Abstract C86: The clinical candidate ZEN-3694, a novel BET bromodomain inhibitor, is efficacious in the treatment of a variety of solid tumor and hematological malignancies, alone or in combination with several standard of care and targeted therapies

2015 ◽  
Author(s):  
Sarah Attwell ◽  
Eric Campeau ◽  
Ravi Jahagirdar ◽  
Olesya Kharenko ◽  
Karen Norek ◽  
...  
Keyword(s):  
Solid Tumor ◽  
Targeted Therapies ◽  
Hematological Malignancies ◽  
Standard Of Care ◽  
Clinical Candidate

Molecular Testing of Solid Tumors

2011 ◽  
Vol 135 (1) ◽  
pp. 67-82 ◽  
Author(s):  
Anne Igbokwe ◽  
Dolores H. Lopez-Terrada
Keyword(s):  
Solid Tumors ◽  
Solid Tumor ◽  
Unknown Origin ◽  
Standard Of Care ◽  
Soft Tissue Tumors ◽  
Molecular Diagnostic ◽  
Original Research ◽  
Molecular Testing ◽  
Neoplastic Disease ◽  
Therapeutic Decisions

Abstract Context—Molecular testing of solid tumors is steadily becoming a vital component of the contemporary anatomic pathologist's armamentarium. These sensitive and specific ancillary tools are useful for confirming ambiguous diagnoses suspected by light microscopy and for guiding therapeutic decisions, assessing prognosis, and monitoring patients for residual neoplastic disease after therapy. Objective—To review current molecular biomarkers and tumor-specific assays most useful in solid tumor testing, specifically of breast, colon, lung, thyroid, and soft tissue tumors, malignant melanoma, and tumors of unknown origin. A few upcoming molecular diagnostic assays that may become standard of care in the near future will also be discussed. Data Sources—Original research articles, review articles, and the authors' personal practice experience. Conclusions—Molecular testing in anatomic pathology is firmly established and will continue to gain ground as the need for more specific diagnoses and new targeted therapies evolve. Knowledge of the more common and clinically relevant molecular tests available for solid tumor diagnosis and management, and their indications and limitations, is necessary if anatomic pathologists are to optimally use these tests and act as consultants for fellow clinicians directly involved in patient care.

scholarly journals Structural Variants as a Basis for Targeted Therapies in Hematological Malignancies

2019 ◽  
Vol 9 ◽  
Author(s):  
Judith Schütte ◽  
Julia Reusch ◽  
Cyrus Khandanpour ◽  
Christine Eisfeld
Keyword(s):  
Targeted Therapies ◽  
Hematological Malignancies ◽  
Structural Variants

Assessment of the Fanconi anemia repair pathway as a predictor of clinical activity of pembrolizumab (PEM).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 2555-2555
Author(s):  
Miguel Angel Villalona-Calero ◽  
John Paul Diaz ◽  
Zuanel Diaz ◽  
Wenrui Duan ◽  
Eric Douglas Schroeder ◽  
...  
Keyword(s):  
Fanconi Anemia ◽  
Solid Tumor ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Primary Objective ◽  
Clinical Activity ◽  
Functional Assay ◽  
Phase 2 Trial

