tbuckley/cabot-search huggingface dataset:
PF-06647020 (PF-7020), an antibody-drug conjugate (ADC) targeting protein tyrosine kinase 7 (PTK7), in patients (pts) with advanced solid tumors: Results of a phase I dose escalation and expansion study.
Authors: Jasgit C. Sachdev, Michael L. Maitland, Manish Sharma, Victor Moreno, Valentina Boni, Shivaani Kummar, Erica Michelle Stringer-Reasor, Andres Forero-Torres, Nehal J. Lakhani, Brenda Gibson, Dawei Xuan, Tenshang Joh, Eric L. Powell, Amy Jackson-Fisher, Xiaohua (Robert) Xin, Anthony W. Tolcher, Emiliano Calvo
Journal: Journal of Clinical Oncology (2018)

5565 Background: PF-7020 is an ADC comprising of a humanized monoclonal antibody against PTK7, a cleavable valine-citrulline linker and auristatin payload that is being investigated in an ongoing Phase I clinical trial in pts with advanced solid tumors resistant to standard of care (SoC). Here we report safety results and clinical activity of PF-7020. Methods: Eligible patients received PF-7020 intravenously once every three weeks (Q3W) in doses ranging from 0.2 - 3.7 mg/kg (mpk) in sequential dose escalation cohorts. Dose limiting toxicity (DLT) evaluation period was 21 days (cycle 1). Dose expansion cohorts of pts with advanced ovarian cancer (OVCA), non-small cell lung cancer (NSCLC), and triple negative breast cancer (TNBC) were treated with PF-7020 at recommended phase 2 dose (RP2D). PTK7 expression was assessed by immunohistochemistry. Adverse events (AEs) were assessed by CTCAE v4.03 and best objective response per RECIST v1.1. Results: As of 24 OCT 2017, 112 pts were treated with PF-7020 in dose escalation and expansion cohorts. The pharmacokinetic exposure of PF-7020 increased in a dose related manner, with a terminal half-life of 3 days at 2.8 mpk. 2 DLTs (Grade (Gr) 3 headache, Gr3 fatigue) were observed in the 3.7 mpk cohort, and a RP2D of 2.8 mpk was established. Toxicities were manageable, most AEs limited to Gr1 or 2 (no Gr5). Common treatment-related AEs were nausea, alopecia, fatigue, headache, neutropenia, and vomiting. Antitumor activity irrespective of PTK7 expression is summarized below and further enriched in PTK7 medium/high pts (not shown). Conclusions: Promising antitumor activity and manageable safety profile of PF-7020 were observed in pts with advanced OVCA, NSCLC and TNBC resistant to SoC. Further investigation of PF-7020 is ongoing. Clinical trial information: NCT02222922.Tumor Median Prior Lines Therapy Total Pts Pts by Dose (mpk) ORR (%) (CR/PR) DCR (%) mDOR (mo) (min - max) mPFS (mo) 95% CI 1.25 2.1 2.8 3.7 OVCA 5 44 0 1 42 1 27 (2/10) 73 4.6 (1.7 – 16.2) 2.9 (2.3; 5.6) NSCLC 3 25 2 1 22 0 16 (0/4) 56 5.8 (2.8 – 10.1) 2.9 (1.4; 6.1) TNBC 4 29 0 2 27 0 21 (0/6) 48 3.6 (1.1– 10.4) 1.7 (1.4; 4.3) DCR = disease control rate; mDOR = median duration of response
Validation of the ELN-2017 risk classification in younger adult patients (pts) with AML.
