tbuckley/cabot-search huggingface dataset:
Multicenter phase II study of trastuzumab deruxtecan (DS-8201) for HER2-positive unresectable or recurrent biliary tract cancer: HERB trial.
Authors: Akihiro Ohba, Chigusa Morizane, Makoto Ueno, Satoshi Kobayashi, Yasuyuki Kawamoto, Yoshito Komatsu, Masafumi Ikeda, Mitsuhito Sasaki, Naohiro Okano, Junji Furuse, Nobuyoshi Hiraoka, Hiroshi Yoshida, Aya Kuchiba, Gakuto Ogawa, Kenichi Nakamura, Naoko Matsui, Yoshiaki Nakamura, Wataru Okamoto, Takayuki Yoshino, Takuji Okusaka
Journal: Journal of Clinical Oncology (2020)

TPS4654 Background: Biliary tract cancer (BTC) is one of the most lethal cancers with limited treatment options. Early clinical trials showed a hint of activity of HER2 blockade for HER2 positive BTC, the prevalence of which was reported to be from 5% to 20%. Trastuzumab deruxtecan (DS-8201) is an antibody-drug conjugate composed of an anti-HER2 antibody, cleavable terapeptide-based linker, and a topoisomerase I inhibitor, which showed durable response in HER2 positive breast cancer as well as in a wide spectrum of cancer subtypes in a phase I study. In addition, preclinical research demonstrated the effectiveness of trastuzumab deruxtecan for HER2 positive BTC patient derived xenograft model. This phase II study is being conducted to evaluate the efficacy and safety of trastuzumab deruxtecan for HER2 positive BTC. Methods: The main inclusion criteria are unresectable or recurrent BTC, histologically diagnosed as adenocarcinoma or adenosquamous carcinoma, confirmed HER2-expressing status by central pathological examination, refractory or intolerant to treatment including gemcitabine, and adequate organ function. Patients are registered and receive 5.4 mg/kg trastuzumab deruxtecan every 3 weeks until disease progression or unacceptable toxicities. Primary endpoint is the overall response rate (ORR) in HER2 positive (defined as IHC3+, or IHC2+/ISH+; ISH+ defined as HER2/ CEP17 ≥2.0) patients by central imaging review. The ORR in all HER2-expressing patients (including HER2 low expressing defined as IHC/ISH status of 0/+, 1+/-, 1+/+, or 2+/-), progression-free survival, overall survival, and incidence of adverse events are assessed as secondary endpoints. Thirty-two patients will be enrolled, including 24 with HER2 positive BTC as primary cohort and 8 with HER2 low expressing BTC. The study has 80% power for primary endpoint in HER2 positive BTC patients, with one-sided alpha error of 5%; threshold ORR of 15% and expected ORR of 40%. Pharmacokinetics and circulating tumor DNA analyses serially are performed. The study was initiated in May 2019 with enrollment ongoing. A total of 15 patients were enrolled as of January 2020. Funding: Japan Agency for Medical Research and Development, and Daiichi Sankyo. Clinical trial information: JMA-IIA00423 .
MAGNIFY phase IIIb interim analysis of induction R<sup>2</sup> followed by maintenance in relapsed/refractory indolent NHL.