2555 Background: Given the activity of immune checkpoint inhibitors (ICI) in mismatch repair deficient tumors, we evaluated if homologous recombination repair deficiency associates with solid tumor response to ICI. Methods: We conducted a phase 2 trial (NCT03274661) of PEM in metastatic solid tumor patients progressing on standard of care and for whom PEM had no FDA approved indication. We evaluated a triple stain (FANCD2foci/DAPI/Ki67) immunofluorescence functional assay of the Fanconi Anemia pathway (FATSI) in treated patients’ archived tumors as a correlative biomarker. Patients with microsatellite unstable tumors were not eligible. The primary objective was objective response rate (iORR, CR+PR) by Immune Response Criteria, with the hypothesis that patients with FATSI negative tumors will have better clinical outcome. Secondary objectives were progression free survival (PFS), 6 months PFS and survival. PEM was given every 3 weeks and computed tomography scans were performed every 6 weeks. We utilized a two-stage phase II trial design to detect an iORR ≥ 20% in the whole population tested vs. the null hypothesis that the true iORR ≤5%. If ≥ 2 of the first 20 evaluable patients had an objective response the trial proceeded to full accrual of 39 evaluable patients. Outcomes were evaluated according to FATSI staining. Results: 42 patients (40 evaluable) (35F,7M; median age 62[36-83]) enrolled. Median # of prior regimens was 2[1-7]. Primary Dx included ovarian/fallopian (13), endometrial (10), colorectal (3), cervix (2), pancreatic(2), vaginal (2) and 1 each of various others. No unexpected toxicities occurred. Response evaluation showed 2 CR, 5 PR, 11 SD, 22 PD and 2 NE (iORR 18%). FATSI tumor analyses results are available in 34 patients; 25 FATSI positive, 9 negative. 2 PR, 8 SD, 14 PD, 1 NE occurred among the FATSI (+) (iORR 8%) and 2 CR, 2 PR, 2 SD, 3 PD among the FATSI (-) patients (iORR 44%). mPFS and 6m-PFS were 54 days and 12% (3/25) in FATSI (+), versus 248 days and 56% (5/9) in FATSI (-) patients; p = 0.017. Conclusions: PEM has meaningful antitumor activity in non MSI-high malignancies with no current FDA approved indications. Evaluation of FATSI as a biomarker supports a biomarker selected population approach. Clinical trial information: NCT03274661.

Profiling and prognostic implications of variants of unknown significance (VUS) in solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e19012-e19012
Author(s):  
Meena Sadaps ◽  
Bassam N. Estfan ◽  
Wei Wei ◽  
Davendra Sohal ◽  
Megan Lynn Kruse
Keyword(s):  
Racial Disparities ◽  
Solid Tumor ◽  
Cleveland Clinic ◽  
Standard Of Care ◽  
Median Number ◽  
Rank Test ◽  
Precision Oncology ◽  
Variant Of Unknown Significance ◽  
Unknown Significance ◽  
Prognostic Implications

e19012 Background: While precision oncology is becoming increasingly integrated into standard of care for most incurable solid tumor malignancies, there is paucity of data regarding the clinical significance of VUS. In this study, we aim to evaluate whether the number of VUS is associated with overall survival (OS). We also analyze racial disparities pertaining to the number of VUS present and identify which, if any, genes possess prognostic implications. Methods: This is a retrospective review of 389 consecutive patients seen at Cleveland Clinic from 2014 to 2016 with incurable solid tumor malignancies, for whom next-generation sequencing (NGS) was ordered using Foundation One™ (Cambridge, MA). Demographics, number of VUS, genes involved, and race were summarized. OS was estimated by Kaplan-Meier and compared by log rank test. Results: Median age was 60 years, 202 (52%) patients were female, 338 (86.7%) were Caucasian, and 31 (8.0%) were African American. On NGS, 376 (97%) patients had VUS reported. The median number of VUS was 9 (range 1-116). When dichotomized at the median, the number of VUS did not affect OS. Genes most commonly implicated in reported VUS were LRP1B (88, 22.6%), MLL3 (83, 21.3%), MLL2 (73, 18.8%), ARID1B (70, 18.0%), PRKDC (60, 15.4%), PREX2 (58, 18.7%), and SPTA1 (56, 14.4%). Patients found to have a variant of unknown significance in MLL2 had worse median OS as compared to those who did not (2.61 vs 3.76 years respectively; p = 0.033). When profiled by race, Caucasians had lower numbers of VUS (p = 0.002; Table). Conclusions: We did not find a clear association between the number of VUS and OS. MLL2, a gene known to predict poor prognosis as a pathogenic variant, was seen in our study to have similarly poor prognostic implications as a variant of unknown significance. Racial disparities in genomics exist as African Americans are under-represented and have greater numbers of VUS as compared to Caucasians. Further research is warranted to elucidate these disparities. [Table: see text]

scholarly journals Invasive Fungal Infections and Targeted Therapies in Hematological Malignancies