Authors: Prajwal Boddu, Tapan M. Kadia, Guillermo Garcia-Manero, Jorge E. Cortes, Gautam Borthakur, Marina Konopleva, Elias Jabbour, Naval Guastad Daver, Courtney Denton Dinardo, Kiran Naqvi, Musa Yilmaz, Nicholas James Short, Graciela M. Nogueras-Gonzalez, Sherry Pierce, Hagop M. Kantarjian, Farhad Ravandi
Journal: Journal of Clinical Oncology (2018)

7053 Background: The revised 2017 European Leukemia Net (ELN) classification of AML divides patients into 3 prognostic risk categories, with additional factors such as FLT3-ITD allele ratio (AR) considered for risk stratification. We evaluated the prognostic utility of ELN-2017 in comparison with ELN-2010 in younger pts with AML treated in our institution. Methods: Pts ( < 60 years) who received idarubicin plus high dose cytarabine (IA) - based induction chemotherapy for newly diagnosed AML were reviewed. Cox regression analyses were fitted with baseline prognostic factors, including cytogenetic and molecular mutation status, with receipt of allogeneic transplant (SCT) as a time-dependent covariate. Results: According to ELN-2017 criteria, the number of pts in the favorable (fav), intermediate (int), and adverse (adv) categories were 198 (28%), 335 (47%), and 185 (26%), respectively. Overall survival (OS) at 5 years (yrs) in the fav, int, and adv groups was 57%, 37%, and 19%, respectively. In comparison, the 5-yr OS probabilities in the fav (n = 192), int-1 (n = 76), int-2 (n = 276), and adv (n = 185) ELN-2010 categories were 59%, 32%, 39%, and 15%, respectively. Although ELN-2010 historically distinguishes prognosis into int-1 and int-2 categories in younger pts, this difference was nullified in our cohort probably due to the use of high dose cytarabine (int-2 vs. int-1: HR 0.61 [0.37 - 1.01]; p = 0.06). By cox-regression, SCT was associated with decreased risk of mortality only in int and adv AML, but not in the fav subgroup. To evaluate whether FLT3-ITD AR impacted prognosis, we compared the two groups (FLT3-ITDlow and FLT3-ITDhigh based on AR cut-off of 0.5) and found no significant differences in survival between these groups, in patients with NPM1 mutated AML (p = 0.40) or in those with wild type NPM1 treated with either with IA alone [n = 55] (p = 0.61) or in combination with FLT3 inhibitors [n = 16] (p = 0.73). Conclusions: The ELN-2017 more accurately distinguishes prognosis by replacing the ELN-2010 int-1 and int-2 groups with a single int category. Prognostic significance of the FLT3-ITD AR needs further evaluation. SCT should be considered in the post remission setting in IR and adv risk AML pts.
Verification of targeted gene expression profiling panel for identifying biomarker signatures for immunotherapy research.
Authors: Aleksandr Pankov, Yuan-Chieh Ku, Warren Tom, Jianping Zheng, Yongming Sun, Timothy Looney, Timothy Looney, Janice Au-Young, Ann Mongan, Fiona Hyland
Journal: Journal of Clinical Oncology (2017)

e23208 Background: Immunotherapy has led to an unprecedented and long-lasting response in susceptible populations. Despite the therapeutic potential of the treatment, identifying biomarkers and stratifying populations that are likely to respond has been a challenge. While gene expression profiling has previously been successfully used to stratify individuals, there exist limitations with the prevalent technologies. In particular, full transcriptome gene expression estimates use limited biological material to measure the concentrations of thousands of uninformative genes and often lacks the depth required to accurately measure expression of lowly-expressed genes. These low-expressing genes may be critical to the identification of a signature associated with susceptible population. Methods: To efficiently measure the expression of the genes potentially informative of an immunotherapy response, we developed a high-throughput targeted gene expression solution measured with our RNA Ion Oncomine™ Immune Response Research Assay panel* containing 395 genes. This panel provides information about the expression of genes involved in tumor checkpoint inhibition, as well as markers of T cell signaling pathway, interferon signaling, tumor infiltrating lymphocytes (TIL). Results: We used publicly-available TCGA data to characterize the complexities of estimating unbiased gene expression from a targeted panel and developed a solution using a new normalization procedure that allows for accurate comparisons of samples within cancer types. Furthermore, we verified that lowering the RNA input amount or changing the assay operator does not contribute to a large variation in the gene expression estimates; each only accounts for less than 10% of variance of the average gene when the assay is compared across biological samples. Conclusions: Creating a panel that achieved high reproducibility and accurate expression estimates of key immune response genes allowed us to accurately separate high and low TIL samples within squamous and adenocarcinoma samples, emphasizing the utility of the panel to biomarker immunotherapy research. *For Research Use Only. Not for use in diagnostic procedures.
