety population includes all pts receiving at least one dose of study treatment. Results:19 pts enrolled from April to July 2016: Median age 62y (43y-82y), 63% male, liver M1 84% pts and extra-liver M1 42% pts, 31% elevated baseline LDH. 11 pts completed cycle 2 and 8 pts stopped after 1 dose (6 PD, 2 toxicity). Treatment-related adverse events were reported in 12 pts and lead to end of treatment in 2 pts. Grade ≥3 toxicities were seen in 7 pts (36.8%): diarrhea, transaminitis, dermatological events, anemia, acute thyroiditis. All G3/4 were resolved following the toxicity guideline. One G5 acute thyroiditis related to NIVO+IPI was reported. ORR was observed in 15.8% and disease stabilization in 47.4%. With a median follow-up of 4.6m, PFS was 4.99m. Median OS was not reached at time of this analysis. Conclusions: Combination of NIVO+IPI is feasible for MUM. In this INTERIM ANALYSIS, ORR did not reach yet 20%, but PFS seems promising. The clinical trial is ongoing. Final results will be updated. Clinical trial information: 2015-004429-15.
Druggable molecular targets in skin adnexal malignancies.
Authors: Stefano Cavalieri, Federica Perrone, Pasquale Quattrone, Laura Locati, Cristiana Bergamini, Roberta Granata, Salvatore Alfieri, Carlo Resteghini, Donata Galbiati, Francesca Platini, Giuseppina Calareso, Lisa F. Licitra, Paolo Bossi
Journal: Journal of Clinical Oncology (2018)

e21619 Background: Skin adnexal cancers (SAC) are a heterogeneous group of rare malignancies with histologic differentiation towards epithelial adnexa. Some histological types are associated with a higher metastatic potential. In case of recurrent or metastatic (RM) disease, effective systemic treatments lack. The aim of this work is to identify any potentially druggable genomic alterations for targeted therapies. Methods: Cases of primary or RM SAC between 2002 and 2014 were identified by searching the cancer registration database of our Institution. Histological sections of all referral cases were reviewed by a dedicated pathologist to confirm SAC diagnosis. Next generation sequencing (NGS) technique was performed to identify targetable mutations (panel of 50 genes analyzed by hot-spot Cancer Panel IonTorrent technology). Mutational analysis of PTCH1 and SMO genes was specifically assessed by PCR as they were not present in the NGS panel. Immunohistochemistry (IHC) was performed to assess the expression of androgen receptors (AR) and human epidermal growth factor receptor type 2 (HER-2). Results: A total of 45 cases with available histological samples were identified (13 primary, 32 RM). The most frequent histological type was porocarcinoma (12), followed by ductal eccrine carcinoma (5). DNA was adequate for NGS analysis in 25 cases. In the majority of cases (17 - 68%) at least one mutation in oncogenes or tumor suppressor genes was found: the most frequent ones involved TP53 (13 cases - 76% of mutated SACs) and PIK3CA (3 cases - 18%). Thirty cases were suitable for SMO and PTCH1 PCR analysis. Rate of PTCH1 mutation was 30% (9/30), while no SMO mutations were observed. All cases were tested for AR. In the overall population, 14 cases (31%) were AR+ (12/32 RM, 38%; 2/13 primary, 15%). HER-2 was shown as 2+ in 8 cases (all RM) out of the 42 specimens tested at IHC. Conclusions: To our knowledge this is the largest case series of molecularly dissected SAC ever reported in the literature. In most subjects (68%) NGS showed at least one cancer associated mutation. Some potential druggable targets were identified. In particular, AR, HER-2, PIK3CA, TP53, and PTCH1 were the most frequently observed. These findings support the use of molecular screening in patients with advanced SAC.
Combinatorial inhibition of Polo-like kinase 1 (PLK1) and microtubule dynamics to induce synthetic lethality in ovarian cancer cells with CCNE1-amplification.
