Publications by authors named "Seth M Steinberg"

432 Publications

Characterization of HLH-Like Manifestations as a CRS Variant in Patients Receiving CD22 CAR T-Cells.

Blood 2021 Sep 15. Epub 2021 Sep 15.

National Institute of Health, Bethesda, Maryland, United States.

CAR T-cell toxicities resembling hemophagocytic lymphohistiocytosis (HLH) occur in a subset of patients with cytokine release syndrome (CRS). As a variant of conventional CRS, a comprehensive characterization of CAR T-cell associated HLH (carHLH) and investigations into associated risk factors are lacking. In the context of 59 patients infused with CD22 CAR T-cells where a substantial proportion developed carHLH, we comprehensively describe the manifestations and timing of carHLH as a CRS variant and explore factors associated with this clinical profile. Amongst 52 subjects with CRS, 21 (40.4%) developed carHLH. Clinical features of carHLH included hyperferritinemia, hypertriglyceridemia, hypofibrinogenemia, coagulopathy, hepatic transaminitis, hyperbilirubinemia, severe neutropenia, elevated lactate dehydrogenase and occasionally hemophagocytosis. Development of carHLH was associated with pre-infusion NK-cell lymphopenia and higher bone marrow T/NK-cell ratio, which was further amplified with CAR T-cell expansion. Following CRS, more robust CAR T-cell and CD8 T-cell expansion in concert with pronounced NK-cell lymphopenia amplified pre-infusion differences in those with carHLH without evidence for defects in NK-cell mediated cytotoxicity. CarHLH was further characterized by persistent elevation of HLH-associated inflammatory cytokines, which contrasted with declining levels in those without carHLH. In the setting of CAR T-cell mediated expansion, clinical manifestations and immunophenotypic profiling in those with carHLH overlap with features of secondary HLH, prompting consideration of an alternative framework for identification and management of this toxicity profile to optimize outcomes following CAR T-cell infusion.
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http://dx.doi.org/10.1182/blood.2021011898DOI Listing
September 2021

Brief Report: Tolerability of COVID-19 Vaccines, BNT162b2 and mRNA-1273, in Patients with Thymic Epithelial Tumors.

JTO Clin Res Rep 2021 Sep 8:100229. Epub 2021 Sep 8.

Thoracic and Gastrointestinal Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

Introduction: Defects in immunological self-tolerance result in an increased risk for development of autoimmune paraneoplastic diseases (AD) and immune-mediated toxicity in response to immune stimulation in individuals with thymic epithelial tumors (TETs). We conducted a survey to evaluate the tolerability of Covid-19 messenger RNA (mRNA) vaccines in patients with TETs, including individuals with pre-existing AD.

Methods: After reviewing published data on adverse events (AEs) associated with the BNT162b2 (Pfizer, Inc., and BioNTech) and mRNA-1273 (ModernaTX, Inc.) mRNA vaccines, we designed and administered a questionnaire to participants at three timepoints: after each dose of vaccination and one month following the final dose. Questions related to AD and use of immunosuppressive drugs were included. Descriptive statistics were used to analyze data and results were compared with previously described results related to the BNT162b2 and mRNA-1273 vaccines.

Results: From February 26 and June 1, 2021, we administered the survey to 54 participants (median age: 58 years; thymoma: 33; pre-existing AD: 19). Common AEs included injection-site pain, fatigue, and headaches. There were no vaccination-related hospitalizations or deaths. Autoimmune flares occurred in three (16%) patients after the first dose and three (17%) patients after the second dose. The majority of AD flares were mild and self-limited. One patient (2%) was diagnosed with a new AD following vaccination.

Conclusions: Tolerability of COVID-19 mRNA vaccines in patients with TETs is comparable to the general population. Most patients with pre-existing AD did not experience disease flares and the development of new AD was rare. Patients with TETs should be encouraged to get vaccinated against COVID-19 due to the documented benefits of vaccination and manageable risk profile.
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http://dx.doi.org/10.1016/j.jtocrr.2021.100229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8423742PMC
September 2021

Clinical characterization and cytokine profile of fatigue in hematologic malignancy patients with chronic graft-versus-host disease.

Bone Marrow Transplant 2021 Aug 25. Epub 2021 Aug 25.

Immune Deficiency and Cellular Therapy Program, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, USA.

Limited information is available regarding clinical and biological properties of fatigue in patients with chronic graft-versus-host disease (cGvHD). Patients with moderate-to-severe cGvHD per NIH criteria were enrolled on a cross-sectional study and categorized as "fatigued" if SF-36 vitality score was <40. Clinical and laboratory parameters of fatigued (n = 109) and nonfatigued patients (n = 72) were compared. In univariate analysis, walk velocity, NIH joint-fascia score, human activity profile, and SF-36 physical and mental health self-report scales were correlates of fatigue. No cGvHD biomarkers were associated with fatigue. NIH joint score, Lee sleep and depression questions, and PG-SGA activities and function score jointly predicted fatigue. Though higher rates of depression and insomnia were reported in the fatigued group, antidepressant or sleep aid use did not differ between groups. Survival ratio was not significantly different by fatigue status. Pathophysiology of fatigue in patients with cGvHD is complex and may involve mechanisms unrelated to disease activity. Patients with cGvHD experiencing fatigue had higher rates of untreated depression and insomnia, highlighting the need to focus clinical management of these conditions to improve health-related quality of life.
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http://dx.doi.org/10.1038/s41409-021-01419-2DOI Listing
August 2021

Subsequent Cancers in Patients Affected with Moderate or Severe Chronic Graft-versus-Host Disease.

Transplant Cell Ther 2021 Aug 8. Epub 2021 Aug 8.

Immune Deficiency Cellular Therapy Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. Electronic address:

Subsequent cancer (SC) is a significant cause of morbidity and mortality in long-term survivors after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Chronic graft-versus-host disease (cGVHD) and treatment-related immunosuppression have been recognized as risk factors for SC. This study sought to investigate the incidence and risk factors for SC in patients with established cGVHD, assessed separately for onset of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)-categorized into nonmelanoma skin cancer (NMSC)-and all cancers other than NMSC. Two hundred and four patients were enrolled in the prospective cross-sectional cGVHD Natural History Study and underwent comprehensive clinical evaluation. Patients were followed-up with an annual survey. The cumulative incidences of NMSC and cancers other than NMSC with competing risks were estimated separately, and transplantation- and cGVHD-related factors were assessed for association with outcomes using Gray's test and multivariable Cox models. The time period for all analyses began at 2 years postevaluation to restrict analyses to patients presumed to not have had SC present at evaluation. Nineteen patients were diagnosed with NMSC and 19 were diagnosed with cancers other than NMSC, with 10-year cumulative incidences of 15.5% (95% confidence interval, 9.0% to 27.6%) and 13.8% (95% CI, 8.2% to 20.8%), respectively. Age at transplantation (hazard ratio [HR], 1.94; 95% CI, 1.23 to 3.06) and higher C-reactive protein level at evaluation (HR, 9.49; 95% CI, 1.26 to 71.58) were jointly associated with NMSC, and gastrointestinal cGVHD at evaluation (HR, 0.26; 95% CI, 0.09 to 0.78) was associated with reduced risk of NMSC. T cell depletion at transplantation (HR, 3.09; 95% CI, 1.17 to 8.20), lymphoma as an indication for transplantation (HR, 3.96; 95% CI, 1.56 to 10.05), and oral cGVHD severity at evaluation (HR, 4.36; 95% CI, 1.52 to 12.46) were jointly associated with cancers other than NMSC. This study estimates the incidence of SC in a population of allo-HSCT recipients with severe cGVHD and identifies correlations with the subsequent development of SC. These factors seem to differ between NMSC and cancers other than NMSC. Further longitudinal investigations accounting for dynamic and cumulative processes are needed to improve our understanding and management of SC.
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http://dx.doi.org/10.1016/j.jtct.2021.08.001DOI Listing
August 2021

Longitudinal Circulating Tumor DNA Analysis in Blood and Saliva for Prediction of Response to Osimertinib and Disease Progression in EGFR-Mutant Lung Adenocarcinoma.