Current results of a phase I study of DKN-01, an anti-DKK1 antibody, in combination with paclitaxel (P) in patients (pts) with advanced DKK1+ esophageal cancer (EC) or gastro-esophageal junction tumors (GEJ).
Authors: David P. Ryan, Janet E. Murphy, Devalingam Mahalingam, Balazs Halmos, Cynthia A. Sirard, Steven B. Landau, Johanna C. Bendell
Journal: Journal of Clinical Oncology (2016)

e15525 Background: DKK1 is an indirect inhibitor of canonical Wnt signaling and has been shown to directly activate non-canonical Wnt pathways including Rho, ROCK and JNK. High DKK1 tissue concentrations in EC correlate with shorter overall survival (OS); published data suggests increased activity of non-canonical signaling by DKK1 may be a reason for shortened OS. DKN-01 is a humanized monoclonal antibody to DKK1 with demonstrated activity in non-small cell lung cancer. This study evaluated the MTD, safety and early activity of DKN-01 in combination with P in EC and GEJ cancer pts. Methods: In Part A, pts with DKK1+ EC or GEJ cancer by IHC staining received DKN-01 in two dose cohorts (150 or 300 mg) with P 80 mg/m2 on days 1, 8, 15 and 22 of each 28 day cycle. Part B (dose expansion) is ongoing. Responses were assessed using RECIST version 1.1. Results: > 90% of screened EC (70 pts) had DKK1+ tumor tissue. In Part A, 9 pts were enrolled: 3 in Cohort 1 (150 mg) and 6 in Cohort 2 (300 mg); 5 pts had a diagnosis of EC [3 with adenocarcinoma (AC); 2 with squamous cell] and 4 pts with GEJ AC. Median number of prior therapies was 3 (range 1, 7). One DLT, G3 peripheral neuropathy, was seen at 300 mg. Treatment emergent adverse events (TEAEs) were fatigue (6 pts), anemia and alopecia (each 5 pts), peripheral neuropathy (4 pts), neutropenia, pyrexia, cough and abdominal pain (each 3 pts). DKN-related TEAE were fatigue, peripheral neuropathy and pyrexia (each 2 pts). The MTD of DKN-01 + P was determined to be 300 mg. Among the 7 AC pts, 3 pts had a partial response (one having had prior P); 3 pts had stable disease. Responders were on therapy between 3 and 10 mos. In AC pts, median progression free survival was 14.1 weeks (5.1 to 40.7). Conclusions: Part A is complete. Most EC and GEJ pts express tumor DKK1 and have obviated the need for evaluation of tumor DKK1+ expression as a study entry prerequisite. Combination of DKN-01+ P is well-tolerated; the addition of DKN-01 does not appear to alter the known P safety profile and has demonstrated initial signs of important enhanced clinical activity; further investigation is ongoing. Clinical trial information: NCT02013154.
Effect of sunitinib in a patient with primary imatinib-resistant gastrointestinal stromal tumor.