Authors: Sven Becker, Monika Raab, Yves Matthes, Mourad Sanhaji, Andrea Krämer, Ahmed El-Balat, Klaus Strebhardt, Sabrina Noack
Journal: Journal of Clinical Oncology (2018)

e17537 Background: High-grade serous ovarian cancer (HGSOC) (70%) has poor prognosis. Drivers of HGSOC are p53 mutations, homologous recombination deficiencies and CCNE1-amplification. Olaparib changed the treatment of BRCA1/2-mutated Tumors. The amplification of CCNE1 in HGSOC without BRCA mutation correlates often with platinum-resistance and an unfavorable outcome. New strategies are needed for the treatment of CCNE1-amplified tumors. Methods: In a siRNA-based kinome-wide screening using OvCar3 cells to identify sensitizers of CCNE1-amplified OC-cells to a taxane-based treatment, we identified PLK1 as key determinant for the survival of CCNE1-amplified cells. PLK1 is a serine/threonine kinase, which is essential for mitotic progression. Remarkably, our cDNA array-based investigation showed an upregulation of PLK1 expression upon paclitaxel treatment highlighting PLK1 as target for paclitaxel-based approaches. Its inhibition resulted in apoptosis due to mitotic catastrophe. We proceeded using the clinical PLK1-inhibitor BI6727 to test for the sensitization of CCNE1-amplified cells to taxane-induced cell death, aiming at dose-reduction for paclitaxel to reduce adverse events associated with microtubule-stabilizing agents. Results: Following the treatment of paclitaxel with BI6727, we observed synergistic effects on cell vitality of CCNE1-amplified ovarian cells, resulting in apoptosis. Induction of the intrinsic apoptotic pathway is promoted via stabilization of Fbw7 and degradation of Mcl1. Paclitaxel-BI6727 treatment induced long-term effects on the colony formation ability of OvCar3. Reduced neurotoxicity in the PC12 cell model was observed. The combined treatment reduced the survival of primary HGSOC cells in 2D assays and 3D spheroids. The importance of PLK1 for OC development was underscored in a Kaplan-Meier-analysis showing negative correlation between its expression and the progression free survival of patients with early stage OC. Conclusions: The combination of paclitaxel with PLK1-inhibitors is a promising novel strategy for the treatment of HGSOC patients with CCNE1-amplification.
METRO-BIBF: Phase II, randomised, placebo controlled, multicentre, trial of low dose (metronomic) cyclophosphamide (MCy) with or without nintedanib in relapsed ovarian cancer (ROC).
Authors: Marcia Hall, Hakim-Moulay Debhi, Shibani Nicum, Rosemary Lord, Susana N. Banerjee, Andrew R. Clamp, Rachel Lilleywhite, Rosalind Margaret Glasspool, Amanda Feeney, Allan Hackshaw, Jonathan A. Ledermann
Journal: Journal of Clinical Oncology (2018)

5551 Background: ROC patients (pts), heavily pretreated with IV chemotherapy (CT) are a heterogenous group, median OS 3-9 mo. Oral MCy is well tolerated, avoids IV CT and has been shown to have clinical benefit. MCy has anti-angiogenic properties, inhibiting growth of tumour, endothelial and host vasculature. Augmentation with bevacizumab showed encouraging results in single arm studies. METRO-BIBF evaluates a novel combination of MCy with either placebo (P) or nintedanib (N)- oral inhibitor VEG/PDG/FGFR tyrosine kinases. Methods: Eligible pts received ≥2 lines of CT; platinum-resistant/intolerant, ECOG PS 0-2, life-expectancy of > 6 weeks. MCy (100mg/d) was given continuously with either N or P, to progression / toxicity. No prior TKI permitted; pts stratified for prior bevacizumab. Priamry aim to increase median OS by 2 mo. PFS, toxicity and QoL also measured. Results: 117 pts were randomised 08/14 – 10/16, median age 64, 87% HGS ROC, 39% pts ≥ 5 lines prior CT. Dose of N/P was reduced from 200 to 