Cancers (Basel) 2021 Jul 3;13(13). Epub 2021 Jul 3.

Thoracic and GI Malignancies Branch, CCR, NCI, NIH, Bethesda, MD 20892, USA.

: We assessed whether serial ctDNA monitoring of plasma and saliva predicts response and resistance to osimertinib in EGFR-mutant lung adenocarcinoma. Three ctDNA technologies-blood-based droplet-digital PCR (ddPCR), next-generation sequencing (NGS), and saliva-based EFIRM liquid biopsy (eLB)-were employed to investigate their complementary roles. : Plasma and saliva samples were collected from patients enrolled in a prospective clinical trial of osimertinib and local ablative therapy upon progression (NCT02759835). Plasma was analyzed by ddPCR and NGS. Saliva was analyzed by eLB. : A total of 25 patients were included. We analyzed 534 samples by ddPCR ( = 25), 256 samples by NGS ( = 24) and 371 samples by eLB ( = 22). Among 20 patients who progressed, ctDNA progression predated RECIST 1.1 progression by a median of 118 days (range: 61-272 days) in 11 (55%) patients. Of nine patients without ctDNA progression by ddPCR, two patients had an increase in mutant by eLB and two patients were found to have ctDNA progression by NGS. Levels of ctDNA measured by ddPCR and NGS at early time points, but not volumetric tumor burden, were associated with PFS. // amplifications, C797S, E545K, V9del, and S45P were key resistance mechanisms identified by NGS. : Serial assessment of ctDNA in plasma and saliva predicts response and resistance to osimertinib, with each assay having supplementary roles.
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http://dx.doi.org/10.3390/cancers13133342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8268167PMC
July 2021

Clinical value of FDG PET/MRI in muscle-invasive, locally advanced, and metastatic bladder cancer.

Urol Oncol 2021 Jun 14. Epub 2021 Jun 14.

Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD. Electronic address:

Objective: Metastatic bladder cancer is an aggressive disease that can often be difficult to diagnose and stage with conventional cross-sectional imaging. The primary objective of this study was to determine the clinical value of fluorine-18 2-fluoro-2-deoxy-D-glucose (F-FDG) PET/MRI for surveillance and restaging of patients with muscle-invasive, locally advanced, and metastatic bladder cancer compared to conventional imaging methods.

Materials And Methods: This retrospective study enrolled patients with muscle-invasive, locally advanced and metastatic bladder cancer in a single institute evaluated with F-FDG PET/MRI. All patients also underwent conventional imaging with CT. Additional imaging may also have included F-FDG PET/CT (F-FDG PET), or sodium fluoride (NaF) PET/CT in some patients. Images were reviewed by a diagnostic radiologist/nuclear medicine physician. Number of lesions and sites of disease were captured and compared between F-FDG PET/MRI and conventional imaging. Lesions were confirmed by sequential imaging or lesion biopsy. All patients were followed for survival.

Results: Fifteen patients (4 for surveillance; 11 for restaging) underwent 34 F-FDG PET/MRI scans. Each patient received a corresponding conventional CT around the time of the F-FDG PET/MRI (median 6 days). The 15 patients (11 male; 4 female) had a median age of 61.5 years (range 37-73) and histologies of urothelial carcinoma (n = 13) and small-cell carcinoma of the bladder (n = 2) diagnosed as stage 4 (n = 13), stage 3 (n = 1), or stage 2 (n = 1). F-FDG PET/MRI detected 82 metastatic malignant lesions involving lymph nodes (n = 22), liver (n = 10), lung (n = 34), soft tissue (n = 12), adrenal glands (n = 1), prostate (n = 1), and bone (n = 2) with a resultant advantage of 36% for lesion visibility in comparison with CT. Serial imaging or biopsy confirmed these lesions as malignant.

Conclusion: F-FDG PET/MRI can detect metastatic lesions which cannot be identified on conventional CT, and this can allow for better treatment planning and improved disease monitoring during therapy.
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http://dx.doi.org/10.1016/j.urolonc.2021.04.024DOI Listing
June 2021

Clinical Indicators for Long-Term Survival with Immune Checkpoint Therapy in Advanced Hepatocellular Carcinoma.

J Hepatocell Carcinoma 2021 31;8:507-512. Epub 2021 May 31.

Gastrointestinal Malignancies Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.

Introduction: Patients with advanced hepatocellular carcinoma have a dismal prognosis; only a subset of patients with advanced HCC will benefit from treatment with immunotherapy. We searched for clinical characteristics predicting exceptional long-term survival in HCC patients treated with immune checkpoint inhibitors.

Methods: We compared clinical characteristics of 59 patients with advanced hepatocellular carcinoma treated with immunotherapy with and without locoregional therapy between 2013-2019. We compared patients who lived less than 12 months with patients who lived more than 3 years. Traits of short-term (31 patients) and long-term (5 patients) survivors were compared. Patients who died between 12 months and 3 years of starting treatment on protocol were not included in the analysis.

Results: Two out of five patients (40%) in the long-term survival group had a partial response (PR) or a complete response (CR) per the modified Response Evaluation Criteria in Solid Tumors (mRECIST), while, of the 31 patients in the short-term survival group, only 2 (6.5%) had a CR or PR. Two of the 5 patients with a long-term survival had immune-related adverse events grade 3 or 4 (IrAEs-3/4). None of the patients in the short-term survival group had IrAEs-3/4. The patients, who presented with IrAEs-3/4, which included colitis and adrenal insufficiency, continued to have a response off treatment. The median overall survival (OS) was 11.8 months (95% CI: 7.8-15.4 months), with a 12-month OS of 46.6% (95% CI: 33.4-58.8%) and a 3-year OS of 12.5% (95% CI: 5.0-23.7%).

Conclusion: We found a possible association between immune-related adverse events grade 3 and 4 and long-term survival in patients with advanced HCC. The cases in our analysis represent extraordinary defiance of the usual predicted dismal course of advanced HCC.
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http://dx.doi.org/10.2147/JHC.S311496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178695PMC
May 2021

Therapeutic targeting of ATR yields durable regressions in small cell lung cancers with high replication stress.

Cancer Cell 2021 Apr;39(4):566-579.e7

Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.

Small cell neuroendocrine cancers (SCNCs) are recalcitrant cancers arising from diverse primary sites that lack effective treatments. Using chemical genetic screens, we identified inhibition of ataxia telangiectasia and rad3 related (ATR), the primary activator of the replication stress response, and topoisomerase I (TOP1), nuclear enzyme that suppresses genomic instability, as synergistically cytotoxic in small cell lung cancer (SCLC). In a proof-of-concept study, we combined M6620 (berzosertib), first-in-class ATR inhibitor, and TOP1 inhibitor topotecan in patients with relapsed SCNCs. Objective response rate among patients with SCLC was 36% (9/25), achieving the primary efficacy endpoint. Durable tumor regressions were observed in patients with platinum-resistant SCNCs, typically fatal within weeks of recurrence. SCNCs with high neuroendocrine differentiation, characterized by enhanced replication stress, were more likely to respond. These findings highlight replication stress as a potentially transformative vulnerability of SCNCs, paving the way for rational patient selection in these cancers, now treated as a single disease.
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http://dx.doi.org/10.1016/j.ccell.2021.02.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048383PMC
April 2021

Long-Term Follow-Up of CD19-CAR T-Cell Therapy in Children and Young Adults With B-ALL.

J Clin Oncol 2021 May 25;39(15):1650-1659. Epub 2021 Mar 25.

Pediatric Oncology Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), NIH, Bethesda, MD.

