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• Blood and Marrow Transplant Clinical Trials Network - Randomized Multicenter Trial Comparing Sirolimus Plus Prednisone and Sirolimus/Calcineurin Inhibitor Plus Prednisone for the Treatment of Chronic Graft-versus-Host Disease (BMT-CTN-0801-BioLINCC)

  Data Access NOTE: Please refer to the “Authorized Access” section below for information about how access to the data from this accession differs from many other dbGaP accessions. ObjectivesFor the phase II component, to compare the responses of patients with graft-versus-host disease who received sirolimus/calcineurin inhibitor plus prednisone versus sirolimus plus prednisone after 6 months of therapy. For the phase III component, to compare the proportion of subjects with complete resolution of all reversible manifestations at 24 months after starting therapy.BackgroundChronic graft-versus-host disease (cGVHD) is the major treatment-related complication among patients who survive after allogeneic hematopoietic cell transplantation (HCT). Standard immunosuppressive therapy (IST) with prednisone ± a calcineurin inhibitor (CNI) has not changed for three decades, but most patients respond inadequately with slow and most often incomplete control of their disease. Renewed understanding of regulatory T cells (Tregs) led to the hypothesis that experimental therapies permissive of Treg expansion would better abrogate GVHD than CNI-containing (control) IST. Sirolimus and extracorporeal photopheresis (ECP) are permissive of Treg expansion. Because of their acceptance in clinical practice, sirolimus and ECP were considered good candidates for adding to prednisone in clinical trials in cGVHD.ParticipantsAdult and pediatric allogeneic HCT recipients were eligible if they had classic cGVHD ± acute GVHD (overlap subtype) that met 2005 NIH diagnostic consensus criteria. This included newly diagnosed patients, defined as individuals who had received One hundred patients were evaluated for the phase II primary endpoint after all had completed 6 months of follow-up. All 151 enrolled subjects were followed for phase III endpoints. 77 patients were randomized to the prednisone/sirolimus arm and 74 patients to the prednisone/sirolimus/CNI arm.DesignThe trial was designed as an adaptive phase II/III randomized, open-label, prospective study of three treatments for chronic GVHD. Phase II was to include two parallel, 100-patient, randomized trials, comparing prednisone/sirolimus or prednisone/sirolimus/ECP versus identical (prednisone/sirolimus/CNI) comparator arms, where centers selected only one trial in which to participate. However, the prednisone/sirolimus/ECP arm was closed prematurely due to poor accrual. Comparison of complete/partial response rates did not support proceeding to phase III and further accrual was suspended.The starting dose of prednisone (or prednisone-equivalent) was 1 mg/kg once daily, unless contraindicated, in which case the prednisone dose began at 0.5–1 mg/kg once daily. It was recommended that the dose of prednisone was tapered down, over 4–8 weeks to reach a dose of 0.5–1 mg/kg every other day, with the tapering starting within 2 weeks after the first evidence of GVHD improvement. Once an every-other-day prednisone (or equivalent) regimen was achieved, this dose remained constant for 10–12 weeks until all reversible chronic GVHD manifestations resolved. The sirolimus therapy began at a dose of 2 mg orally once daily (1 mg/m2 per day if the patient weighed Health-related quality of life was measured by self-report instruments, including the Functional Assessment of Cancer Therapy Bone Marrow Transplantation (FACT-BMT), Short Form-36 (SF-36).For phase II, the primary outcome was complete or partial response after 6 months of therapy. For phase III, the primary outcome was complete response at 24 months.ConclusionsInitial therapy of chronic GVHD with prednisone/sirolimus is an acceptable alternative and better tolerated than therapy with prednisone/sirolimus/CNI.Carpenter PA, Logan BR, Lee SJ, et al. A phase II/III randomized, multicenter trial of prednisone/sirolimus versus prednisone/ sirolimus/calcineurin inhibitor for the treatment of chronic graft-versus-host disease: BMT CTN 0801 (Carpenter PA et al. Haematologica, 2018).