Authors: David Jacob Andorsky, Morton Coleman, Abdulraheem Yacoub, Jason M. Melear, Suzanne R. Fanning, Kathryn S. Kolibaba, Frederick Lansigan, Chris Reynolds, Grzegorz S. Nowakowski, Mecide Gharibo, Jung Ryun Ahn, Ju Li, Mathias J. Rummel, Jeff P. Sharman
Journal: Journal of Clinical Oncology (2020)

8046 Background: Patients (pts) with relapsed iNHL have limited standard treatment options. The immunomodulatory agent lenalidomide shows enhanced activity with rituximab (ie, R 2 ), which recently reported 39.4-mo median PFS in R/R iNHL pts (AUGMENT; J Clin Oncol. 2019;37:1188). Methods: MAGNIFY is a multicenter, phase IIIb trial in pts with R/R FL gr1-3a, MZL, or MCL (NCT01996865) exploring optimal lenalidomide duration. Lenalidomide 20 mg/d, d1-21/28 + rituximab 375 mg/m 2 /wk c1 and then q8wk c3+ (R 2 ) are given for 12c followed by 1:1 randomization in pts with SD, PR, or CR to R 2 vs rituximab maintenance for 18 mo. Data presented here focus on induction R 2 in efficacy-evaluable FL and MZL pts (MCL not included) receiving ≥ 1 treatment with baseline/post-baseline assessments to analyze the primary end point of ORR by 1999 IWG criteria. Results: As of June 16, 2019, 393 pts (81% FL gr1-3a; 19% MZL) were enrolled with a median follow up of 23.7 mo (range, 0.6-57.8) for censored pts (n = 335). Median age was 66 y (range, 35-91), 83% had stage III/IV disease, with a median of 2 prior therapies (95% prior rituximab-containing). ORR was 69% with 40% CR/CRu (Table). Median DOR was 39.0 mo, and median PFS was 40.1 mo. 199 pts (51%) have completed 12c of R 2 , and 188 (48%) have been randomized and entered maintenance. 139 pts (35%) prematurely discontinued both lenalidomide and rituximab, primarily due to AEs (n = 52, 13%) or PD (n = 45, 11%). Most common all-grade AEs were 48% fatigue, 43% neutropenia, 36% diarrhea, 31% nausea, and 30% constipation. Grade 3/4 AE neutropenia was 36% (9 pts [2%] had febrile neutropenia); all other grade 3/4 AEs occurred in &lt; 7% of pts. Conclusions: R 2 is active with a tolerable safety profile in pts with R/R FL and MZL, including rituximab-refractory, double-refractory, and early relapse pts. Clinical trial information: NCT01996865 . [Table: see text]
Home ePRO compliance in prostate cancer clinical studies.
Authors: Sarah Tressel Gary, Nadeeka Dias, Elisa Conrad, Kenneth G Faulkner
Journal: Journal of Clinical Oncology (2020)

2063 Background: Patient-reported outcomes (PRO) and electronic PRO (ePRO) play an important role in the development and approval of cancer products. Regulatory agencies are encouraging the inclusion of PRO-based endpoints that are indicative of clinical benefit in terms of patient symptoms and overall quality of life (QOL). Compliance with completion of ePRO assessments is an important component for obtaining accurate and high-quality data when conducting clinical trials. Traditionally, ePRO data in oncology trials has been collected mainly at clinic visits due to concerns over poor compliance at home. However, since symptoms and QOL can vary widely through a treatment course, it is often necessary to collect ePRO data more frequently in between clinic visits. It has been hypothesized that home completion, length of time in a study, and number of assessments may affect compliance. Methods: To address this hypothesis, ePRO compliance data was analyzed from two clinical studies in prostate cancer. Both studies used a handheld smartphone that contained an application to collect ePRO data. At the randomization visit, subjects completed ePRO assessments in clinic (2-3 questionnaires). Subsequently, all assessments were completed at home, including a daily diary and 1-4 questionnaires completed every 4-8 weeks for up to 14 months. Compliance was calculated as the number of assessments received divided by the number of assessments expected in a given assessment period. To evaluate assessment burden, each assessment period was categorized as requiring a lower number (daily diary and 1 questionnaire) or higher number (daily diary and 2-4 questionnaires) of assessments. Results: A total of 1,040 patients were included in the analysis. Overall compliance at the single clinic visit was 100%, which was expected since it was a required randomization visit. Overall compliance at home over 14 months was 80%. Compliance ranged from 78% to 89% over the duration of the studies, with no effect of time in the study on compliance. Compliance remained high even as patient numbers declined. Compliance when patients were required to complete a lower number of assessments (80%) was similar to compliance when patients were required to complete a higher number of assessments (79%). Compliance by region varied from 72% (Middle East) to 87% (Asia and Eastern Europe). Conclusions: The collection of ePRO at home provided high compliance that did not vary with length of time in the study or due to assessment burden. At home ePRO assessments provide an effective and feasible approach for recording symptoms and QOL in prostate cancer patients.
