62e41260-3a5f-44f8-a9c2-c2ab5dc9ce86 - samples
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PROVIDER: EGAD00001009830 | EGA |
REPOSITORIES: EGA
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Project description:Combining venetoclax, a selective BCL-2 inhibitor, with low-dose navitoclax, a BCL-XL/BCL-2 inhibitor, may potentiate therapeutic BCL-2 and BCL XL inhibition without dose-limiting thrombocytopenia associated with navitoclax monotherapy. The safety and preliminary efficacy of venetoclax with low-dose navitoclax and chemotherapy was assessed in this phase 1 dose escalation study (NCT03181126) in pediatric and adult patients with relapsed/refractory acute lymphoblastic leukemia or lymphoblastic lymphoma. Forty-seven patients received treatment. A recommended phase 2 dose of 50 mg navitoclax for adults and 25 mg for patients <45 kg with 400 mg adult-equivalent venetoclax was identified. Delayed hematopoietic recovery was the primary safety finding. The complete remission rate was 60%, including responses in patients who had previously received hematopoietic cell transplantation or immunotherapy. Thirteen (28%) patients proceeded to transplantation or CAR T-cell therapy on study. Venetoclax with navitoclax and chemotherapy was well tolerated and had promising efficacy in this heavily pretreated patient population.
2021-02-17 | GSE162894 | GEO
Project description:T cells in cutaneous T-cell lymphoma (CTCL) are functionally exhausted, expressing immune inhibitory molecules such as PD1 and PD-L1. Durvalumab selectively targets PD-L1 on exhausted T cells and distinct cells within the CTCL tumor microenvironment (TME) and may restore an anti-tumor immune response. The oral immunomodulator lenalidomide, which has shown activity in CTCL, may enhance immune checkpoint blockade by durvalumab. We initiated a phase 1/2 clinical trial of lenalidomide and durvalumab in patients with refractory/advanced CTCL (NCT03011814). Primary objectives were to assess safety and tolerability and identify the maximum tolerated dose/recommended phase 2 dose. Secondary and tertiary objectives were to investigate efficacy and the effects on the TME. Thirteen patients enrolled in sequential cohorts received fixed dose durvalumab and dose escalation of lenalidomide. Thirteen patients were evaluable for toxicities and 12 for response in phase 1. No serious adverse events (AEs) or dose-limiting toxicities (DLTs) were observed during cycles 1-3 (DLT evaluation period). The most frequent AEs were tumor flare, fatigue, neutropenia and leukopenia. Three patients developed grade 1/2 autoimmune thyroiditis that resolved with treatment. Median cycles of treatment were 11 (range, 3-42+). Median duration of response was 25.5 (range 8-36.5) months. Anti-PD-L1/lenalidomide showed clinical activity; there were 7 partial responses, 4 stable disease and 1 progressive disease. Adaptive and innate immune signatures potentially predictive of response seen in gene expression profiling of serial skin samples were downregulation of TNF-alpha signaling via NFκB, IFN-gamma, and PI3-AKT-mTOR signaling pathways in responders vs up-regulation of MYC targets and pro-inflammatory pathways in non-responders. Profiling of immune cell compositions revealed changes in individual immune cell clusters based on treatment status and response.