Purpose: CD19 chimeric antigen receptor (CD19-CAR) T cells induce high response rates in children and young adults (CAYAs) with B-cell acute lymphoblastic leukemia (B-ALL), but relapse rates are high. The role for allogeneic hematopoietic stem-cell transplant (alloHSCT) following CD19-CAR T-cell therapy to improve long-term outcomes in CAYAs has not been examined.

Methods: We conducted a phase I trial of autologous CD19.28ζ-CAR T cells in CAYAs with relapsed or refractory B-ALL. Response and long-term clinical outcomes were assessed in relation to disease and treatment variables.

Results: Fifty CAYAs with B-ALL were treated (median age, 13.5 years; range, 4.3-30.4). Thirty-one (62.0%) patients achieved a complete remission (CR), 28 (90.3%) of whom were minimal residual disease-negative by flow cytometry. Utilization of fludarabine/cyclophosphamide-based lymphodepletion was associated with improved CR rates (29/42, 69%) compared with non-fludarabine/cyclophosphamide-based lymphodepletion (2/8, 25%; = .041). With median follow-up of 4.8 years, median overall survival was 10.5 months (95% CI, 6.3 to 29.2 months). Twenty-one of 28 (75.0%) patients achieving a minimal residual disease-negative CR proceeded to alloHSCT. For those proceeding to alloHSCT, median overall survival was 70.2 months (95% CI, 10.4 months to not estimable). The cumulative incidence of relapse after alloHSCT was 9.5% (95% CI, 1.5 to 26.8) at 24 months; 5-year EFS following alloHSCT was 61.9% (95% CI, 38.1 to 78.8).

Conclusion: We provide the longest follow-up in CAYAs with B-ALL after CD19-CAR T-cell therapy reported to date and demonstrate that sequential therapy with CD19.28ζ-CAR T cells followed by alloHSCT can mediate durable disease control in a sizable fraction of CAYAs with relapsed or refractory B-ALL (ClinicalTrials.gov identifier: NCT01593696).
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http://dx.doi.org/10.1200/JCO.20.02262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8274806PMC
May 2021

Improving the Odds in Advanced Breast Cancer With Combination Immunotherapy: Stepwise Addition of Vaccine, Immune Checkpoint Inhibitor, Chemotherapy, and HDAC Inhibitor in Advanced Stage Breast Cancer.

Front Oncol 2020 5;10:581801. Epub 2021 Mar 5.

Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States.

Breast tumors commonly harbor low mutational burden, low PD-L1 expression, defective antigen processing/presentation, and an immunosuppressive tumor microenvironment (TME). In a malignancy mostly refractory to checkpoint blockade, there is an unmet clinical need for novel combination approaches that increase tumor immune infiltration and tumor control. Preclinical data have guided the development of this clinical trial combining 1) BN-Brachyury (a poxvirus vaccine platform encoding the tumor associated antigen brachyury), 2) bintrafusp alfa (a bifunctional protein composed of the extracellular domain of the TGF-βRII receptor (TGFβ "trap") fused to a human IgG1 anti-PD-L1), 3), entinostat (a class I histone deacetylase inhibitor), and 4) T-DM1 (ado-trastuzumab emtansine, a standard of care antibody-drug conjugate targeting HER2). We hypothesize that this tetratherapy will induce a robust immune response against HER2 breast cancer with improved response rates through 1) expanding tumor antigen-specific effector T cells, natural killer cells, and immunostimulatory dendritic cells, 2) improving antigen presentation, and 3) decreasing inhibitory cytokines, regulatory T cells, and myeloid-derived suppressor cells. In an orthotopic HER2 murine breast cancer model, tetratherapy induced high levels of antigen-specific T cell responses, tumor CD8 T cell/Treg ratio, and augmented the presence of IFNγ- or TNFα-producing CD8 T cells and IFNγ/TNFα bifunctional CD8 T cells with increased cytokine production. Similar effects were observed in tumor CD4 effector T cells. Based on this data, a phase 1b clinical trial evaluating the stepwise addition of BN-Brachyury, bintrafusp alfa, T-DM1 and entinostat in advanced breast cancer was designed. Arm 1 (TNBC) receives BN-Brachyury + bintrafusp alfa. Arm 2 (HER2) receives T-DM1 + BN-Brachyury + bintrafusp alfa. After safety is established in Arm 2, Arm 3 (HER2) will receive T-DM1 + BN-Brachyury + bintrafusp alfa + entinostat. Reimaging will occur every 2 cycles (1 cycle = 21 days). Arms 2 and 3 undergo research biopsies at baseline and after 2 cycles to evaluate changes within the TME. Peripheral immune responses will be evaluated. Co-primary objectives are response rate and safety. All arms employ a safety assessment in the initial six patients and a 2-stage Simon design for clinical efficacy (Arm 1 if ≥ three responses of eight then expand to 13 patients; Arms 2 and 3 if ≥ four responses of 14 then expand to 19 patients per arm). Secondary objectives include progression-free survival and changes in tumor infiltrating lymphocytes. Exploratory analyses include changes in peripheral immune cells and cytokines. To our knowledge, the combination of a vaccine, an anti-PD-L1 antibody, entinostat, and T-DM1 has not been previously evaluated in the preclinical or clinical setting. This trial (NCT04296942) is open at the National Cancer Institute (Bethesda, MD).
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http://dx.doi.org/10.3389/fonc.2020.581801DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7977003PMC
March 2021

Characteristics and outcomes of KSHV-associated multicentric Castleman disease with or without other KSHV diseases.

Blood Adv 2021 03;5(6):1660-1670

HIV & AIDS Malignancy Branch and.

Kaposi sarcoma (KS)-associated herpesvirus (KSHV)-associated multicentric Castleman disease (MCD) is a relapsing and remitting systemic lymphoproliferative disorder characterized by severe inflammatory symptoms most common among people living with HIV (PLWH). Patients with KSHV-MCD may present with concurrent KSHV-associated diseases, such as KS and/or primary effusion lymphoma (PEL). We evaluated clinical and immunologic characteristics, the effects of concurrent KSHV malignancies, and treatments from the largest prospective natural history study of participants with KSHV-MCD within the United States. Treatment options administered at investigator discretion included high-dose zidovudine with valganciclovir (AZT/VGC), rituximab, or rituximab with liposomal doxorubicin (R-Dox) during KSHV-MCD flares. Survival analyses and prognostic factors were explored for all participants. Sixty-two participants with HIV were enrolled, including 20 with KSHV-MCD alone, 34 with KSHV-MCD and KS, 1 with KSHV-MCD and PEL, and 7 with all KSHV-associated diseases. Forty-four percent of KSHV-MCD diagnoses were made at our institution. Forty-four participants received rituximab-based therapies, 20 of whom had maintenance AZT/VGC or interferon. Participants receiving R-Dox and then maintenance AZT/VGC had the highest 5-year progression-free survival (89%). Cytokine profiles during KSHV-MCD flares did not differ by the presence of concurrent KSHV-associated diseases. The 10-year survival was 71% (95% confidence interval [CI], 56% to 82%) for all participants. A concurrent diagnosis of PEL negatively impacted survival (PEL hazard ratio, 5.4; 95% CI, 1.8 to 16.8). KSHV-MCD is an underdiagnosed condition among PLWH, including those with KS. KSHV-MCD has an excellent prognosis with appropriate treatment. Physicians should be alert for patients with multiple KSHV diseases, which impact optimal treatment and survival outcomes. This study was registered at www.clinicaltrials.gov as #NCT00099073.
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http://dx.doi.org/10.1182/bloodadvances.2020004058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993110PMC
March 2021

Randomized, Double-Blind, Placebo-Controlled Phase II Study of Yeast-Brachyury Vaccine (GI-6301) in Combination with Standard-of-Care Radiotherapy in Locally Advanced, Unresectable Chordoma.

Oncologist 2021 05 9;26(5):e847-e858. Epub 2021 Mar 9.

Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.

Background: Brachyury is a transcription factor overexpressed in chordoma and is associated with chemotherapy resistance and epithelial-to-mesenchymal transition. GI-6301 is a recombinant, heat-killed Saccharomyces cerevisiae yeast-based vaccine targeting brachyury. A previous phase I trial of GI-6301 demonstrated a signal of clinical activity in chordomas. This trial evaluated synergistic effects of GI-6301 vaccine plus radiation.

Materials And Methods: Adults with locally advanced, unresectable chordoma were treated on a randomized, placebo-controlled trial. Patients received three doses of GI-6301 (80 × 10 yeast cells) or placebo followed by radiation, followed by continued vaccine or placebo until progression. Primary endpoint was overall response rate, defined as a complete response (CR) or partial response (PR) in the irradiated tumor site at 24 months. Immune assays were conducted to evaluate immunogenicity.

Results: Between May 2015 and September 2019, 24 patients enrolled on the first randomized phase II study in chordoma. There was one PR in each arm; no CRs were observed. Median progressive-free survival for vaccine and placebo arms was 20.6 months (95% confidence interval [CI], 5.7-37.5 months) and 25.9 months (95% CI, 9.2-30.8 months), respectively. Hazard ratio was 1.02 (95% CI, 0.38-2.71). Vaccine was well tolerated with no vaccine-related serious adverse events. Preexisting brachyury-specific T cells were detected in most patients in both arms. Most patients developed T-cell responses during therapy, with no difference between arms in frequency or magnitude of response.

Conclusion: No difference in overall response rate was observed, leading to early discontinuation of this trial due to low conditional power to detect statistical difference at the planned end of accrual.

Implications For Practice: Chordoma is a rare neoplasm lacking effective systemic therapies for advanced, unresectable disease. Lack of clinically actionable somatic mutations in chordoma makes development of targeted therapy quite challenging. While the combination of yeast-brachyury vaccine (GI-6301) and standard radiation therapy did not demonstrate synergistic antitumor effects, brachyury still remains a good target for developmental therapeutics in chordoma. Patients and their oncologists should consider early referral to centers with expertise in chordoma (or sarcoma) and encourage participation in clinical trials.
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http://dx.doi.org/10.1002/onco.13720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100546PMC
May 2021

Avelumab, a PD-L1 Inhibitor, in Combination with Hypofractionated Radiotherapy and the Abscopal Effect in Relapsed Refractory Multiple Myeloma.

Oncologist 2021 04 10;26(4):288-e541. Epub 2021 Mar 10.

Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.

Lessons Learned: Despite the initial optimism for using immune checkpoint inhibition in the treatment of multiple myeloma, subsequent clinical studies have been disappointing. Preclinical studies have suggested that priming the immune system with various modalities in addition to checkpoint inhibition may overcome the relative T-cell exhaustion or senescence; however, in this small data set, radiotherapy with checkpoint inhibition did not appear to activate the antitumor immune response.

Background: Extramedullary disease (EMD) is recognized as an aggressive subentity of multiple myeloma (MM) with a need for novel therapeutic approaches. We therefore designed a proof-of-principle pilot study to evaluate the synergy between the combination of the anti-PD-L1, avelumab, and concomitant hypofractionated radiotherapy.

Methods: This was a single-arm phase II Simon two-stage single center study that was prematurely terminated because of the COVID-19 pandemic after enrolling four patients. Key eligibility included patients with relapsed/refractory multiple myeloma (RRMM) who had exhausted or were not candidates for standard therapy and had at least one lesion amenable to radiotherapy. Patients received avelumab until progression or intolerable toxicity and hypofractionated radiotherapy to a focal lesion in cycle 2. Radiotherapy was delayed until cycle 2 to allow the avelumab to reach a study state, given the important observation from previous studies that concomitant therapy is needed for the abscopal effect.

Results: At a median potential follow-up of 10.5 months, there were no objective responses, one minimal response, and two stable disease as best response. The median progression-free survival (PFS) was 5.3 months (95% confidence interval [CI]: 2.5-7.1 months), and no deaths occurred. There were no grade ≥3 and five grade 1-2 treatment-related adverse events.

Conclusion: Avelumab in combination with radiotherapy for patients with RRMM and EMD was associated with very modest systemic clinical benefit; however, patients did benefit as usual from local radiotherapy. Furthermore, the combination was very well tolerated compared with historical RRMM treatment regimens.
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http://dx.doi.org/10.1002/onco.13712DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018315PMC
April 2021

Predictors of hematologic malignancy relapse in patients with advanced chronic graft-versus-host disease.

Bone Marrow Transplant 2021 07 1;56(7):1584-1592. Epub 2021 Feb 1.

Immune Deficiency Cellular Therapy Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 9000 Rockville Pike, Building 10, Room CRC 4-3130, Bethesda, MD, 20892, USA.

Malignancy relapse remains a major barrier to treatment success in patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Chronic graft-versus-host disease (cGVHD) markedly reduces hematologic malignancy relapse risk, but relapses still occur in these patients. Patients (n = 275) with moderate or severe cGVHD were enrolled on the National Cancer Institute (NCI) prospective cross-sectional natural history study (NCT00092235). Subjects were median 36 months after allo-HSCT and were followed subsequently for malignancy relapse and survival. Seventeen patients experienced relapse. In a multivariable model including time-dependent influences on relapse, risk factors associated with increased risk of relapse included shorter time from transplant to cGVHD evaluation (HR 0.279, 95% CI 0.078-0.995) and lower number of prior lines of systemic immunosuppressive therapy for cGVHD (HR 0.260, 95% CI 0.094-0.719). In a model excluding time-dependent influences on relapse risk, lower number of prior lines of systemic immunosuppressive therapy for cGVHD (HR 0.288, 95% CI 0.103-0.804), lower C4 complement level (HR 0.346, 95% CI 0.129-0.923), and higher body mass index (HR 3.222, 95% CI 1.156-8.974), were all associated with increased relapse risk. Parameters indicating cGVHD severity and activity are associated with risk of malignancy relapse. Classical predictors of relapse after allo-HSCT do not seem to be prognostic.
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http://dx.doi.org/10.1038/s41409-021-01211-2DOI Listing
July 2021

Whole-exome sequencing reveals germline-mutated small cell lung cancer subtype with favorable response to DNA repair-targeted therapies.

Sci Transl Med 2021 01;13(578)

Developmental Therapeutics Branch, Center for Cancer Research, NCI, Bethesda, MD 20892, USA.

Because tobacco is a potent carcinogen, secondary causes of lung cancer are often diminished in perceived importance. To assess the extent of inherited susceptibility to small cell lung cancer (SCLC), the most lethal type of lung cancer, we sequenced germline exomes of 87 patients (77 SCLC and 10 extrapulmonary small cell) and considered 607 genes, discovering 42 deleterious variants in 35 cancer-predisposition genes among 43.7% of patients. These findings were validated in an independent cohort of 79 patients with SCLC. Loss of heterozygosity was observed in 3 of 14 (21.4%) tumors. Identification of variants influenced medical management and family member testing in nine (10.3%) patients. Unselected patients with SCLC were more likely to carry germline RAD51 paralog D (), checkpoint kinase 1 (), breast cancer 2 (), and mutY DNA glycosylase () pathogenic variants than healthy controls. Germline genotype was significantly associated with the likelihood of a first-degree relative with cancer or lung cancer (odds ratio: 1.82, = 0.008; and 2.60, = 0.028), and longer recurrence-free survival after platinum-based chemotherapy ( = 0.002), independent of known prognostic factors. Treatment of a patient with relapsed SCLC and germline pathogenic mutation of interacting protein C-terminal helicase 1 (), a homologous recombination-related gene, using agents synthetically lethal with homologous recombination deficiency, resulted in a notable disease response. This work demonstrates that SCLC, currently thought to result almost exclusively from tobacco exposure, may have an inherited predisposition and lays the groundwork for targeted therapies based on the genes involved.
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http://dx.doi.org/10.1126/scitranslmed.abc7488DOI Listing
January 2021

Phase II study of selumetinib, an orally active inhibitor of MEK1 and MEK2 kinases, in KRAS-mutant pancreatic ductal adenocarcinoma.