  Study phs004641

• RNA Sequencing Analysis of Patient-Derived Xenograft Tissue PIM-084 Treated with L-NMMA+Alpelisib vs Vehicle Control

  This dataset contains RNA-seq analysis of vehicle control compared to L-NMMA+alpelisib treated metaplastic breast cancer PDX PIM084 tumors (RNA sequencing and analysis performed by Novogene). The submitted data contains the gene ID, gene name, normalized read counts from all samples from control group and combination treatment group, log2-fold change derived from DESeq2 R/EdgeR package, p-value, adjusted p-value, read counts from each group, and gene FPKM from the each sample in the group. Due to patient privacy, we are submitting only the processed and desensitized RNA sequencing analysis to this repository.

  Study phs003814

• The Study of Somatic LINE1 Activity in Cancers

  This study focuses exclusively on the quantification of LINE1 mobilization. We analyzed a recent whole genome sequencing data release from multiple Cancer Genome Atlas (TCGA) sub-projects. In addition to the somatic LINE1 insertions (present in tumor and having no support in the matched normal) there are "pseudo-germline" non-reference LINE1 elements identified in tumor tissue and having some support in the matched normal. This dataset reports such "pseudo-germline" LINE1 retrotranspositions. Individual level data for TCGA can be accessed by requesting access to phs000178.

  Study phs003888

• NCI's Collection of Studies for General Cancer Research

  This collection contains all of NCIs authorized individual-level genomic datasets currently in dbGaP that are approved for Cancer Research (DS-CA) use only and limitations outlined in the model Data Use Certification Agreement. Access to this study will include any additional authorized individual-level DS-CA datasets that become available. Renewal of this study is required annually. To request access to this study collection, select phs003967.v1.p1 in the dbGaP Authorized Access System.

  Study phs003967

• Involvement of the FGF8/FGF Receptor Signaling Pathway in the Maintenance and Progression of Fusion-Positive Rhabdomyosarcoma

  In our previous work, we used a myoblast model of fusion-positive rhabdomyosarcoma (FP-RMS) to demonstrate that FGF8, a target of the PAX3-FOXO1 (P3F) transcription factor, is essential for tumorigenicity driven by P3F. When aberrantly expressed, FGF8 can also sustain tumorigenicity in recurrent tumors that are independent of P3F. In this study, we report that FGF8, along with its receptors FGFR1 and FGFR4, is often highly expressed in FP-RMS tumors. We found that high levels of FGF8 expression in FP-RMS cells correlate with increased sensitivity to an FGFR4 inhibitor and a pan-FGFR inhibitor. Conversely, downregulating FGF8 led to a loss of sensitivity to these inhibitors. Interestingly, when FGF8 was upregulated in myoblasts, it resulted in decreased FGFR4 expression and sensitized the cells to an FGFR1 inhibitor and a pan-FGFR inhibitor. The downregulation of FGFR4 expression mediated by FGF8 could be reversed by inhibiting FGFR1, MEK, or ERK, thereby defining a signaling pathway through which FGF8 exerts its regulatory effects. Additionally, we discovered that high FGF8 expression in P3F-independent recurrent tumors is due to a rearrangement of viral long terminal repeat (LTR) sequences into the 3' untranslated region (UTR) of FGF8, leading to increased stability of FGF8 mRNA. These findings indicate that FGF8 plays an oncogenic role in FP-RMS through FGFR4 and may also exert oncogenic effects in P3F-independent relapses via FGFR1. Our study highlights the functional significance of FGF8 in FP-RMS and supports the rationale for preclinical investigations of FGFR inhibitors in treating this type of cancer.

  Study phs004009

• Human Cancer-Targeted Immunity via Transgenic Hematopoietic Stem Cell Progeny

  Analysis of a patient biopsy from the clinical trial (NCT03240861), a first-in-human study of transgenic NY-ESO-1 TCR- T cells and NY-ESO-1 TCR+ sr39tk autologous hematopoietic stem cells tandem therapy for solid tumors after myeloablative conditioning chemotherapy with busulfan and fludarabine. Single-cell RNAseq and single-cell ATACseq analysis from peripheral blood mononuclear cells obtained from subject NYSCT-03.