2024-07-11 | GSE271668 | GEO
Project description:Afamitresgene autoleucel, an HLA-restricted autologous specific peptide enhanced affinity receptor (SPEAR) T-cell therapy targeting MAGE-A4, was developed to treat HLA-A*02 positive patients with MAGE-A4 expressing solid tumors. A multicenter, dose-escalation, Phase 1 trial (NCT03132922) was conducted evaluating afamitresgene autoleucel in patients with relapsed or refractory (≥1 prior line of therapy) metastatic solid tumors. The primary endpoint was safety. The secondary endpoint was anti-tumor activity including overall response rate, best overall response, time to response, duration of response, duration of stable disease, progression-free survival and overall survival. Thirty-eight patients were treated with afamitresgene autoleucel across 9 tumor types, including 16 with synovial sarcoma (SS). Overall, afamitresgene autoleucel was well tolerated. The most common adverse events were cytopenias. Cytokine release syndrome occurred in 55% of all patients with severity grade ≤2 in 90% of reported cases. Overall response rate (ORR) was 24% and disease control rate (DCR) was 74% with objective responses in 7 patients with SS, 1 patient with non-small cell lung cancer, and 1 patient with head and neck squamous cell carcinoma. ORR in patients with SS, all prior treated with ifosfamide chemotherapy, was 44%, and DCR was 94%. Median progression-free survival and overall survival were 20.4 weeks (95% CI: 10.0, 52.1) and 58.1 weeks (95% CI: 36.3,-), respectively, for patients with SS and 12.3 weeks (95% CI: 10.857, 19.1) and 42.9 weeks (95% CI: 20.7, -), respectively, for the overall population. Translational findings demonstrated that afamitresgene autoleucel infiltrates into tumors, has an IFNγ-driven mechanism-of-action, and triggers adaptive immune responses. Overall, afamitresgene autoleucel has an acceptable safety profile with early and durable responses in HLA-A*02 positive patients with MAGE-A4 expressing solid tumors, especially in patients with metastatic SS. The recommended treatment regimen for Phase 2 evaluation involves lymphodepleting chemotherapy consisting of cyclophosphamide 600 mg/m2 x 3 days and fludarabine 30 mg/m2 x 4 days followed by afamitresgene autoleucel at a dose range of 1 to 10 billion transduced T-cells.
2022-05-05 | GSE202156 | GEO
Project description:We report the RNA sequencing data from the REPEAT study, in which patients with beyond first-line esophagogastric cancer were treated with regorafenib and paclitaxel. For the RNA sequencing, biopsies from metastatic lesions were obtained on baseline (n=21) and fifteen days following treatment initiation (n=13). PURPOSE: Regorafenib monotherapy, a multikinase-inhibitor of angiogenesis, tumor microenvironment, and oncogenesis, showed promising results in gastric cancer. We aimed to assess the tolerability of regorafenib and paclitaxel in advanced esophagogastric cancer (EGC) patients refractory to first-line treatment, and explore potential biomarkers. METHODS: Patients received paclitaxel (80 mg/m2) on days 1, 8, and 15 of a 28-day cycle and regorafenib (80/120/160 mg) on day 1-21 in the dose-escalation cohort, and the maximum-tolerated dose (MTD) in the dose-expansion cohort. Exploratory, overall- (OS) and progression-free survival (PFS) were compared to a propensity-score matched cohort receiving standard second/third line systemic treatment. Paclitaxel pharmacokinetics were assessed using D1 and D15 samples. We performed ELISA measurements of galectin-1, RNA sequencing and shallow whole-genome sequencing of metastatic tumor biopsies for biomarker analyses. RESULTS: In the dose-escalation cohort (n=14), the MTD of regorafenib was 120 mg. Thirty-four patients were enrolled in the dose-expansion cohort. Most common toxicities (all grades; grade ≥3) were fatigue (79%; 4%) and sensory neuropathy (63%; 4%). Best responses achieved were partial response (28%) and stable disease (54%). Median OS and PFS were 7.8 and 4.2 months, respectively (median follow-up 7.8 months). OS (p=0.08) and PFS (p=0.81) were not significantly improved compared to the matched cohort. Paclitaxel concentrations were significantly increased with regorafenib (D15) compared with paclitaxel only (D1; p<0.05); no associations were observed with toxicity or efficacy. An increase in circulating galectin-1 compared to baseline was associated with shorter OS (p<0.01). Enrichment of angiogenesis-related gene expression was observed in short-survivors measured by RNA sequencing. Chromosome 19q13.12-q13.2 amplification was associated with shorter OS (p=0.02) and PFS (p=0.02). CONCLUSION: Treatment with regorafenib and paclitaxel is tolerable and shows promising efficacy in advanced EGC refractory to first-line treatment. Galectin-1 and chromosome 19q13.12-q13.2 amplification could serve as negative predictive biomarkers for treatment response.