Invest New Drugs 2021 Jun 6;39(3):821-828. Epub 2021 Jan 6.

Thoracic & GI Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.

Background Preclinical evidence has suggested that a subset of pancreatic cancers with the G12R mutational isoform of the KRAS oncogene is more sensitive to MAPK pathway blockade than pancreatic tumors with other KRAS isoforms. We conducted a biomarker-driven trial of selumetinib (KOSELUGO™; ARRY-142886), an orally active, allosteric mitogen-activated protein kinase 1 and 2 (MEK1/2) inhibitor, in pancreas cancer patients with somatic KRAS mutations. Methods In this two-stage, phase II study (NCT03040986) patients with advanced pancreas cancer harboring somatic KRAS variants who had received at least one standard-of-care systemic therapy regimen received 75 mg selumetinib orally twice a day until disease progression or unacceptable toxicity occurred. The primary outcome of the study was best objective response (BOR). Results From August 2017 to February 2018 a total of 8 patients with confirmed somatic KRAS mutations and a median age of 61.5 years were treated with selumetinib. Seven out of eight (87.5%) had received two or more lines of prior systemic chemotherapy. After a median follow-up period of 8.5 months (range 2 to 20), three patients had stable disease for more than 6 months while receiving selumetinib. No patients achieved an objective partial response. Median progression-free survival (PFS) was 3.0 months (95% CI, 0.8-8.2) and median overall survival (OS) 9 months (95% CI, 2.5-20.9). Conclusion This study in heavily pre-treated pancreatic adenocarcinoma patients suggests alternative strategies beyond single agent MEK inhibition are required for this unique, molecular subset of pancreatic cancer patients. The trial was registered on February 2nd, 2017 under identifier NCT03040986 with ClinicalTrials.gov .
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http://dx.doi.org/10.1007/s10637-020-01044-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8068685PMC
June 2021

Characteristics of Matriculants to Thoracic Surgery Residency Training Programs.

Ann Thorac Surg 2020 Dec 27. Epub 2020 Dec 27.

Surgical Oncology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland; Surgical Oncology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. Electronic address:

Background: Thoracic surgery (TS) residency positions are in high demand. There is no study describing the nationwide attributes of successful matriculants in this specialty. We examined the characteristics of TS resident applicants and identified factors associated with acceptance.

Methods: Applicant data from 2014 to 2017 application cycles was extracted from the Electronic Residency Application System and stratified by matriculation status. Medical education, type of general surgery residency, and research achievements were analyzed. The number of peer-reviewed publications and the corresponding impact factor for the journals where they were published were quantified.

Results: There were 492 applicants and 358 matriculants. The overall population was primarily male (79.5%), white (55.1%), educated at United States allopathic medical schools (66.5%), and trained at university-based general surgery residencies (59.6%). Education at United States allopathic schools (odds ratio [OR], 2.54; P < .0001), being a member of the American Osteopathic Association (OR, 3.27; P = .021), general surgery residency affiliation with a TS residency (OR, 2.41; P = .0003) or National Cancer Institute designated Comprehensive Cancer Center (OR, 1.76; P = .0172), and being a first-time applicant (OR, 4.71, P < .0001) were independently associated with matriculation. Matriculants published a higher number of manuscripts than nonmatriculants (median of 3 vs 2, P < .0001) and more frequently published in higher impact journals (P < .0001).

Conclusions: Our study includes objective and quantifiable data from recent application cycles and represents an in-depth examination of applicants to TS residency. The type of medical school and residency, as well as academic productivity, correlate with successful matriculation.
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http://dx.doi.org/10.1016/j.athoracsur.2020.12.017DOI Listing
December 2020

Evaluation of Factors Associated With Successful Matriculation to Colon and Rectal Surgery Fellowship.

Dis Colon Rectum 2021 02;64(2):234-240

National Cancer Institute, National Institutes of Health, Bethesda, Maryland.

Background: As an increasing number of general surgery residents apply for fellowship positions, it is important to identify factors associated with successful matriculation. For applicants to colon and rectal surgery, there are currently no objective data available to distinguish which applicant attributes lead to successful matriculation.

Objective: The purpose of this study was to identify objective factors that differentiate colon and rectal surgery fellowship applicants who successfully matriculate with those who apply but do not matriculate.

Design: This was a retrospective analysis of colon and rectal surgery applicant characteristics.

Settings: Deidentified applicant data provided by the Association of American Medical Colleges from 2015 to 2017 were included.

Main Outcome Measures: Applicant demographics, medical school and residency factors, number of program applications, number of publications, and journal impact factors were analyzed to determine associations with successful matriculation.

Results: Most applicants (n = 371) and subsequent matriculants (n = 248) were white (61%, 62%), male (65%, 63%), US citizens (80%, 88%) who graduated from US allopathic medical schools (66%, 75%). Statistically significant associations included graduation from US allopathic medical schools (p < 0.0001), US citizenship (p < 0.0001), and number of program applications (p = 0.0004). Other factors analyzed included American Osteopathic Association membership (p = 0.57), university-based residency (p = 0.51), and residency association with a colon and rectal surgery training program (p = 0.89). Number of publications and journal impact factors were not statistically different between cohorts (p = 0.067, p = 0.150).

Limitations: American Board of Surgery In-Training Examination scores, rank list, and subjective characteristics, such as strength of interview and letters of recommendation, were not available using our data source.

Conclusions: Successful matriculation to a colon and rectal surgery fellowship program was found to be associated with US citizenship, graduation from a US allopathic medical school, and greater number of program applications. The remaining objective metrics analyzed were not associated with successful matriculation. Subjective and objective factors that were unable to be measured by this study are likely to play a determining role. See Video Abstract at http://links.lww.com/DCR/B415.

Evaluacin De Factores Vinculados En La Inmatriculacin Exitosa Para Becas De Ciruga Colorrectal: ANTECEDENTES:A medida que un número cada vez mayor de residentes de Cirugía General solicitan una beca, es importante identificar los factores vinculados con una inmatriculación exitosa. Para los candidatos a una beca en Cirugía Colorrectal, hoy en día no existen datos objetivos disponibles para distinguir qué atributos del solicitante conducen a una inmatriculación exitosa.OBJETIVO:Identificar objetivamente los factores que diferencian un candidato a una beca en Cirugía Colorrectal que se inmatricula con éxito de aquel que aplica pero no llega a inmatricularse.DISEÑO:Análisis retrospectivo de las características de los solicitantes de beca para Cirugía Colorrecatl.AJUSTES:Datos de los solicitantes no identificados, proporcionados por la Asociación de Colegios Médicos Estadounidenses de 2015 a 2017.PRINCIPALES MEDIDAS DE RESULTADO:Se analizaron los factores demográficos del solicitante, las facultades de medicina y los factores de la residencia, el número de solicitudes de programas, el número y el factor de impacto de las publicaciones realizadas para determinar la asociación con una inmatriculación exitosa.RESULTADOS:La mayoría de los solicitantes (n = 371) que posteriormente fueron inmatriculados exitosamente (n = 248) eran blancos (61%, 62%, respectivamente), hombres (65%, 63%), ciudadanos estadounidenses (80%, 88%) que se graduaron de Facultades de medicina alopática en los EE. UU. (66%, 75%). Las asociaciones estadísticamente significativas incluyeron la graduación de las escuelas de medicina alopática de los EE. UU. (P <0,0001), la ciudadanía de los EE. UU. (P <0,0001) y el número de solicitudes de programas (p = 0,0004). Otros factores analizados incluyeron: membresía AOA (p = 0,57), la residencia universitaria (p = 0,51) y asociación de la residencia con un programa de formación en Cirugía Colorrectal (p = 0,89). El número de publicaciones y los factores de impacto de las revistas no fueron estadísticamente diferentes entre las cohortes (p = 0,067, p = 0,15, respectivamente).LIMITACIONES:El Score ABSITE, la posición en lista de clasificación y las características subjetivas como el de una buena entrevista y las cartas de recomendación no se encontraban disponibles en la fuente de datos.CONCLUSIONES:Se encontró que la inmatriculación exitosa a un programa de becas de Cirugía Colorreectal estaba asociada con la ciudadanía estadounidense, la graduación en una Facultad de medicina alopática en los EE. UU, y al mayor número de solicitudes de programas. El analisis de las medidas objetivas restantes no se asociaron con una inmatriculación exitosa. Es probable que los factores subjetivos y objetivos que no pudieron ser medidos por este estudio jueguen un papel determinante. Consulte Video Resumen en http://links.lww.com/DCR/B415. (Traducción-Dr Xavier Delgadillo).
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http://dx.doi.org/10.1097/DCR.0000000000001849DOI Listing
February 2021