Authors: Zhigang Xue, Zhiqiang Ma, Weiming Kang, Jianchun Yu
Journal: Journal of Clinical Oncology (2018)

e23516 Background: For newly diagnosed small intestinal GIST with hepatic metastases, imatinib (IM) resistance is sometimes seen during targeted therapy preoperatively. Subsequent treatment preferring to escalated IM dose or switch to sunitinib (SU) is not that clear in Chinese. Methods: Summarize a newly diagnosed case of small intestine GIST with hepatic metastases. In June 2014, the patient firstly visited to our hospital with the main complaint, abdominal pain with fever for 6 months. Basic test showed mild anemia, OB (+), ESR 51mm/h (normal 0-5). Abd and pelv enhanced CTshowed a low density area about 4.7 cm in hepatic VI Seg and another 1.0 cm in V Seg, and the 6th group of SI wall thickened with enhancement. MDT suspected it as SI-GIST, and a CT-guided liver biopsy was followed. Histological results confirmed the lesion as a metastatic GISTs (mitotic 5/10HPF) with IHC: CD117 (+), CD34 (-). Therefore, imatinib (IM) was prescribed as 400mg per day. Two months later, CT indicated primary imatinib resistance. We prescribed SU 37.5 mg per day orally for 1 month. And the CT implied positive SU response. 4 months after SU, CT showed a further reduction in SI as well as in VI Seg, while slightly increase in V seg. After SU for 6 months, partial small bowel resection and liver metastases resection (VI and V Segment) were performed on April, 2015. Results: Pathological results indicate that lesions in SI is GIST with metastases, 8x9x5 cm in size and mitotic count is 2/50 HPF after TKIs, and pelvic nodules and masses on liver V and VI seg are metastatic GIST (1-2/50 HPF). IHC results showed that SI mass is CD117 (+), CD34 (partial +), DOG (+), pelvic nodules, V and VI segment are CD117 (+), DOG-1 (+) . DNA testing shows that mass on SI has a KIT 9 exon ins-mutation, as well both of masses on liver V and VI seg are KIT 9 exon ins. Leukopenia and mouth ulcers occurred 2 months after surgery, and symptomatic treatment can manage these side effects. CT was performed every 3 to 6 months. No signs of recurrences in the liver and pelvis were found until Jan, 2018. Conclusions: For newly diagnosed SI-GIST with hepatic metastases, timely switching to SU after neoadjuvant primary IM-resistance may effectively control the disease in the long term.
Immunogenicity results using human papillomavirus (HPV) specific DNA vaccine, INO-3112 (HPV16/HPV18 plasmids + IL-12) in HPV+ head and neck squamous cell carcinoma (HNSCCa).
Authors: Charu Aggarwal, Roger B. Cohen, Matthew P Morrow, Kimberly Kraynyak, Joshua Bauml, Gregory S. Weinstein, Jean Boyer, Jian Yan, Drishty Mangrolia, Sandra Oyola, Susan Duff, David B. Weiner, Ildiko Csiki, Mark L. Bagarazzi
Journal: Journal of Clinical Oncology (2017)

6073 Background: Oropharyngeal HNSCCa is frequently associated with HPV. We hypothesize that immunotherapy with INO-3112 will generate immune responses in patients (pts) with HPV+ HNSCCa. Methods: This Phase I/IIa trial included pts with p16+ locally advanced HNSCCa, ECOG PS 0-1. INO-3112 was delivered IM along with electroporation with the CELLECTRA device, Q3 weeks x 4 doses. Cohort 1 (C1) pts received INO-3112 pre and post-surgery; Cohort 2 (C2) pts received INO-3112 post cisplatin-based definitive chemoradiation. 1° and 2° endpoints were safety and immune responses. Pre- and post INO-3112 tissue samples (C1) were assessed for tumor infiltrating lymphocytes (TILs). Peripheral immune responses were assessed by ELISA for HPV16/18 specific antibody levels, and by IFNɤ ELISpot for antigen specific response, at each dose visit and q3 months (mos). Results: As of 08/2016, 22 pts were treated, completing accrual. C1: n = 6, C2: n = 16; 20 male, median age 57.5 years (32-76); base of tongue = 10, tonsil = 12; never smoker = 10. All pts are alive, median follow up is 15.9 mos (1-26). INO-3112 was well-tolerated with no related Grade 3-5 AEs. In 5 C1 pts post immunotherapy, increase in CD8+ infiltration into tumor was noted in 2 pts (1.6-3.6 fold) and decrease in FoxP3+ was noted in the other 3 (1.8-2.1 fold). This resulted in positive shift in CD8+/FoxP3+ ratio in neoplastic tissue in 4/5 pts. Peak mean/median antibody responses to HPV16 E7 and HPV18 E7 antigens for 19 evaluable pts were 1:1235/1:150 and 1:2853/1:450, respectively. As compared to baseline, 18 evaluable pts showed elevated HPV16/HPV18 specific T cell activity (by IFNɤ ELISpot), with peak mean/median responses of 179.99/68.33 SFU per 10 6 PBMC (HPV16) and 107.18/53.3 SFU per 10 6 PBMC (HPV18). Persistent cellular responses &gt; 100 SFU/10 6 PBMC were noted out to 12 mos. 3 pts have progressed; 1 pt received Nivolumab for progressive disease, and remains in CR. Conclusions: These data show that INO-3112 generates HPV-specific peripheral humoral and cellular immune responses that may persist out to 12 months and influences the composition of CD8+ and FoxP3+ immune infiltration into tumor tissue in HPV+ HNSCCa. Clinical trial information: NCT02163057.