  Study phs003898

• CDK2 Inhibition Demonstrates RB-Independent Efficacy in CDK4/6 Inhibitor-Resistant HR-Positive/HER2-Negative Breast Cancer

  Preliminary clinical data from hormone receptor (HR)-positive, human epidermal growth factor receptor-2 (HER2)-negative metastatic breast cancer (MBC) patients with resistance to CDK4/6 inhibitors treated with the CDK2 inhibitor PF-07104091 as monotherapy indicate that therapeutic efficacy correlates with TP53 status, but not with RB expression or phosphorylation. Using a panel of HR+/HER2- MBC patient-derived (PD) cell lines, including both CDK4/6 inhibitor-naïve and resistant models, we found that CDK2, unlike CDK4/6, is dispensable for RB phosphorylation. Notably, in models derived from tumors that had progressed on CDK4/6 inhibitor therapy, as well as in models with acquired in vitro resistance, CDK2 inhibition reduced DNA replication rate, induced DNA damage, and inhibited mitotic entry in an RB-independent manner. Data available through this dbGaP submission include whole-exome sequencing (WES) from four CDK4/6 inhibitor-naïve HR+/HER2- MBC PD cell lines (MGH10035.1, MGH10035.2, MGH358.1, and MGH358.2), their corresponding isogenic derivatives with acquired in vitro resistance to the CDK4/6 inhibitor palbociclib, and one PD cell line (MGH321.4) derived from a letrozole/ribociclib-resistant HR+/HER2- MBC tumor. MGH10035.1 and MGH10035.2 were derived from the same patient at different stages of treatment, as were MGH358.1 and MGH358.2.

  Study phs004466

• NCTN: Phase III Trial of Tamoxifen Alone vs. Tamoxifen Plus Radiation Therapy for Good Risk Duct Carcinoma In-Situ (DCIS) of the Female Breast (RTOG-98-04)

  Study ID: RTOG-98-04 NCT Number: NCT00003857 NRG Oncology Submitted in collaboration with the NCTN/NCORP Data Archive Trial Title: NCTN: Phase III Trial of Tamoxifen Alone vs. Tamoxifen plus Radiation Therapy for Good Risk Duct Carcinoma In-Situ (DCIS) of the Female Breast (RTOG-98-04) Trial Description: RATIONALE: Radiation therapy uses high-energy x-rays to damage tumor cells. Estrogen can stimulate the growth of breast cancer cells. Hormone therapy using tamoxifen may fight breast cancer by blocking the uptake of estrogen by the tumor cells. It is not yet known if radiation therapy is more effective than observation, with or without tamoxifen, in treating ductal carcinoma in situ. PURPOSE: Randomized phase III trial to compare the effectiveness of radiation therapy with that of observation, with or without tamoxifen, in treating women who have ductal carcinoma in situ.Clinical data presented in the following publication(s): • PMID 25605856 Disease type(s): Breast Neoplasm - Breast Neoplasm, Miscellaneous Clinical Dataset(s) included: • NCT00003857-D1 (PMID 25605856): This dataset is for RTOG-98-04's primary publication 25605856. The dataset contains reasons for exclusion, baseline characteristics, survival, local failure, distant metastasis, salvage mastectomy, and toxicity data. You are encouraged to view the PDF data dictionaries found in the “Documents” tab of the dbGaP study page, which may contain additional information regarding the data or the associated publication(s).

  Study phs004264

• Blood and Marrow Clinical Trials Network (BMT CTN) A Phase III Randomized, Multicenter Trial Comparing Sirolimus/Tacrolimus With Tacrolimus/Methotrexate as Graft-versus-Host Disease Prophylaxis After HLA-Matched, Related Peripheral Blood Stem Cell Transplantation (BMT-CTN-0402-BioLINCC)

