tbuckley/cabot-search huggingface dataset:
Trabectedin for advanced soft-tissue sarcoma: A single-center experience of over 10 years.
Authors: Imran Syed, Madhuri Sudan, William Tseng, Prarthana Parthasarathy, William Esteves Mendanha, Neal Shiv Chawla, Rishi Nanda, Justin Daneshrad, Bryan Leong, Babak Aryanfar, Susan Arasheben, Katherine Kim, Erlinda Maria Gordon, Kamalesh Kumar Sankhala, Sant P. Chawla
Journal: Journal of Clinical Oncology (2016)

11052 Background: Trabectedin (T) is an anti-tumor agent used in the treatment of advanced soft-tissue sarcomas (STS). It interferes with DNA replication, causing double strand breaks and apoptosis, and may deplete tumor-associated macrophages in the tumor microenvironment. T was recently USFDA- approved for advanced liposarcoma and leiomyosarcoma. We report the largest known single-center experience in advanced soft-tissue sarcoma treated with T. Methods: This retrospective study includes 442 advanced STS patients treated with T from 2005-2015 as part of various clinical trials. Baseline characteristics and treatment outcomes by histologic subtypes were assessed by RECIST 1.1 criteria. Progression-free survival (PFS) in months was determined in evaluable patients who completed at least 2 cycles of T, and had a follow-up CT scan or MRI. Results: The table shows the demographics and PFS of various subtypes of sarcoma. The median PFS for advanced leiomyosarcoma and liposarcoma (3.7 and 4.3 months respectively) was similar to that reported by Demetri et al., 2014, in a Phase 3 study using trabectedin vs dacarbazine (4.2 vs 1.5 months respectively) (1). Notably, durable disease control was also noted in synovial cell sarcoma and chondrosarcoma (median PFS 6.8 and 4.5 months respectively). Adverse events profile of T was similar to previous studies. Conclusions: Taken together, the data suggests that T may also prolong progression-free survival in patients with advanced synovial cell sarcoma and chondrosarcoma, warranting further studies. Clinical trial information: Multiple clinical trials.Patient characteristics and progression-free survival in trabectedin-treated patients with advanced STS. N (%) PFS: Median (Range) Sex: Male / Female 196 (44%) / 246 (56%) - Age (years): Median (Range) 53 (11-90) - All subtypes Leiomyosarcoma 121 (28%) 3.7 (0.7-59.5) Liposarcoma 71 (16%) 4.3 (0.9-46.1) Undiff. Pleomorphic Sarcoma 57 (13%) 1.8 (0.9-11.3) Synovial Sarcoma 37 (8%) 6.8 (1.2-53.8) Chondrosarcoma 21 (5%) 4.5 (1.1-63.1) Other 133 (30%) 2.9 (0.5-51.7)
The "INSIGHT" trial: An explorative, open-labeled phase I study to evaluate the feasibility and safety of intra-tumoral, intra-peritoneal, and subcutaneous injections with IMP321 (LAG-3Ig fusion protein) for advanced stage solid tumor entities.
Authors: Daniel Wilhelm Mueller, Thorsten Oliver Goetze, Regina Eickhoff, Alexander Reichart, Salah-Eddin Al-Batran
Journal: Journal of Clinical Oncology (2018)

TPS3129 Background: The INSIGHT study evaluates feasibility and safety of intratumoral and intraperitoneal injections of IMP321 (mono-agent) for the treatment of advanced stage solid tumors as well as to generate first efficacy data. This proof-of-concept data could build the basis for further clinical studies exploring the therapeutic potential of active immunotherapy with IMP321 by direct injection into the tumor mass or the peritoneal space. Furthermore, safety and efficacy of combining standard-of-care (SOC) chemo(immuno-)therapies with IMP321 subcutaneous (s.c.) injections in various solid tumor entities will be assessed. IMP321 is a soluble form of the LAG-3 T cell surface receptor with a dual mode of action (MOA) consisting of activation of antigen presenting cells (primary MOA) and prevention of exhaustion of activated T-cells (secondary MOA at high local concentration). Methods: This is a prospective investigator initiated phase I trial consisting of three strata. Stratum A: Pretreated patients with solid tumors which are accessible for repeated injections and biopsies receive q2w intra-tumoral injections of IMP321 as a monotherapy. Stratum B: Pretreated patients with solid tumors and additional peritoneal carcinomatosis receive q2w intra-peritoneal IMP321 injections via direct injection or a silicon catheter. Both strata are performed in a classical 3 patient cohort study design consisting of intra-patient dose-escalation and consolidation cohorts. Stratum C: Patients with solid tumors treated with SOC chemo(immuno-)therapy in first or second line receive concomitant s.c. IMP321 injections. It is planned to enroll 9 patients each in Stratum A and Stratum B and 20 patients in Stratum C. Main efficacy endpoint is the overall response rate according to RECIST criteria. The trial is accompanied by an extensive biomarker research program. Recruitment has started; currently (Feb 2018) 4 patients have been enrolled (3 Stratum A, 1 Stratum B). Up to now, no DLTs have been observed. ClinicalTrials.gov Identifier: NCT03252938; EudraCT: 2016-002309-20. Clinical trial information: NCT03252938.