First prospective observational study in diffuse-type tenosynovial giant cell tumors.
Authors: Monique Mastboom, Emanuela Palmerini, Silvia Stacchiotti, Eric Staals, Bart Schreuder, Sebastian Bauer, John H. Healey, Julio López Bastida, Hans Gelderblom, Andreas Leithner, Michiel van de Sande
Journal: Journal of Clinical Oncology (2018)

11560 Background: Tenosynovial giant cell tumor (TGCT) is a rare, benign, but potentially locally aggressive and often recurrent disease. Its impact on patient quality of life and ability to work is not well defined. This is the first prospective registry detailing economic impact, management and burden of TGCT. Methods: This international, multicenter, prospective, non-interventional observational registry enrolled patients with histologically proven diffuse-TGCT. Patient data was collected at baseline (time of patient enrolment) and at follow up data collection points, performed at 12 and 24 months. Results: This snapshot analysis included 88 TGCT patients with complete baseline data from six active international sites between November 2016 and September 2017: 58% female; mean age at enrolment 45 years (standard deviation [SD] 14 years). Most (73%) patients had tumors located in the knee. Fifty six (64%) patients with a primary diagnosis of TGCT were included, 32 (36%) with recurrent disease. Mean time from first symptoms until diagnosis was 42 months (median 21 months) and the most commonly reported symptom was pain (78%). A total of 63 (72%) patients had surgery, primarily open synovectomy (54%). Thirty eight (43%) patients received systemic therapy, pexidartinib [55%] and imatinib [42%]. Over 12 months, 44 (50%) patients reported that TGCT compromised their ability to work with a mean of 51 days of work (median 21 days) missed due to TGCT. Eight (9%) patients were fully unemployed due to TGCT, 2 (2%) were partially unemployed and 1 (1%) patient had retired prematurely. On average, a clinically significant impairment of physical function at baseline was observed as compared with the reference population based on PROMIS Physical Function score (42 [SD 7] vs 50 [SD 10]). Mean EQ-5D-5L at baseline was 0.75 (SD 0.19). Conclusions: This disease-registry in six sites, with a two-year recruitment period and two-year follow-up per patient, showed that TGCT has a major impact on daily living in a relatively young and working population. Clinical trial information: NCT02948088.
Overall survival (OS) results of randomized phase III study (ADMYRE trial) of plitidepsin and dexamethasone (DXM) vs<i>.</i> DXM alone in patients with relapsed/refractory multiple myeloma (RRMM): Evaluation of the crossover impact.