  ObjectivesThe primary objective was to determine if the combination of tacrolimus and sirolimus (Tac/Sir) was more effective than tacrolimus and methotrexate (Tac/Mtx) in preventing acute graft-versus-host disease and early mortality after allogeneic related donor hematopoietic cell transplantation.BackgroundStem cell transplantation is a standard therapy for leukemia and myelodysplastic disorders. Recipients of human leukocyte antigen (HLA)-matched, related donor (MRD) stem cell transplants are at risk for a number of infections and complications. One of these complications is a condition known as acute graft-versus-host disease (GVHD). Recipients of HLA-MRD stem cell transplants for the treatment of myelodysplastic disorders and leukemia experience a 35% incidence of GVHD. Furthermore, GVHD contributes significantly to 1-year early treatment-related mortality (TRM) estimates of approximately 20%.The standard prophylaxis regimen for GVHD is a calcineurin inhibitor combined with methotrexate. Calcineurin inhibitors block calcineurin, a protein phosphatase that catalyzes some of the intracellular processes associated with T-lymphocyte activation. Inhibition is achieved by binding to immunophilins. The result is reduced production of interleukin-2 and reduced proliferation of T-cells. Methotrexate, an antineoplastic antimetabolite, has immunosuppressant properties that prevents the synthesis of tetrahydrofolate. Tetrahydrofolate is necessary for synthesis of thymidylate, an essential component of DNA. Of particular clinical concern is the theory that the injury caused by methotrexate to tissues could play a contributory role in initiation of the cytokine cascade associated with GVHD.The standard prophylaxis regimen for GVHD was established in the mid-1980s. Minor alterations to the standard regimen have shown limited effect on TRM outcomes in spite of the improvements that have been made to allogeneic hematopoietic cell transplantation (HCT) outcomes. Sirolimus, a rapamycin inhibitor, has been suggested as an alternative for methotrexate. Previous studies have suggested that sirolimus use results in decreased incidence of acute GVHD and treatment-related toxicity after HLA-MRD and unrelated donor transplantation, at the expense of higher rates of endothelial injury syndromes. Sirolimus has additional immunomodulatory properties that include effects on antigen-presenting cells, the thymus, and preservation of regulatory T-cell subsets after transplantation. The purpose of this study was to determine if sirolimus, in place of methotrexate, would produce improved outcomes in GVHD and TRM.ParticipantsEligible participants were 2 to 60 years of age, of either gender, and were undergoing transplantation for one of the following conditions: acute leukemia in remission, myelodysplastic disorder, or chronic myeloid leukemia in chronic or accelerated phase. All participants were required to have a 6/6 Class I HLA-A and B and molecular Class II DRB1 matched sibling donor medically able and willing to donate peripheral blood stem cells that also met institutional criteria for stem cell donation.Participants were excluded from participating in the trial for the following: prior allogenic or autologous transplant, HIV or another uncontrolled active infection, pregnant or breast-feeding, known allergy to sirolimus, requiring voriconazole at time of study entry, currently receiving another investigational drug (unless cleared by protocol officer or chair), or participants with a history of cancer.Participants were excluded from continuation for the following laboratory criteria if measured within 4 weeks of study entry: measured creatinine clearance 500mg/dL; forced vital capacity (FVC) or forced expiratory volume (FEV1) 45% in adults or A total of 304 participants were enrolled in the study. 151 participants were randomized to the tacrolimus/sirolimus (Tac/Sir) treatment, which 149 completed and 2 did not undergo transplantation. 153 participants were randomized to the tacrolimus/methotrexate (Tac/Mtx) treatment, which 152 completed and 1 did not undergo transplantation.DesignBMT 0402 was an interventional study with the purpose of determining the best combination of medications for the prevention of GVHD after HLA-MRD peripheral blood stem cell transplantation. Two GVHD prophylaxis conditioning regimens were tested: tacrolimus/sirolimus (Tac/Sir) and tacrolimus/methotrexate (Tac/Mtx). The study was Phase III, and designed to be multicenter, randomized, open label, and with parallel assignment treatment arms. Randomization occurred within 7 days of initiation of pretransplantation conditioning therapy, and was performed in a 1:1 ratio with the use of random block sites, stratified by transplantation center. The transplant physician selection of treatment occurred prior to participant's assignment to the study. All parties involved in the trial knew the treatment arm assigned to each participant.Participants received pretransplantation myeloablative conditioning with total body irradiation in combination with either cyclophosphamide or etoposide. Initially, a conditioning regimen comprised of myeloablative doses of busulfan with CY was permitted, however this was removed due to excess toxicity and veno-occulusive disease of the liver. The participants that received busulfan-based conditioning were not included in the primary outcome analyses. PBSC donors received filgrastim and underwent large volume apheresis with a goal of collecting 2 to 10 × 106/kg CD34+ stem cells. No graft manipulation was allowed prior to the infusion of the stem-cell product.For GVHD prophylaxis, tacrolimus was begun on day −3 for all participants at a dose of 0.02 mg/kg/day by continuous IV infusion, adjusted to maintain a serum concentration of 5 to 10 ng/mL. For participants in the Tac/Sir group, sirolimus was started on day −3 with a 12 mg oral loading dose, followed by daily oral doses of 4 mg, adjusted to maintain a serum trough concentration of 3 to 12 ng/mL. For participants in the Tac/Mtx group, methotrexate was IV administered on day +1 (15 mg/m2), +3, +6, and +11 (10 mg/m2 each day).The primary endpoint of grades II-IV acute GVHD-free survival was assessed 114 days from the time of randomization based on intention-to-treat. The study had 80% power to detect a 15% difference between the 2 prophylaxis strategies based on the standardized difference in Kaplan-Meier estimates with a 2-sided α of 5%. A committee of investigators blinded to GVHD prophylaxis assignment reviewed all case records, focusing on the incidence of acute and chronic GVHD, relapse, toxicity, and causes of death. Participants were followed for two years after transplantation for evaluation of secondary endpoints, which included cumulative incidence of acute GVHD, time to neutrophil and platelet engraftment, mucositis severity, rate of veno-occlusive disease, thrombotic microangiopathy infection, cytomegalovirus reactivation, treatment-related mortality, malignant disease relapse, all infections, overall survival, and time to discharge after transplant.ConclusionsParticipants who received Tac/Sir engrafted significantly earlier and had significantly less severe oropharyngeal mucositis after transplantation; however, no difference was observed in the primary end point of GVHD-free survival at 114 days post randomization between participants treated with Tac/Sir and Tac/Mtx (Cutler C. et al., Blood 2014).