Correlation of isotope count with sentinel node positivity in vulvar cancer.
Authors: Linn Lena Woelber, Simon Joosse, Donata Grimm, Sven Mahner, Eike Burandt, Barbara Schmalfeldt, Susanne Klutmann, Katharina Prieske
Journal: Journal of Clinical Oncology (2017)

e17033 Background: Sentinel node biopsy (SNB) has become standard of care in early stage vulvar cancer. As the correlation of isotope count with the presence of metastases remains unclear, often several active nodes are excised per groin. This can result in increased morbidity in node-negative disease despite of SNB. In the current analysis we assess, whether resection of the hottest node could be sufficient to detect sentinel lymph node (SNL) metastasis. Methods: All patients with primary vulvar cancer receiving a SNB with radioactive tracer at the University Medical Center Hamburg-Eppendorf between 2008 and 2015 were evaluated. The day before surgery, patients received four peritumoral intradermal deposits at 3, 6, 9 and 12 o’clock with an overall mean dosage of 85±12MBq 99m Tc–nanocolloid. Planar lymphscintigraphy was performed one hour after injection. Intraoperatively, a handheld gamma counter was used to identify the SNL. Results: 146 patients with SNB were included; thereof 145 pts underwent bilateral SNB, resulting in 291 analyzed groins. A median of 2 (range 1-7) SNL per groin were removed. From 95/291 (32.6%) groins more than 2 SNL were excised. Median overall SNL isotope count was 1400. In 52 groins, a positive SNL was detected (unilateral in 38 patients, bilateral in 7). The median number of positive SNL per groin was 1 (range 1-4). There was no difference of median count in negative compared to positive SNL (median count 1396 vs. 1614; p=0.90). The SNL with the highest isotope count carried metastases in 36/48 groins (75.0%; in 4 cases the highest count was unknown). In 12/48 (25.0%) positive groins, the SNL with the highest count was not the metastatic SNL (11/12 second highest count). Median count of these 12 SNL was 58.8% of the highest count with a range from 6.0% to 74.0%. Conclusions: The highest isotope count does not reliably detect the positive SNL in vulvar cancer. To prevent mostly fatal groin recurrences, surgeons should continue to remove all SNL accumulating relevant radioactive tracer over minimal background activity.
Tolerability and response of the novel SYK/JAK inhibitor cerdulatinib in a phase 2a study in relapsed/refractory peripheral t cell lymphoma (PTCL).