Authors: Javier Gomez, Sonia Extremera, Antonio Nieto
Journal: Journal of Clinical Oncology (2018)

8018 Background: Plitidepsin is a synthetic cyclic depsipeptide isolated from the marine tunicate Aplidium albicans targeting the proto-oncogene eEF1A2, which is over-expressed in multiple myeloma cells. In ADMYRE trial, Plitidepsin plus dexamethasone (DXM) (Arm A) met the primary endpoint (progression-free survival) and showed a survival improvement versus DXM alone (Arm B) (ASH 2017). Methods: RRMM patients with at least three but not more than six prior regimens, including at least bortezomib and lenalidomide/thalidomide, were randomized at 2:1 ratio to receive plitidepsin 5 mg/m2 D1 and 15 plus DXM 40 mg D1,8,15 and 22 (Arm A), or DXM 40 mg D1,8,15 and 22 (Arm B) every four weeks. The rank preserving structural failure time (RPSFT) and the two-stage methods were used to present overall survival (OS) results after mitigating the crossover effect. Results: Two-hundred fifty-five patients were enrolled: (Arm A: 171/Arm B: 84). Thirty-seven patients in Arm B (44%) switched to Arm A after progression. Intention-to-treat (ITT) analysis not discounting the crossover effect showed a 20.3% risk reduction in favor of Arm A (median OS: A 11.6 mo. B: 8.9 mo.; HR = 0.797; log-rank p = 0.1261). Risk reduction improved to 32.4% with the RPSFT method (median OS: A 11.6 mo. B: 7.2 mo.; HR = 0.676; log-rank p = 0.0103) and to 37.8% with the two-stage method (median OS: A 11.6 mo. B: 6.4 mo.; HR = 0.622; log-rank p = 0.0015). Although assumptions for RPFST and two-stage analyses were plausibly met, statistically significant risk reductions were still maintained when severe penalizations were applied, with median OS differences around four months. Conclusions: Plitidepsin in combination with DXM demonstrated a clinically significant benefit in terms of overall survival in heavily pretreated RRMM, a disease where new therapeutic alternatives are still needed. Clinical trial information: NCT01102426.
PET/CT's utility in identifying the primary and altering management in cancers of unknown primary.
Authors: Hannah Marie Cherniawsky, Maria Yi Ho, Michael B. Sawyer
Journal: Journal of Clinical Oncology (2016)

e18105 Background: The role of PET/CT in staging and management of cancers of unknown primary (CUP) remains poorly defined. Our study sought to 1) evaluate the utility of PET/CT versus standard CT in determining the primary site, lymph node status and extent of metastases, and 2) assess whether results of PET scans altered management in CUP patients. Methods: A retrospective chart review approved by the Alberta Cancer Research Ethics Committee was performed to measure concordance rates between PET/CT and CT scans in patients diagnosed with CUP at the Cross Cancer Institute, Canada from 2008 to 2015. Results: We identified 60 patients who had standard CT and PET/CT during their work-up. Standard CT imaging detected 36.7% of primaries compared to 26.7% on PET/CT. 58.3% of primaries were concordantly identified on both modalities. PET/CT identified 2 primaries not seen on CT whereas standard CT identified 8 primaries not seen on PET/CT. Concordance rates between PET/CTs and standard CTs were 61.7% [37/60] and 50.0% [30/60] with respect to lymph node status and extent of metastases, respectively. In those with discordant imaging, standard CT was superior in identifying greater extent of lymph node involvement (56.5% versus 43.5%); whereas, PET/CT was superior in determining greater extent of metastases (63.3% versus 36.7%). Notably, in patients who had discordant imaging in either domain or identification of primary by PET/CT, there were no cases in which PET/CT alone provided information that changed patient management. Conclusions: Our results suggest PET/CT scans do not provide additional diagnostic information in comparison to CT scans with respect to identifying the primary site. PETs were superior in clarifying extent of metastases, but this did not alter therapy. Future studies investigating the impact of PET/CT scans on therapeutic management and cost effectiveness in CUP are of crucial importance.
TCT-301 CHA2DS2-VASc Score is Highly Predictive of In-hospital Mortality and Procedural Complications in Patients with Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention
Authors: Ashraf Abugroun, Abdalla Hassan, Safwan Gaznabi, Ahmed Subahi, Abdelhaleem Sideeg, Hakeem Ayinde, Lloyd Klein
Journal: Journal of the American College of Cardiology (2018)
TCT-43 First-in-human experience of a novel transradial device for embolic deflection during transcatheter aortic valve replacement
Authors: Darren Mylotte, Inga Narbute, Antoinette Neylon, Ulrich Schäfer, Nikos Werner, Renu Virmani, Frank Kolodgie, Robert Zivadinov, Andrejs Erglis
Journal: Journal of the American College of Cardiology (2018)