Role of E2F3 and shugoshin I in epithelial-to-mesenchymal transition and cell invasion in breast cancer.
Authors: Shirley Jusino, Srikumar P. Chellappan, Harold I. Saavedra
Journal: Journal of Clinical Oncology (2020)

e13100 Background: Triple-negative breast cancer (TNBC) is the most aggressive and poorly prognostic breast cancer subtype, yet there are currently no biological therapies against this subtype. Our laboratory is finding the sources of novel biological targets in TNBC by studying the E2F transcription factors, which are essential for cellular proliferation and maintenance of genomic stability. While the deregulated Rb/E2F pathway signals the epithelial-to-mesenchymal transition (EMT), the underlining mechanism of how E2Fs drive EMT in TNBC remains unknown. We recently published that the E2F transcriptional activators (E2Fs) are overexpressed in the vast majority of TNBC and that their overexpression upregulates mitotic kinases such as TTK, which we have shown to induce EMT and invasion in TNBC cells. We also demonstrated that the E2Fs maintain genomic integrity in part through Shugoshin I (SGO1), which normally controls chromosome cohesion; however, the role of SGO1 in EMT in breast cancer is unknown. Our hypothesis is that E2F3 and SGO1 are highly expressed in TNBC and that their overexpression modulates EMT genes, thus promoting cell invasion. Methods: To test our hypothesis, we conducted siRNA transfection to knockdown E2F3 and SGO1 in MDA-MB-231 and Hs578t, which are TNBC cells. After 48 hours, we evaluated mRNA levels of EMT-related genes after E2F3 or SGO1 depletion using RT-PCR analysis. We also evaluated the effects of SGO1 depletion in protein localization by immunofluorescence. Furthermore, we evaluated the invasive behavior of MDA-MB-231 and Hs578t cells after SGO1 depletion using a Boyden Chamber Assay. Results: Our results demonstrate that E2F3 and SGO1 depletion decrease MMP3 mRNA levels. Moreover, E2F3 and SGO1 depletion restore E-cadherin expression and localization. Furthermore, E2F3 and SGO1 depletion significantly reduce cell invasion in MDA-MB-231 and Hs578t cells. Conclusions: Our results suggest that SGO1 is a promising drug target for breast cancer metastasis since EMT and invasion are essential early steps in breast cancer metastasis and E2F3 is presently undruggable.
First-in-human clinical trial of the autologous CD7-CART for relapsed/refractory ACUTE lymphoblastic leukemia/lymphoma.
Authors: Mingzhi Zhang, Lin Yang, Xiaorui Fu, Lei Zhang, Huimin Meng, Ling Li, Xin Li, Xinhua Wang, Zhenchang Sun, Hui Yu, Zhaoming Li, Feifei Nan, Yu Chang, Zhiyuan Zhou, Jiaqin Yan, Jiwei Li, Min Wang, Fengtao You, Yu-Sheng Chen, Bozhen Zhang
Journal: Journal of Clinical Oncology (2020)

3026 Background: CD7 represents a potential target for T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/T-LBL). We developed CD7 nanobody derived chimeric antigen receptor T-cells (CD7-CART), and established a non-gene editing strategy by anchoring CD7 in the ER and/or Golgi to overcome the CART fratricide. Methods: This single-arm, open-label, phase I study is to investigate CD7-CART cell manufacturing feasibility without contamination of malignant T cells, and the safety and efficacy of the CART on patients with CD7 positive relapsed/refractory T-ALL/T-LBL. 3 subjects, identified as both CD4 and CD8 negative T-ALL or T-LBL were enrolled. CART cells were manufactured by using CD4+/CD8+ sorted T cells from leukapheresis. All patients (Pts) were pretreated with Flu/Cy prior to CART infusion. 