Authors: Steven M. Horwitz, Paul A. Hamlin, Tatyana Feldman, Brian T. Hess, Anthony R. Mato, Javier Munoz, Manish R. Patel, Jing Christine Ye, Andrew Steele, Anjali Pandey, Matt Birrell, Janet Leeds, Greg Coffey, John T Curnutte
Journal: Journal of Clinical Oncology (2018)

e19532 Background: Pre-clinical data suggest a role for SYK and JAK signaling pathways as oncogenic drivers in PTCL. Most compelling is the frequent demonstration of SYK expression (not expressed in normal T-cells) in PTCL and that transgenic expression of SYK in mouse T cells drives a lethal lymphoproliferative disorder. Frequent activating mutations to JAK/STAT pathways are also observed. Cerdulatinib is a small molecule reversible ATP competitive inhibitor of SYK and JAK1, JAK3 and TYK2. Methods: Eighteen relapsed/refractory PTCL patients were enrolled as part of a phase 2a study, receiving 30 mg cerdulatinib orally BID. Response was assessed by Lugano classification criteria at the end of 2 months and every 3 cycles thereafter. Results: Patients included PTCL-NOS (7), AITL (6), ALCL (2), HSTCL (1), Gamma-delta TCL (1), and EITL (1); median age 70 [48-84]; prior transplant 28%; and 44% refractory to last therapy. Eleven patients were evaluated for clinical response, 3 discontinued prior to evaluation (2 due to progression; 1 withdrew consent), and 4 patients have yet to be evaluated. Six patients have responded (ORR 43%). Of these, 4 achieved a CR after 2 cycles, 2 achieved a PR, and 2 SD. Four responding patients remain on drug: 1 for 11+ months and the remaining for 3-7 months. A patient with CR was referred to allogeneic transplant and censored after cycle 2. An additional patient achieved complete remission of target lesions, but discontinued therapy due to a new lesion. The majority of responses were observed in PTCL-NOS and AITL. Importantly, CRs and PRs occurred in patients who failed multiple lines of therapy, including pralatrexate, romidepsin, belinostat, and an investigational PI3K inhibitor. The most common AEs of any grade were diarrhea (33%), fatigue (22%), lipase increase (17%), and nausea (17%). Grade 3+ AEs occurring in ≥2 patients are neutropenia (4), diarrhea (3), lipase increase (2), and pneumonia (2). The target PK range was achieved with an average SSCmin of ~0.8 µM. Conclusions: These data suggest that cerdulatinib is well tolerated and capable of generating durable complete responses in heavily pre-treated PTCL. Clinical trial information: NCT01994382.
Total 1-year cost of diffuse large B-cell lymphoma (DLBCL) beyond first line (1L) therapy: A retrospective cohort analysis.
Authors: Anna Purdum, Ryan Tieu, Sheila R. Reddy, Michael Broder
Journal: Journal of Clinical Oncology (2017)

e18333 Background: This cohort study estimated cost and healthcare use among DLBCL patients who progressed beyond 1L therapy. Methods: Using the MarketScan database, patients ≥18 years old who had R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) as 1L therapy and a claim for DLBCL (ICD-9-CM 200.7X) in the year before or 90 days after 1L start were selected for 2 cohorts: nonrelapsers who had no second line (2L) treatment for ≥2 years and 2L patients with non-R-CHOP chemotherapy after 1L. Patients not continuously enrolled for 6 months before and ≥2 years after 1L initiation, or those treated with maintenance rituximab or lenalidomide were excluded. 2L was subgrouped based on time between 1L end and 2L start: refractory (≤3 months), early (4-12 months), and late relapse (&gt;12 months). Descriptive statistics compared cost and use between groups. Subsequent 2-year and 3-year data will be presented. Results: There were 217 (15.8%) 2L and 1,157 (84.2%) nonrelapse patients identified. Among 2L patients, 61 had hematopoietic stem cell transplant (HSCT) within 1 year. Of these HSCTs, 42.6% were early relapse patients vs. 24.6% late and 32.8% refractory (p=0.05). Mean total cost was $210,488 (SD $172,851) in 2L and $25,044 (SD $32,441) in non-relapsers (p&lt;.001). Within 2L, mean total 1-yr cost was $232,796 in early relapse, $213,866 in late, and $191,079 in refractory (p=0.3314). For HSCT patients, cumulative 1-yr and 2-yr costs were $301,426 (Table) and $421,739. Conclusions: DLBCL treatment beyond 1L is resource intensive; chemotherapy and HSCT are major drivers of cost despite a low rate of HSCT. Cost in early relapsers may be higher than late relapsers or refractory patients due to higher transplant rates. [Table: see text]
Therapeutic Genome Editing for Myotonic Dystrophy Type 1 Using CRISPR/Cas9