150 mg bd after planned review of N/P/MCy in first 46 pts. 96 patients have died. N had no effect on OS (HR 1.08, p = 0.72). Table shows OS/PFS by arm. Combining MCy pts from both arms, median OS was 6.4 mo and 26 patients (23%) took MCy for ≥ 6 mo. Pts without prior bev treatment (69%) stayed longer on MCy than pts with prior bev (31%) (mean diff: 53 days, p < 0.01). Grade 3-4 toxicity as expected in 64.4% pts on N/MCy vs. 54.5% pts on P/MCy; more N/MCy pts had neutropenia and diarrhoea. Two treatment-related deaths: 1 bowel perforation, possibly disease-progression (N), 1 liver failure (P). QoL did not differ between arms. Conclusions: Adding N to MCy did not improve OS/PFS. But in this large study of MCy in heavily pre-treated ROC, almost one quarter remained on therapy for > 6 months, suggesting either more indolent disease and/or MCy has longer-term cytostatic or immunological benefits requiring further investigation. Clinical trial information: NCT01610869. Placebo (N = 55*) *3 pts did not start M/Cy Nintedanib (N = 59) Median OS (95% CI) mo 6.4 (5.0-10.1) 6.8 (4.5-9.5) OS: 6 mo 50.9% 55% OS: 12 mo 31.3% 20% Median PFS (95% CI) mo 2.7 (2.5-4.7) 2.9 (2.7-4.6) PFS: 6 mo 22.8% 29.6% PFS: 12 mo 5.7% 5.9%
Real-world outcomes with panobinostat in patients with penta- and quad-refractory multiple myeloma.
Authors: Noa Biran, David H. Vesole, Shijia Zhang, Joshua Ryan Richter, Yen Hong Kuo, Linda Schmidt, Laura McBride, Palka Anand, Kristin Ivanovski, Amy Pierre, Susan Kumka, Carmella Cucurrulo, David Siegel
Journal: Journal of Clinical Oncology (2017)

e19522 Background: Panobinostat (pano) is a pan histone de-acetylatase inhibitor (HDAC-i) approved by the FDA for use with bortezomib (btz) and dexamethasone (dex) for patients with multiple myeloma (MM) who have had ≥2 prior lines of therapy including both btz and an immunomodulatory agent (IMiD). The goal of this retrospective study is to evaluate the efficacy and safety of pano in combination with a variety of FDA approved agents as would be utilized in a real world management in relapsed/refractory (RR) MM. Methods: Between February 2015 and July 2016, 37 consecutive patients with RRMM treated with commercial pano were identified and the electronic medical record was reviewed. Results: Median age was 62 (range 27-78), with 57% percent male. Ten (27%) had high-risk FISH as defined by t(14;16), t(4;14), del p53, and gain 1q21. Median number of prior lines was 6 (range 2-9). All patients were RR to their last line of therapy, and 20 (54%) were btz-refractory, 27 (73%) were lenalidomide-refractory, 29 (78%) were pomalidomide-refractory, and 29 (78%) were carfilzomib-refractory. Thirty-three (89%) were penta-refractory; eight (21%) were penta-refractory, and 4 (11%) were refractory to prior HDAC-i therapy. Median number of cycles with pano was 2 (range 0.25 - 10). The overall response rate (≥ partial response) was 29.4% and the clinical benefit rate (≥ minor response) was 71.4%. Median progression-free survival was 2.4 months (95% CI: [1.63 – 4.43]). Median duration of response (≥SD) was 4.1 months. Median overall survival from initiation of pano was 7.5 months (95% CI: [5.17, NA]). One patient discontinued pano due to AEs. Grade 3 and 4 non-hematologic toxicities were diarrhea (N = 1), and respiratory failure (N = 1). Grade 3 and 4 hematologic adverse events (AEs) occurred in 13 (35%) patients, with 7 (19%) anemia, 11 neutropenia (30%), and 10 (37%) thrombocytopenia. Serious AEs included acute kidney injury, GI bleed, and febrile neutropenia each occurring in 1 patient. Conclusions: Use of pano outside of the FDA indication in combination with PI and IMiD-based regimens has activity and is well tolerated in quad and penta-refractory MM patients.