1x10 6 /kg CART cells were given to case 2 and 3, while 1.5x10 6 /kg to case 1. Results: Case 1 was diagnosed as refractory ALL with myeloid differentiation, who had received intensive chemotherapy and allogeneic hematopoietic stem cell microtransplantation. Case 2 was diagnosed as ALL (T/B mixed type) but relapsed with CNS involvement, and received radiotherapy in addition to intensive chemotherapy. Prior to CART infusion, case 2 had no abnormal B cells but 17.69% of abnormal early T cellsfrom BM. Case 3 had stage VI of T-LBL, which recurred after multi-cycle chemotherapy of BFM-90 regimen and autologous SCT. After CART treatment, no neurotoxicity was observed in all pts. Case 1 had grade 3 CRSwhile case 2 and 3 had grade 1, although increased IL-6 was detected in all pts. Significant CART expansion and persistence were observed in case 2 and 3, and MRD negative CR was confirmed on day 28 in both pts. The number of generalized lymphadenopathy, lymph node size, and the degree of metabolism were all significantly reduced in case 3. Case 1 had only moderate CART expansion, but abnormal early T cells from BM decreased from 70.03% to 19.57% on day 30. After CART infusion, the number of peripheral abnormal T cells became either undetectable in case 2 and 3, or significantly decreased in case 1. Interestingly, CART had unsustained effect on normal T cells in all pts. As of Feb-10-2020, case 1 has 5 months of OS, including 3 months of PFS. Case 2 and 3 has reached 2 and 1 months of PFS and is still in remission. Conclusions: CD7-CART cells can be manufactured without contamination of malignant T cells. CD7-CART therapy is well-tolerated and has great therapeutic potential for relapsed/refractory CD7 positive T cell malignancies. Clinical trial information: NCT04004637 .
Locally advanced GCTB recurrence after neoadjuvant denosumab use.
Authors: Gabriela Monte Tenorio Taveira, Felipe Da Silva Marinho, Antonio Marcelo Gonçalves de Souza, Wagner cabral Gomes Carneiro
Journal: Journal of Clinical Oncology (2020)

e23507 Background: Giant Cell Tumor of Bone is a RANK/RANK-ligand (RANKL) positive, aggressive, locally destructive tumor leading to pain and impairment of movement and limb function. Even though surgery remains the standard treatment, the use of denosumab, monoclonal antibody RANK-L inhibitor is associated with tumor response and surgical morbidity, with downstaging benefit. Methods: All GCTB patients from 2005 to 2020 from Pernambuco Cancer Center Hospital were included in the study and followed up. All patients received Denosumab 120mg on D1, D8 and D15 (attack phase), and maintenance phase of 120mg monthly. Results: A total of Fifty GCTB Patients were included in the study, being mostly women (62%), between 21-40 yrs. old (56%), Capanacci III (72%), with tumors located in femur (41%), tibia (23%), and more rarely in talus or orbit. Denosumab neoadjuvant was prescribed to 40 patients, being 28 locally advanced disease and 12 irresectable or metastatic disease, with a median of 10 doses received. Among resectable Patients, after neoadjuvant denosumab, 25 were submitted to intralesional surgery (curettage/bone cement) and 3 to en-bloc surgery/prothesis. Overall recurrence after neoadjuvant denosumab was observed in 22% (9/40) and 32% (8/25) among Patients that received neoadjuvant denosumab and intralesional surgery. Denosumab was approved for irresectable GCTB, or when surgery may render high morbidity. Neoadjuvant Denosumab use has been related to lower recurrence rate, as well as reduction in invasive procedures morbidity and sequelae in motricity. In the present study, recurrence rate of 22%, regardless of the therapeutic modality applied, corroborates recurrence rates in published data (16-30%). Among locally advanced patients, even though recurrence rates are expectedly higher, there were lower rates of aggressive surgery and joint preservation. Motor sequelae was observed in 12,5% (5/40) of patients, with quality of life improvement and pain reduction after treatment. Conclusions: Neoadjuvant denosumab for GCTB provides promising results, with acceptable recurrence rates, as well as a less aggressive approach, with lower risk of morbidity or sequelae and excellent safety profile.