Authors: Yanlin Wang, Lei Hao, Hongcai Wang, Katherine Santostefano, Arjun Thapa, John Cleary, Hui Li, Xiuming Guo, Naohiro Terada, Tetsuo Ashizawa, Guangbin Xia
Journal: Molecular Therapy (2018)

Myotonic dystrophy type 1 (DM1) is caused by a CTG nucleotide repeat expansion within the 3′ UTR of the Dystrophia Myotonica protein kinase gene. In this study, we explored therapeutic genome editing using CRISPR/Cas9 via targeted deletion of expanded CTG repeats and targeted insertion of polyadenylation signals in the 3′ UTR upstream of the CTG repeats to eliminate toxic RNA CUG repeats. We found paired SpCas9 or SaCas9 guide RNA induced deletion of expanded CTG repeats. However, this approach incurred frequent inversion in both the mutant and normal alleles. In contrast, the insertion of polyadenylation signals in the 3′ UTR upstream of the CTG repeats eliminated toxic RNA CUG repeats, which led to phenotype reversal in differentiated neural stem cells, forebrain neurons, cardiomyocytes, and skeletal muscle myofibers. We concluded that targeted insertion of polyadenylation signals in the 3′ UTR is a viable approach to develop therapeutic genome editing for DM1. Myotonic dystrophy type 1 (DM1) is caused by a CTG nucleotide repeat expansion within the 3′ UTR of the Dystrophia Myotonica protein kinase gene. In this study, we explored therapeutic genome editing using CRISPR/Cas9 via targeted deletion of expanded CTG repeats and targeted insertion of polyadenylation signals in the 3′ UTR upstream of the CTG repeats to eliminate toxic RNA CUG repeats. We found paired SpCas9 or SaCas9 guide RNA induced deletion of expanded CTG repeats. However, this approach incurred frequent inversion in both the mutant and normal alleles. In contrast, the insertion of polyadenylation signals in the 3′ UTR upstream of the CTG repeats eliminated toxic RNA CUG repeats, which led to phenotype reversal in differentiated neural stem cells, forebrain neurons, cardiomyocytes, and skeletal muscle myofibers. We concluded that targeted insertion of polyadenylation signals in the 3′ UTR is a viable approach to develop therapeutic genome editing for DM1.
A phase Ib study of napabucasin plus weekly paclitaxel in patients with advanced melanoma.
Authors: William Jeffery Edenfield, Carlos Becerra, Fadi S. Braiteh, Alexander I. Spira, Ryan J. Sullivan, Timothy J. Panella, Wei Li, Janet Huang, Youzhi Li, Keith Flaherty, Matthew Hitron, Chiang Li
Journal: Journal of Clinical Oncology (2017)

9553 Background: Napabucasin is a first-in-class cancer stemness inhibitor, identified by its ability to inhibit STAT3-driven gene transcription and spherogenesis of cancer stem cells (Li et al PNAS 112 (6):1839, 2015). Synergistic anti-tumor activity with paclitaxel was observed in pre-clinical testing, and a favorable clinical safety profile was established in a phase I/II trial in patients (pts) with advanced solid tumors. A phase 1b trial was established to evaluate the safety and preliminary signs of anti-cancer activity of the combination regimen in pts with advanced melanoma. Methods: Pts with melanoma were enrolled after failure of standard therapies for advanced disease. Napabucasin 480 or 500 mg orally twice daily was administered with paclitaxel 80 mg/m2 IV weekly for 3 of every 4 weeks. Adverse events were evaluated using CTCAE v4.03 and objective tumor assessments were obtained every 8 weeks and evaluated per RECIST 1.1 criteria. Results: A total of 12 pts with advanced melanoma were enrolled after a median 3 prior lines of therapy (including immune checkpoint inhibitors, BRAF-inhibitor if presence of BRAF V600E mutation). Protocol therapy was well tolerated with grade 3 AEs including diarrhea (n = 3), abdominal pain (n = 1), and fatigue (n = 1). Partial response (PR) was observed in 1 pt. Stable disease of at least 24 weeks or more was achieved by 33% of patients (n = 4) and the median progression-free survival (mPFS) was 3.7 months. Prolonged survival of 1 year or more was achieved by 33% of pts (n = 4), with a median overall survival (mOS) of 10.4 months. Conclusions: Napabucasin plus weekly paclitaxel has shown clinical safety and encouraging anti-tumor activity in a cohort of pts with previously treated advanced melanoma. The RP2D in combination with weekly paclitaxel was established to 480 mg orally bid. The data suggest that targeting stemness pathways with napabucasin may be a novel therapeutic strategy for melanoma. Clinical trial information: NCT01325441.