  Study phs004629

• NCTN: A Phase III Trial Evaluating the Addition of Trastuzumab to Trimodality Treatment of HER2-Overexpressing Esophageal Adenocarcinoma (RTOG-1010)

  Study ID: RTOG-1010NCT Number: NCT01196390 NRG OncologySubmitted in collaboration with the NCTN/NCORP Data ArchiveTrial Title: NCTN: A Phase III Trial Evaluating the Addition of Trastuzumab to Trimodality Treatment of HER2-Overexpressing Esophageal Adenocarcinoma (RTOG-1010)Trial Description: This randomized phase III trial studies how well radiation therapy, paclitaxel, and carboplatin with or without trastuzumab work in treating patients with esophageal cancer. Radiation therapy uses high-energy x-rays to kill tumor cells. Drugs used in chemotherapy, such as paclitaxel and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Monoclonal antibodies, such as trastuzumab, may interfere with the ability of tumor cells to grow and spread. It is not yet known whether giving radiation therapy and combination chemotherapy together with or without trastuzumab is more effective in treating esophageal cancer. Clinical data presented in the following publication(s):PMID 35038433Disease type(s): Gastrointestinal Neoplasm - Gastroesophageal CancerClinical Dataset(s) included:NCT01196390-D1 (PMID 35038433): There are three datasets for RTOG-1010's primary publication 35038433 (-D1 through -D3). This dataset, NCT01196390-D1, contains the baseline characteristics, treatment, reasons for treatment discontinuation, surgery information, survival, and toxicity data. NCT01196390-D2 (PMID 35038433): There are three datasets for RTOG-1010's primary publication 35038433 (-D1 through -D3). This dataset, NCT01196390-D2, contains the treatment-related adverse event data. NCT01196390-D3 (PMID 35038433): There are three datasets for RTOG-1010's primary publication 35038433 (-D1 through -D3). This dataset, NCT01196390-D3, contains the treatment-related serious adverse event data. You are encouraged to view the PDF data dictionaries found in the “Documents” tab of the dbGaP study page, which may contain additional information regarding the data or the associated publication(s).

  Study phs004237