Circulating Tumor Cell Subtypes and T-cell Populations as Prognostic Biomarkers to Combination Immunotherapy in Patients with Metastatic Genitourinary Cancer.

Clin Cancer Res 2021 Mar 1;27(5):1391-1398. Epub 2020 Dec 1.

NCI, Bethesda, Maryland.

Purpose: Circulating tumor cells (CTC) are under investigation as a minimally invasive liquid biopsy that may improve risk stratification and treatment selection. CTCs uniquely allow for digital pathology of individual malignant cell morphology and marker expression. We compared CTC features and T-cell counts with survival endpoints in a cohort of patients with metastatic genitourinary cancer treated with combination immunotherapy.

Experimental Design: Markers evaluated included pan-CK/CD45/PD-L1/DAPI for CTCs and CD4/CD8/Ki-67/DAPI for T cells. ANOVA was used to compare CTC burden and T-cell populations across timepoints. Differences in survival and disease progression were evaluated using the maximum log-rank test.

Results: From December 2016 to January 2019, 183 samples from 81 patients were tested. CTCs were found in 75% of patients at baseline. CTC burden was associated with shorter overall survival (OS) at baseline ( = 0.022), but not on-therapy. Five morphologic subtypes were detected, and the presence of two specific subtypes with unique cellular features at baseline and on-therapy was associated with worse OS (0.9-2.3 vs. 28.2 months; < 0.0001-0.013). Increasing CTC heterogeneity on-therapy had a trend toward worse OS ( = 0.045). PD-L1 CTCs on-therapy were associated with worse OS ( < 0.01, cycle 2). Low baseline and on-therapy CD4/CD8 counts were also associated with poor OS and response category.

Conclusions: Shorter survival may be associated with high CTC counts at baseline, presence of specific CTC morphologic subtypes, PD-L1 CTCs, and low %CD4/8 T cells in patients with metastatic genitourinary cancer. A future study is warranted to validate the prognostic utility of CTC heterogeneity and detection of specific CTC morphologies.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2891DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925349PMC
March 2021

Cabozantinib plus docetaxel and prednisone in metastatic castration-resistant prostate cancer.

BJU Int 2021 04 23;127(4):435-444. Epub 2020 Oct 23.

Genitourinary Malignancies Branch, NCI, Bethesda, MD, USA.

Objective: To evaluate the safety and efficacy of cabozantinib combined with docetaxel.

Patients And Methods: This was a phase 1/2 multicentre study in patients with metastatic castration-resistant prostate cancer (mCRPC). Docetaxel (75 mg/m every 3 weeks with daily prednisone 10 mg) was combined with escalating doses of daily cabozantinib (20, 40 and 60 mg). Based on the results of the phase 1 study, the investigation was expanded into a randomized study of docetaxel with prednisone (hereafter 'docetaxel/prednisone') plus the maximum tolerated dose (MTD) of cabozantinib compared with docetaxel/prednisone alone.

Results: A total of 44 men with mCRPC were enrolled in this phase 1/2 trial. An MTD of 40 mg cabozantinib plus docetaxel/prednisone was determined. Dose-limiting toxicities were neutropenic fever and palmar-plantar erythrodysesthesia, and there was one death attributable to a thromboembolic event. In addition, grade 3 or 4 myelosuppression, hypophosphataemia and neuropathy were seen in three or more patients. In the phase 1 study, the median time to progression (TTP) and overall survival (OS) time were 13.6 and 16.3 months, respectively. In the phase 2 study, which was terminated early because of poor accrual, the median TTP and OS favoured the combination (n = 13) compared to docetaxel/prednisone alone (n = 12; 21.0 vs 6.6 months; P = 0.035 and 23.8 vs 15.6 months; P = 0.072, respectively).

Conclusion: Despite the limited number of patients in this study, preliminary data suggest that cabozantinib can be safely added to docetaxel/prednisone with possible enhanced efficacy.
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http://dx.doi.org/10.1111/bju.15227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8265825PMC
April 2021

Pediatric PK/PD Phase I Trial of Pexidartinib in Relapsed and Refractory Leukemias and Solid Tumors Including Neurofibromatosis Type I-Related Plexiform Neurofibromas.

Clin Cancer Res 2020 12 17;26(23):6112-6121. Epub 2020 Sep 17.

Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.

Purpose: Simultaneously targeting the tumor and tumor microenvironment may hold promise in treating children with refractory solid tumors. Pexidartinib, an oral inhibitor of tyrosine kinases including colony stimulating factor 1 receptor (CSF-1R), KIT, and FLT3, is FDA approved in adults with tenosynovial giant cell tumor. A phase I trial was conducted in pediatric and young adult patients with refractory leukemias or solid tumors including neurofibromatosis type 1-related plexiform neurofibromas.

Patients And Methods: A rolling six design with dose levels (DL) of 400 mg/m, 600 mg/m, and 800 mg/m once daily for 28-day cycles (C) was used. Response was assessed at regular intervals. Pharmacokinetics and population pharmacokinetics were analyzed during C1.

Results: Twelve patients (4 per DL, 9 evaluable) enrolled on the dose-escalation phase and 4 patients enrolled in the expansion cohort: median (lower, upper quartile) age 16 (14, 16.5) years. No dose-limiting toxicities were observed. Pharmacokinetics appeared linear over three DLs. Pharmacokinetic modeling and simulation determined a weight-based recommended phase II dose (RP2D). Two patients had stable disease and 1 patient with peritoneal mesothelioma (C49+) had a sustained partial response (67% RECIST reduction). Pharmacodynamic markers included a rise in plasma macrophage CSF (MCSF) levels and a decrease in absolute monocyte count.

Conclusions: Pexidartinib in pediatric patients was well tolerated at all DL tested, achieved target inhibition, and resulted in a weight-based RPD2 dose.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-1696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7909006PMC
December 2020

Phase I Study of Cabozantinib and Nivolumab Alone or With Ipilimumab for Advanced or Metastatic Urothelial Carcinoma and Other Genitourinary Tumors.

J Clin Oncol 2020 11 11;38(31):3672-3684. Epub 2020 Sep 11.

Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.

Purpose: We assessed the safety and efficacy of cabozantinib and nivolumab (CaboNivo) and CaboNivo plus ipilimumab (CaboNivoIpi) in patients with metastatic urothelial carcinoma (mUC) and other genitourinary (GU) malignances.

Patients And Methods: Patients received escalating doses of CaboNivo or CaboNivoIpi. The primary objective was to establish a recommended phase II dose (RP2D). Secondary objectives included objective response rate (ORR), progression-free survival (PFS), duration of response (DoR), and overall survival (OS).