A longitudinal retrospective case series of the real-world toxicities encountered among cancer patients receiving anti-PD-L1 checkpoint inhibitor immunotherapy.
Authors: Anastasios L. Boutis, Aglaia Skolariki, Nikolaos Diamantopoulos, Alexandros Bokas, Georgios Chatsidis, Georgios Rizos, Pavlos Papakotoulas
Journal: Journal of Clinical Oncology (2018)

e15117 Background: Immunotherapy with anti-PD-L1 immune checkpoint inhibitors is currently a major component of systemic therapy in advanced solid tumors. Their toxicity profile has been well established through clinical trials, however the rapid integration of these agents in routine cancer care did not allow the identification of the complete spectrum of unusual or rare immune-related adverse events. Methods: We retrospectively reviewed the records of 142 patients, who received nivolumab or pembrolizumab between June 2015 and January 2018. Eligible patients received at least 2 cycles (2-45, median 8) and only grade 3-5 or mild toxicities that required intervention were recorded. Routine clinical and laboratory exams, including TSH, were performed every 1-2 cycles, along with imaging, when clinically indicated. Results: A total of 127 patient-records were eligible for documentation of treatment-related toxicity. Underlying disease was lung cancer (69%), melanoma (16%), renal (16%) and urothelial cancer (6%). Skin toxicity was exhibited in 10% of patients (N = 13). A case of persistent, generalized vitiligo appeared after 15 cycles of therapy, but did not require therapy modification. 2 out of 11 patients with gastrointestinal toxicity, developed grade 3-4 colitis that resolved with conservative treatment. Among 5 patients (3.9%) with pulmonary toxicity, only one with pneumonitis grade 3 required permanent cessation of therapy. Thyroid dysfunction was the most commonly recorded toxicity; hypothyroidism in 16.4% (N = 21) and hyperthyroidism in 11,8% (N = 15) of patients. All cases were successfully managed with medical intervention and did not delay immunotherapy. Further endocrine toxicities included a case of diabetes and two cases of adrenal insufficiency. Other rare entities were a case of interstitial nephritis grade 3 confirmed with renal biopsy and a grade 3 hepatitis. Conclusions: Real-world experience with anti-PD-L1 immune checkpoint inhibitors revealed a wide spectrum of immune-related adverse events. Special caution is required for the prompt identification of mild toxicity before it escalates to life-threatening situations.
Analysis of <i>Fusobacterium nucleatum</i>, <i>Streptococcus gallolyticus</i> and <i>Porphyromonas gingivalis</i> in saliva in colorectal cancer patients and healthy controls.