2021 ◽  
Vol 7 (12) ◽  
pp. 1058
Author(s):  
Jessica S. Little ◽  
Zoe F. Weiss ◽  
Sarah P. Hammond
Keyword(s):  
Targeted Therapies ◽  
Hematological Malignancies ◽  
Fungal Infections ◽  
High Risk Patient ◽  
Underlying Disease ◽  
Infectious Complications ◽  
Invasive Fungal Infections ◽  
Individual Risk ◽  
Increased Risk ◽  
The Impact

The use of targeted biologic therapies for hematological malignancies has greatly expanded in recent years. These agents act upon specific molecular pathways in order to target malignant cells but frequently have broader effects involving both innate and adaptive immunity. Patients with hematological malignancies have unique risk factors for infection, including immune dysregulation related to their underlying disease and sequelae of prior treatment regimens. Determining the individual risk of infection related to any novel agent is challenging in this setting. Invasive fungal infections (IFIs) represent one of the most morbid infectious complications observed in hematological malignancy. In recent years, growing evidence suggests that certain small molecule inhibitors, such as BTK inhibitors and PI3K inhibitors, may cause an increased risk of IFI in certain patients. It is imperative to better understand the impact that novel targeted therapies might have on the development of IFIs in this high-risk patient population.

scholarly journals Intensity of End of Life Care for Hematologic Malignancy Patients in Western Washington, United States and Alberta, Canada

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 21-21
Author(s):  
Ali Raza Khaki ◽  
Yuan Xu ◽  
Shasank R Chennupati ◽  
Scott D Ramsey ◽  
Catherine Fedorenko ◽  
...  
Keyword(s):  
End Of Life ◽  
Solid Tumor ◽  
Research Funding ◽  
Hematological Malignancies ◽  
Hematologic Malignancy ◽  
Cancer Registries ◽  
Cancer Surveillance ◽  
Healthcare Use ◽  
Ed Visits ◽  
Western Washington

Background: Aggressive care at the end of life (EOL) leads to unnecessary suffering and healthcare costs for patients with cancer. We have previously shown that among patients with solid tumor malignancies, EOL utilization of chemotherapy, intensive care unit (ICU) admissions and >1 emergency department (ED) visits are higher in Washington State vs Alberta (AB). In this study, we use cancer registry and claims data to compare EOL care among patients with hematological malignancies between western Washington (WW) and AB. Methods: Adult patients with hematological malignancies diagnosed between 2007 and 2017 who died before December 31, 2018 were identified from regional population-based cancer registries in WW and AB. Data sources were 1) WW Cancer Surveillance System (a regional SEER registry) with data from 13 counties linked to enrollment files and claims from four regional insurers and 2) Canada National Ambulatory Care Reporting System, Discharge Abstracts Database, and chemotherapy records from AB Health Services. Proportions of patients receiving chemotherapy, ICU admission, or >1 ED visit in the last 30 days of life (DOL) in WW and AB were determined among all patients and those ≥65 years and compared using two sample z-test with two-tailed hypothesis (α=0.006 after Bonferroni correction). Results: 7859 AB and 3767 WW patients met study inclusion criteria. Median age was 76 (IQR 66-83) and 79 (IQR 71-86) for AB and WW, respectively; 78% and 85% were over age 65, 33% and 59% with ≥2 Charlson Comorbidity Score. Cancer distribution was 33% (AB) and 54% (WW) non-Hodgkin lymphoma, 14% (AB) and 20% (WW) myeloma and 27% (AB) and 19% (AB) leukemia. Table 1 shows utilization of chemotherapy, >1 ED visits and ICU admissions in AB and WW for all patients and Table 2 in those ≥65 years. More patients in WW vs AB were treated with chemotherapy (21% WW vs 7% AB) and admitted to ICU (34% WW vs 9% AB) in the last 30 DOL, whereas multiple ED visits were more similar between WW and AB (17% vs 19%, respectively). Similarly, among patients ≥65 years, chemotherapy use and ICU admissions were higher in WW. The same was true for patients in the last 60 and 90 DOL. Conclusions: Similar to what was noted in solid tumor patients, intensity of healthcare use at EOL is greater in WW vs AB for patients with hematological malignancies. However, ≥1 ED visits were similar between populations. Further work is needed to understand drivers of high intensity healthcare use and identify interventions to minimize low value care at EOL. Disclosures Khaki: Merck: Other: share/stockholder; Pfizer: Other: share/stockholder. Ramsey:AstraZeneca: Other: Personal Fees. Cowan:Janssen: Consultancy, Research Funding; Abbvie: Research Funding; Cellectar: Consultancy; Sanofi: Consultancy; Bristol Myers Squibb: Research Funding.