Gastric-type adenocarcinoma of the cervix: Genomic drivers and clinical outcomes.
Authors: Dib Sassine, Alli M. Straubhar, Carol Aghajanian, Kaled M. Alektiar, Vance Broach, Karen Anne Cadoo, Elizabeth Lin Jewell, Chrisann Kyi, Mario M. Leitao, Jennifer Jean Mueller, Rajmohan Murali, Roisin Eilish O'Cearbhaill, Kay J. Park, Yukio Sonoda, Britta Weigelt, Dmitriy Zamarin, Nadeem Abu-Rustum, Claire Frances Friedman
Journal: Journal of Clinical Oncology (2020)

6030 Background: Cervical Gastric-type adenocarcinoma (CGA) is a non-HPV-associated adenocarcinoma, comprising 10% of all cervical adenocarcinomas (Park et al, 2019). The optimal management approach is unclear, given that most data in advanced cervical cancer is driven by HPV-positive disease. We summarize our experience with this rare tumor type at a large cancer center. Methods: A retrospective review was performed for all women diagnosed with CGA 6/1/2002- 7/1/2019. Patients who did not follow up after a single visit were excluded. Kaplan-Meier survival analysis was performed to determine progression-free survival (PFS) and overall survival (OS) from date of diagnosis. Tumors from a subset of patients were subjected to MSK-IMPACT targeted sequencing and analysis (Zehir et al, 2017). Results: A total of 68 women were identified; 47 met inclusion criteria. The median age at diagnosis was 52 years (range 27-83). The majority of patients were white (70%), an additional 19% were Asian. The majority of patients (60%, n=28) presented with advanced disease (FIGO 2018, stage II-IV), while 40% (n=19) were Stage I. Of note, 26% (n=12) had positive pelvic lymph nodes and 13% (n=6) had ovarian metastases at time of surgical resection. For upfront treatment: 13% (n=6) had surgery alone of whom 83% had stage 1 disease, 36% (n=17) had surgery followed by adjuvant therapy, 30% (n =14) received definitive chemo-radiation (CRT). All patients with stage IV disease 15% (n=7) received chemotherapy alone. At completion of primary treatment, 19% (n=9) of patients had persistent disease. In patients who received CCRT, 65% (n=22) recurred, the majority (64%) within 12 months of completion of upfront therapy. Pelvic recurrence was the most common site (n=14, 64%). With a median follow up time of 30 months (range 1-159), the median PFS for Stage I was 34.4 months, compared to 17.5 months in patients with Stage II-IV disease (p= 0.29). Of the 24 patients that had MSK-IMPACT, the most common mutation was TP53 (n=16, 64%) followed by mutations in the RAS pathway (n=8, 33%), PIK3CA (n=3, 12.5%), STK11 (n=3, 12.5%), and ERBB2 alterations (n=2, 8.3 %). 2 (8.3%) women enrolled on a clinical trial based on their NGS results, one targeting ERBB2 and one targeting PIK3CA. Conclusions: Consistent with prior published literature, CGA is an aggressive form of cervical cancer with poor median OS in the advanced setting. With universal HPV vaccination, HPV negative cervical cancer will represent a larger percentage of newly diagnosed cancers and further research is needed to identify the optimal management approach.
Enrichment of circulating tumor DNA from cell-free DNA of hematopoietic origin.