Results: Fifty-four patients were enrolled at eight dose levels with a median follow-up time of 44.6 months; data cutoff was January 20, 2020. Grade 3 or 4 treatment-related adverse events (AEs) occurred in 75% and 87% of patients treated with CaboNivo and CaboNivoIpi, respectively, and included fatigue (17% and 10%, respectively), diarrhea (4% and 7%, respectively), and hypertension (21% and 10%, respectively); grade 3 or 4 immune-related AEs included hepatitis (0% and 13%, respectively) and colitis (0% and 7%, respectively). The RP2D was cabozantinib 40 mg/d plus nivolumab 3 mg/kg for CaboNivo and cabozantinib 40 mg/d, nivolumab 3 mg/kg, and ipilimumab 1 mg/kg for CaboNivoIpi. ORR was 30.6% (95% CI, 20.0% to 47.5%) for all patients and 38.5% (95% CI, 13.9% to 68.4%) for patients with mUC. Median DoR was 21.0 months (95% CI, 5.4 to 24.1 months) for all patients and not reached for patients with mUC. Median PFS was 5.1 months (95% CI, 3.5 to 6.9 months) for all patients and 12.8 months (95% CI, 1.8 to 24.1 months) for patients with mUC. Median OS was 12.6 months (95% CI, 6.9 to 18.8 months) for all patients and 25.4 months (95% CI, 5.7 to 41.6 months) for patients with mUC.

Conclusion: CaboNivo and CaboNivoIpi demonstrated manageable toxicities with durable responses and encouraging survival in patients with mUC and other GU tumors. Multiple phase II and III trials are ongoing for these combinations.
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http://dx.doi.org/10.1200/JCO.20.01652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605393PMC
November 2020

Phase 1 study of the immunotoxin LMB-100 in patients with mesothelioma and other solid tumors expressing mesothelin.

Cancer 2020 11 1;126(22):4936-4947. Epub 2020 Sep 1.

Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.

Background: LMB-100 is an antibody-toxin conjugate with an antimesothelin Fab linked to a 24-kilodalton portion of Pseudomonas exotoxin A with mutations that decrease immunogenicity. The objective of the current first-in-human phase 1 study was to determine the maximum tolerated dose (MTD) and safety in patients with advanced solid tumors expressing mesothelin.

Methods: Cohorts of 1 to 7 patients received intravenous LMB-100 at 7 dose levels from 40 µg/kg to 250 µg/kg intravenously on days 1, 3, and 5 of a 21-day cycle.

Results: Of the 25 patients accrued, 17 had mesothelioma, 3 each had ovarian or pancreatic cancer, and 2 patients had gastric cancer. Dose-limiting toxicities occurred in 2 of 4 patients treated at a dose of 250 µg/kg (capillary leak syndrome) and in 3 of 7 patients treated at a dose of 170 µg/kg (creatinine increase). The MTD of LMB-100 was 140 µg/kg. Of the 10 patients with mesothelioma who were treated at doses of 170 µg/kg or 140 µg/kg, 8 had stable disease and 2 developed progressive disease. Peak LMB-100 plasma concentrations were dose-dependent during cycle 1. The development of antidrug antibodies decreased LMB-100 blood levels in 8 of 21 patients (38%) who received cycle 2 and 9 of 11 patients (81.8%) who received cycle 3.

Conclusions: The MTD for single-agent LMB-100 was found to be 140 µg/kg given on a schedule of every other day for 3 doses every 3 weeks. Although less immunogenic than the first-generation antimesothelin immunotoxin SS1P, the majority of patients developed antidrug antibodies after 2 cycles, indicating that LMB-100 has limited antitumor efficacy as a single agent. Phase 2 studies of LMB-100 plus pembrolizumab currently are ongoing for patients with mesothelioma and lung cancer.

Lay Summary: Mesothelin, a cell surface antigen, is an attractive target for cancer therapy given its limited expression in normal human tissues and high expression in many human cancers. LMB-100 is a recombinant antimesothelin immunotoxin consisting of a humanized antimesothelin antibody fragment fused to a truncated Pseudomonas exotoxin A. In the current study, the authors determined the safety, maximum tolerated dose, and pharmacokinetics of LMB-100, as well as the generation of antidrug antibodies. Ongoing phase 2 clinical trials are evaluating the combination of LMB-100 plus pembrolizumab in patients with treatment-refractory mesothelioma and non-small cell lung cancer.
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http://dx.doi.org/10.1002/cncr.33145DOI Listing
November 2020

Phase II trial of bevacizumab and sorafenib in recurrent ovarian cancer patients with or without prior-bevacizumab treatment.

Gynecol Oncol 2020 10 1;159(1):88-94. Epub 2020 Aug 1.

Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, United States of America.

Objective: To examine whether blocking multiple points of the angiogenesis pathway by addition of sorafenib, a multi-kinase inhibitor against VEGFR2/3, Raf, c-Kit, and PDGFR, to bevacizumab would yield clinical activity in ovarian cancer (OvCa).

Methods: This phase II study tested bevacizumab plus sorafenib in two cohorts; bevacizumab-naïve and bevacizumab-exposed patients. Bevacizumab (5 mg/kg IV every 2 weeks) was given with sorafenib 200 mg bid 5 days-on/2 days-off. The primary objective was response rate using a Simon two-stage optimal design. Progression-free survival (PFS) and toxicity were the secondary endpoints. Exploratory correlative studies included plasma cytokine concentrations, tissue proteomics and dynamic contrast-enhanced-magnetic resonance imaging (DCE-MRI).

Results: Between March 2007 and August 2012, 54 women were enrolled, 41 bevacizumab-naive and 13 bevacizumab-prior, with median 5 (2-9) and 6 (5-9) prior systemic therapies, respectively. Nine of 35 (26%) evaluable bevacizumab-naive patients attained partial responses (PR), and 18 had stable disease (SD) ≥ 4 months. No responses were seen in the bevacizumab-prior group and 7 (54%) patients had SD ≥ 4 months, including one exceptional responder with SD of 27 months. The overall median PFS was 5.5 months (95%CI: 4.0-6.8 months). Treatment-related grade 3/4 adverse events (≥5%) included hypertension (17/54 [31%]; grade 3 in 16 patients and grade 4 in one patient) and venous thrombosis or pulmonary embolism (5/54 [9%]; grade 3 in 4 patients and grade 4 in one patient). Pretreatment low IL8 concentration was associated with PFS ≥ 4 months (p = .031).

Conclusions: The bevacizumab and sorafenib combination did not meet the pre-specified primary endpoint although some clinical activity was seen in heavily-pretreated bevacizumab-naive OvCa patients with platinum-resistant disease. Anticipated class toxicities required close monitoring and dose modifications.
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http://dx.doi.org/10.1016/j.ygyno.2020.07.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541580PMC
October 2020

Cabozantinib in patients with platinum-refractory metastatic urothelial carcinoma: an open-label, single-centre, phase 2 trial.

Lancet Oncol 2020 08 6;21(8):1099-1109. Epub 2020 Jul 6.

Developmental Therapeutics Branch, Magnuson Clinical Center, Bethesda, MD, USA.

Background: Cabozantinib is a multikinase inhibitor of MET, VEGFR, AXL, and RET, which also has an effect on the tumour immune microenvironment by decreasing regulatory T cells and myeloid-derived suppressor cells. In this study, we examined the activity of cabozantinib in patients with metastatic platinum-refractory urothelial carcinoma.