scholarly journals Ned-170: A combination anti-cancer therapy targeting late stage, heavily pre-treated solid tumor malignancies.

2019 ◽  
Vol 5 (suppl) ◽  
pp. 141-141
Author(s):  
Edward Graeme Garmey ◽  
Kristan Meetze ◽  
Bridget Martell
Keyword(s):  
Clinical Trial ◽  
Tumor Growth ◽  
Solid Tumor ◽  
Late Stage ◽  
Phase 1 ◽  
Xenograft Model ◽  
Standard Of Care ◽  
Tumor Growth Inhibition ◽  
Tumor Growth And Metastasis ◽  
Grade 3

141 Background: NED-170 is a 7-component regimen of both marketed drugs and nutraceuticals with established safety and tolerability profiles and antineoplastic activity. These components, including metronomically-dosed cyclophosphamide (CTX), metformin, naltrexone, alpha lipoic acid, genistein, curcumin, and melatonin, target four key pathways driving tumor growth and metastasis. Methods: NED-170 was evaluated pre-clinically for tolerability and efficacy using a murine CT-26 syngeneic xenograft model. After tumor volume reached 80-120 mm³, mice were randomized into three groups of 10. Experimental arms included: NED-170 allometrically scaled to provide comparable exposure to human clinical trial doses, vehicle, CTX alone, or an anti-PD-1 antibody. In parallel to these studies, a compassionate expanded access program (EAP) was established in 2013 as a precursor to formal clinical trials. To date, 21 pts. with stage IIIc/IV advanced solid tumor malignancies (5 ovarian, 6 sarcoma, 4 Br. Ca, 2 NSCLC, & 4 other cancers) who either sought alternatives to standard-of-care (SOC) chemotherapy or whose tumors progressed through available SOC options have been enrolled. Results: In pre-clinical studies, NED-170 demonstrated 78% tumor growth inhibition (TBI) which exceeded vehicle in a statistically significant fashion (p < 0.001). In contrast, anti-PD-1 treatment failed to achieve anti-tumor activity and CTX alone achieved 50% TBI. In parallel, 21 EAP pts. have been treated with a combined 1,217 months (mos.) of NED-170 therapy (median = 11.8 mos; range = 1.0-60.2). For all pts., the regimen has been safe and well-tolerated with no drug-related grade-3-4 adverse events or dose reductions/discontinuations reported. Observational data reported by pts. or physicians demonstrated that 81% of pts. derived benefit and improved quality of life in this late stage setting. Conclusions: Based on these encouraging data, NED-170 may provide late stage cancer pts. with a safe, effective, and lower cost alternative to standard chemotherapy. A multinational phase 1-2b clinical trial commencing in late 2019 is planned.

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