Authors: Deniz Can Guven, Omer Dizdar, Alpaslan Alp, Fatma Nur Akdogan Kittana, Derya Karakoc, Erhan Hamaloglu, Sahin Lacin, Yusuf Karakas, Saadettin Kilickap, Mutlu Hayran, Suayib Yalcin
Journal: Journal of Clinical Oncology (2018)

e15617 Background: The aim of this study was to examine the prevalence and amount of Fusobacterium nucleatum (Fn), Porphyromonas gingivalis (Pg) and Streptococcus gallolyticus subspecies gallolyticus (Sg) in saliva samples of colorectal cancer (CRC) patients and healthy controls. Methods: Patients with newly diagnosed CRC who have not yet received any treatment were included in the study. Control group consisted of individuals over 50 years of age without a prior diagnosis of malignancy. PCR analyzes were performed for identification and quantification of Fn, Sg and Pg strains. Results: Seventy one patients and 77 controls were included in the study. The total amount of bacteria (7,51±0,50 vs 7,45±0,62 log10 copies/ml, p = 0,549) and prevalence of Fn (97% vs 96%), Sg (31% vs 27%) and Pg (76% vs 75%) were similar in patient and control groups, respectively. Saliva samples of the patients had higher amount of Fn (6,89±1,07 vs. 6,35±0,78 log10 copies/ml in controls, p = 0.001) and Sg (4,12±0,99 vs. 3,15±0,58 log10 copies/ml in controls, p < 0.001) compared with the control group. The salivary Pg quantities were similar in the two groups (4,28±1,72 vs 4,22±1,24 log10 copies / ml, p = 0,837). The prevalence and amount of Fn, Sg, and Pg did not differ significantly according to tumor localization (right vs left colon) and stage (stage 1-2-3 vs stage 4). Amount of Fn and Sg were lower in the microsatellite insability (MSI) (+) group than in the MSI (-) group (6,15 vs. 7,03 log10 copies/ml, p = 0,036 for Fn; 3,44 vs. 4,13 log10 copies/ml, p = 0,022 for Sg, respectively). Evaluation of the salivary Sg amount by ROC curve analysis found to have diagnostic value for CRC (AUC: 0,84, %95 GA 0,72-0,96, p < 0,001). Quantity of Sg above 3,32 log10 copy/ml was the best predictor cutoff value for CRC with 82% sensitivity and 76% specificity. Conclusions: In this study, we have found higher amounts of Fn and Sg in the salivary samples of CRC patients compared with healthy controls. The quantity of salivary Sg could be dichotomized at a certain level with high diagnostic sensitivity and specificity. These findings might have implications for etiopathogenesis, screening, diagnosis and prevention of CRC.
Activity of RX-3117, an oral antimetabolite nucleoside, in subjects with metastatic bladder cancer resistant to gemcitabine: Preliminary results of a phase Ia/IIb study.
Authors: Jun Gong, Vincent M. Chung, Joel Picus, Scott T. Tagawa, Sumati Gupta, Julie Poore, Christine Peterson, Ely Benaim, Sumanta K. Pal
Journal: Journal of Clinical Oncology (2017)

4544 Background: RX-3117 is an oral small molecule antimetabolite, cyclopentyl pyrimidyl nucleoside that is activated by uridine cytidine kinase 2. RX-3117 has shown efficacy in xenograft models of gemcitabine resistant pancreatic, bladder and colorectal cancer. Preliminary data from an analysis of a phase 1b/2a clinical study of RX3117 in metastatic bladder cancer is described. Methods: This phase 1b/2a study (NCT02030067) was designed to evaluate safety, tolerability and efficacy following treatment with 700 mg administered orally once-daily for 5 consecutive days with 2 days off per week for 3 weeks with 1 week off in each 4 week cycle in a 2-stage design. Eligible subjects (aged ≥ 18 years) were those with relapsed/refractory metastatic bladder cancer with any number of prior therapies. Prior therapy with platinum-based chemotherapy was required. The primary endpoint was to assess the efficacy and safety of RX-3117 in metastatic bladder cancer, with secondary aims of evaluating PFS and CBR. Results: With 9 subjects enrolled, median age was 66 years, ECOG PS was 0-1. All subjects had received gemcitabine/cisplatin in the perioperative or metastatic setting, and 4 subjects had received 3 or more prior therapies. The most frequent related adverse events were anemia, mild-moderate fatigue, vomiting and diarrhea. No dose limiting toxicities were observed. PFS and CBR will be presented at the meeting, as 5 subjects continue to receive therapy at the time of this submission. One subject continues on treatment at 139 days with persistent stable disease. Molecular profiling of his bladder tumor showed alterations in ARID1A, FBXW7, FGFR3, NF1, and TERT. The patient previously responded to an FGFR3 inhibitor but progressed after 9 months, with ctDNA assessments showing incurrence of TP53 alteration. Clinical benefit with RX-3117 was achieved in spite of incurrence of this alteration. Conclusions: RX-3117 demonstrated an excellent safety profile, and prolonged stable disease was seen in 1 subject who failed prior cisplatin/gemcitabine and FGFR3 inhibition. Activity persisted despite development a putative resistance alteration detected by ctDNA. Clinical trial information: NCT02030067.