Authors: Jason Terrell, Priscilla Van den Ackerveken, Alison Lobbens, Mark Eccleston, Clotilde Hannart, Jean-Philippe Deglasse, Jean-Valery Turatsinze, Marielle Herzog, Jake Micallef
Journal: Journal of Clinical Oncology (2020)

e13534 Background: In liquid biopsy, circulating tumor DNA (ctDNA) is more fragmented than background cell free DNA, peaking at 147bp (equivalent to a mono-nucleosome) instead of 165bp (nucleosome with an additional 20bp of linker DNA). Isolation of these shorter cell free DNA fragments from longer, extracted cell-free DNA improves detection of ctDNA as demonstrated by enrichment of tumor specific mutations. Nuclease protection of the additional 20bp of linker DNA, conferred by bound linker proteins such as Histone 1, would account for the 165bp peak in host background DNA. We hypothesised that extracting intact nucleosomes with linker DNA using a novel, H1 antigen based, immunocapture approach would enrich the ctDNA fraction in the remaining nucleosomes. Methods: We expressed H1.0 protein in E. coli and following extraction, purification and chemically immobilised it to tosyl-activated magnetic beads. The beads were first used to immunodeplete mono-nucleosomes from HeLa cell digests and the level of immunocaptured nucleosomes was determined by immunoassay targeting intact nucleosomes. The level of nucleosome levels determined before and after depletion was further determined by ELISA targeting H3.1 containing intact nucleosomes. DNA was extracted from the H1 immunocaptured “long” nucleosomes and size profiles compared with the remaining nucleosomes in the supernatant by BioAnalyzer. Then, the method was applied to clinical plasma samples and the size distribution of NGS Libraries (Illumina system) prepared from five colorectal cancer and three healthy samples, their immune depleted supernatants and the immunocaptured nucleosomes were then compared. Enrichment of specific genomic regions was also evaluated. Results: We observed relative enrichment of nucleosomes with short DNA in supernatants following H1 immuno-depletion of the cancer samples as evidenced by a change in size distribution by Bioanalyzer and NGS-sequencing. We also observed potential enrichment of TSS is the H1 immunocaptured nucleosomes consistent with linker DNA positioning of TF binding sites. Conclusions: Histone 1.0 has the highest affinity of H1 mammalian isoforms and successfully immunodepleted plasma samples containing cell free circulating nucleosomes with DNA longer that 147bp. Immobilized H1.0 effectively formed a pseudo-chromatosome by binding to free linker DNA or displacing endogenous H1 and other linker associated proteins. H1 antigen based immuno-depletion offers a simple way to enrich tumour derived nucleosomes and thus cell free DNA.
The association of adaptive early phase study design and late phase study results in oncology using clinicaltrials.gov data.
Authors: Donna Elise Levy, Srikanta Banerjee, Fred K Tabung
Journal: Journal of Clinical Oncology (2020)

e14078 Background: Traditional methods such as the 3+3 design developed in the 1940s continue to be used in the majority of early phase oncology studies. Researchers have found that the traditional methods identify the appropriate dose level only 30% of the time. Patients are also exposed to sub-therapeutic doses due to the conservative methods. With these limitations on traditional design options, innovative methods need to be developed, adopted and assessed. Methods: This quantitative study assessed the association of the design methods (adaptive versus traditional) used for early phase oncology studies (adaptive versus traditional) and the outcome of late stage clinical trials. Differences by cancer type and by drug classification were also assessed. A sample of studies for this analysis was extracted from the National Institute of Health Clinical registry and results database. The data used for the analysis was extracted by the Clinical Trials Transformation Initiative (CTTI) Aggregate Analysis of ClinicalTrials.gov (AACT). Results: When assessing study design and outcome, there were lower odds of a positive outcome when adaptive methods were used though this association was not statistically significant (OR [95% highest posterior density (HPD)]:0.66 [0.20, 1.21]). Among the different drug types, using adaptive compared to traditional methods was associated with significantly higher odds of a positive outcome for taxanes, OR: 2.75, 95% HPD: 1.01, 5.16) and other, OR: 3.23, 95% HPD: 1.58, 5.46) but no association among studies of monoclonal antibodies or protein kinase inhibitors. There were no significant associations between early phase study design and outcome in late phase studies by cancer type (lung, breast, other). Conclusions: While results associated with the use of adaptive methods were not significant, further research should be conducted using all completed oncology clinical trials in the database to more precisely determine the relationship between adaptive study design in early phase oncology studies and outcomes in late stage studies. In addition, improvements in traditional versus adaptive design capture in the ClinicalTrials.gov database needs to be considered.