Methods: This study was an open-label, single-arm, three-cohort phase 2 trial done at the National Cancer Institute (Bethesda, MD, USA). Eligible patients were 18 years or older, had histologically confirmed urothelial carcinoma or rare genitourinary tract histologies, Karnofsky performance scale index of 60% or higher, and documented disease progression after at least one previous line of platinum-based chemotherapy (platinum-refractory). Cohort one included patients with metastatic urothelial carcinoma with measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Two additional cohorts that enrolled in parallel (patients with bone-only urothelial carcinoma metastases and patients with rare histologies of the genitourinary tract) were exploratory. Patients received cabozantinib 60 mg orally once daily in 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed objective response rate by RECIST in cohort one. Response was assessed in all patients who met the eligibility criteria and who received at least 8 weeks of therapy. All patients who received at least one dose of cabozantinib were included in the safety analysis. This completed study is registered with ClinicalTrials.gov, NCT01688999.

Findings: Between Sept 28, 2012, and Oct, 20, 2015, 68 patients were enrolled on the study (49 in cohort one, six in cohort two, and 13 in cohort three). All patients received at least one dose of cabozantinib. The median follow-up was 61·2 months (IQR 53·8-70·0) for the 57 patients evaluable for response. In the 42 evaluable patients in cohort one, there was one complete response and seven partial responses (objective response rate 19%, 95% CI 9-34). The most common grade 3-4 adverse events were fatigue (six [9%] patients), hypertension (five [7%]), proteinuria (four [6%]), and hypophosphataemia (four [6%]). There were no treatment-related deaths.

Interpretation: Cabozantinib has single-agent clinical activity in patients with heavily pretreated, platinum-refractory metastatic urothelial carcinoma with measurable disease and bone metastases and is generally well tolerated. Cabozantinib has innate and adaptive immunomodulatory properties providing a rationale for combining cabozantinib with immunotherapeutic strategies.

Funding: National Cancer Institute Intramural Program and the Cancer Therapy Evaluation Program.
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http://dx.doi.org/10.1016/S1470-2045(20)30202-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8236112PMC
August 2020

Enhanced efficacy of mesothelin-targeted immunotoxin LMB-100 and anti-PD-1 antibody in patients with mesothelioma and mouse tumor models.

Sci Transl Med 2020 07;12(550)

Thoracic and GI Malignancies Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA.

LMB-100 is an immunotoxin targeting the cell surface protein mesothelin, which is highly expressed in many cancers including mesothelioma. Having observed that patients receiving pembrolizumab off protocol after LMB-100 treatment had increased tumor responses; we characterized these responses and developed animal models to study whether LMB-100 made tumors more responsive to antibodies blocking programmed cell death protein 1 (PD-1). The overall objective tumor response in the 10 patients who received PD-1 inhibitor (pembrolizumab, 9; nivolumab, 1) after progression on LMB-100 was 40%, and the median overall survival was 11.9 months. Of the seven evaluable patients, four had objective tumor responses, including one complete response and three partial responses, and the overall survival for these patients was 39.0+, 27.7, 32.6+, and 13.8 months. When stratified with regard to programmed death ligand 1 (PD-L1) expression, four of five patients with tumor PD-L1 expression had objective tumor response. Patients with positive tumor PD-L1 expression also had increased progression-free survival (11.3 versus 2.1 months, = 0.0018) compared with those lacking PD-L1 expression. There was no statistically significant difference in overall survival (27.7 versus 6.8 months, = 0.1). LMB-100 caused a systemic inflammatory response and recruitment of CD8 T cells in patients' tumors. The enhanced antitumor effects with LMB-100 plus anti-PD-1 antibody were also observed in a human peripheral blood mononuclear cell-engrafted mesothelioma mouse model and a human mesothelin-expressing syngeneic lung adenocarcinoma mouse model. LMB-100 plus pembrolizumab is now being evaluated in a prospective clinical trial for patients with mesothelioma.
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http://dx.doi.org/10.1126/scitranslmed.aaz7252DOI Listing
July 2020

Multicenter Study of Risk-Adapted Therapy With Dose-Adjusted EPOCH-R in Adults With Untreated Burkitt Lymphoma.

J Clin Oncol 2020 08 26;38(22):2519-2529. Epub 2020 May 26.

Lymphoid Malignancies Branch, National Cancer Institute, Bethesda, MD.

Purpose: Burkitt lymphoma is an aggressive B-cell lymphoma curable with dose-intensive chemotherapy derived from pediatric leukemia regimens. Treatment is acutely toxic with late sequelae. We hypothesized that dose-adjusted etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, and rituximab (DA-EPOCH-R) may obviate the need for highly dose-intensive chemotherapy in adults with Burkitt lymphoma.

Methods: We conducted a multicenter risk-adapted study of DA-EPOCH-R in untreated adult Burkitt lymphoma. Low-risk patients received three cycles without CNS prophylaxis, and high-risk patients received six cycles with intrathecal CNS prophylaxis or extended intrathecal treatment if leptomeninges were involved. The primary endpoint was event-free survival (EFS), and secondary endpoints were toxicity and predictors of EFS and overall survival (OS).

Results: Between 2010 and 2017, 113 patients were enrolled across 22 centers, and 98 (87%) were high risk. The median age was 49 (range, 18-86) years, and 62% were ≥ 40 years. Bone marrow and/or CSF was involved in 29 (26%) of patients, and 28 (25%) were HIV positive. At a median follow-up of 58.7 months, EFS and OS were 84.5% and 87.0%, respectively, and EFS was 100% and 82.1% in low- and high-risk patients. Therapy was equally effective across age groups, HIV status, and International Prognostic Index risk groups. Involvement of the CSF identified the group at greatest risk for early toxicity-related death or treatment failure. Five treatment-related deaths (4%) occurred during therapy. Febrile neutropenia occurred in 16% of cycles, and tumor lysis syndrome was rare.

Conclusion: Risk-adapted DA-EPOCH-R therapy is effective in adult Burkitt lymphoma regardless of age or HIV status and was well tolerated. Improved therapeutic strategies for adults with CSF involvement are needed (funded by the National Cancer Institute; ClinicalTrials.gov identifier: NCT01092182).
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http://dx.doi.org/10.1200/JCO.20.00303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7392744PMC
August 2020

Results of a Randomized, Double-Blinded, Placebo-Controlled, Phase 2.5 Study of Saracatinib (AZD0530), in Patients with Recurrent Osteosarcoma Localized to the Lung.

Sarcoma 2020 30;2020:7935475. Epub 2020 Apr 30.

Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California Children's Hospital Los Angeles, 4650 Sunset Blvd Mail Stop 57, Los Angeles, CA 90027, USA.

Purpose: Osteosarcoma is a rare cancer and a third of patients who have completed primary treatment will develop osteosarcoma recurrence. The Src pathway has been implicated in the metastatic behavior of osteosarcoma; about 95% of samples examined express Src or have evidence of downstream activation of this pathway. Saracatinib (AZD0530) is a potent and selective Src kinase inhibitor that was evaluated in adults in Phase 1 studies. The primary goal of this study was to determine if treatment with saracatinib could increase progression-free survival (PFS) for patients who have undergone complete resection of osteosarcoma lung metastases in a double-blinded, placebo-controlled trial. . Subjects with recurrent osteosarcoma localized to lung and who had complete surgical removal of all lung nodules were randomized within six weeks after complete surgical resection. Saracatinib, or placebo, was administered at a dose of 175 mg orally, once daily, for up to thirteen 28-day cycles.

Results: Thirty-seven subjects were included in the analyses; 18 subjects were randomized to receive saracatinib and 19 to receive placebo. Intent-to-treat analysis demonstrated a median PFS of 19.4 months in the saracatinib treatment group and 8.6 months in the placebo treatment group (=0.47). Median OS was not reached in either arm.

Conclusions: Although saracatinib was well tolerated in this patient population, there was no apparent impact of the drug in this double-blinded, placebo-controlled trial on OS, and Src inhibition alone may not be sufficient to suppress metastatic progression in osteosarcoma. There is a suggestion of potential clinical benefit as evidenced by longer PFS in patients randomized to saracatinib based on limited numbers of patients treated.
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http://dx.doi.org/10.1155/2020/7935475DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7211262PMC
April 2020
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