2022-03-11 | GSE198136 | GEO
Project description:Phase I Safety, Pharmacokinetic and Pharmacogenomic Trial of ES-285, a Novel Marine Cytotoxic Agent Administered as an Infusion over 24 h Every 21 Days in Patients with Solid Tumors Purpose: A dose-escalation, phase I study evaluated the safety, pharmacokinetics, pharmacogenomics and efficacy of ES-285, a novel agent isolated from a marine mollusc, in adult cancer patients. Experimental design: Patients received a 24-hour i.v. infusion of ES-285 once every 3 weeks until disease progression or unacceptable toxicity. The starting dose was 4mg/m2. Dose escalation proceeded according to the worst toxicity observed in the previous cohort. Results: 28 patients were treated with 72 courses of ES-285 across 8 dose levels. No doselimiting toxicities (DLTs) were seen between 4mg/m2 and 128mg/m2. Two out of 4 patients treated at 256mg/m2 had dose-limiting reversible grade 3 transaminitis; one patient at 256mg/m2 also had transient grade 3 central neurotoxicity. One of 3 patients subsequently treated at 200mg/m2 died following drug-related central neurotoxicity. Pharmacokinetic studies indicated dose-proportionality with high volume of distribution (median Vss at 256mg/m2 was 2389L, range 1615-4051L) and long elimination half life (median t1/2 at 256mg/m2 was 29h, range 21-32h). The 3 patients with DLT had the highest drug exposure. Pharmacogenomic studies of paired surrogate tissue samples identified changes in gene expression following treatment that correlated with increasing dose. Pre-treatment 59- and 49-gene sets were identified in blood and skin respectively, that may predict DLT. Disease stabilisation for 6 to 18 weeks was recorded in 9 patients. Conclusion: Using this schedule, 128 mg/m2 was considered safe and feasible. At this dose, pharmacologically relevant concentrations of drug were safely achieved with pharmacogenomic studies indicating changes in the expression of genes of potential biological relevance. Keywords: dose response
2009-04-01 | GSE12062 | GEO
Project description:The T cell receptor (TCR) provides the fine specificity of T cells to recognize mutations in cancer cells 1-3. We developed a clinical-grade approach based on CRISPR/Cas9 non-viral precision genome editing to simultaneously knock-out the two endogenous TCR genes, TCRα (TRAC) and TCRβ (TRBC), and insert in the TRAC locus the two chains of a neoantigen-specific TCR (neoTCR), isolated from the patient’s own circulating T cells using a personalized library of soluble predicted neoantigen-HLA capture reagents. Sixteen patients with refractory solid cancers received up to three distinct neoTCR-transgenic cell products, each expressing a patient-specific neoTCR, in a cell dose-escalation, first-in-human phase 1 clinical trial (NCT03970382). One patient had grade 1 cytokine release syndrome, and one grade 3 encephalitis. All had the expected side effects from the lymphodepleting chemotherapy. Five patients had stable disease, and the other 11 had disease progression as best response on therapy. NeoTCR-transgenic T cells were detected in tumour biopsies post-infusion at frequencies higher than the native TCRs pre-infusion. This study demonstrates the feasibility of isolating and cloning multiple TCRs recognizing mutational neoantigens, the simultaneous knock-out of the endogenous TCR and knock-in of the neoTCRs using single-step, non-viral precision genome editing, the manufacturing of neoTCR engineered T cells at clinical grade, the safety of infusing up to three gene edited neoTCR T cell products, and the ability of the transgenic T cells to traffic to the patients’ tumours.
| EGAS00001006898 | EGA
Project description:The study objective was to propose molecular mechanisms of action of the histone deacetylase inhibitor vorinostat. In the PRAVO phase 1 study, patients that were scheduled to receive pelvic palliative radiation to 30 Gy in 3-Gy fractions for gastrointestinal carcinoma, were enrolled onto four sequential dose levels of vorinostat, starting at 100 mg daily with dose escalation in increments of 100 mg. Endpoints included treatment safety and tolerability, tumor response, and biological activity of vorinostat. For the purpose of identifying biomarkers of vorinostat action, peripheral blood mononuclear cells, representing normal tissue exposed to vorinostat, were used. The samples were collected, one at baseline and two on-treatment samples. The time points for sample collection were chosen based on our previous data from experimental colorectal carcinoma models exposed to vorinostat, demonstrating that the maximum tumor histone acetylation 2-3 hours after drug exposure was restored to baseline after 24 hours. In PRAVO study patients, tumor histone hyperacetylation was observed 3 hours after vorinostat administration. From the 17 patients enrolled onto the PRAVO study, a full set of three samples was obtained from 14 individuals: one baseline sample collected prior to commencement of vorinostat treatment (T0), and two on-treatment samples collected 2 and 24 hours after the patient had received the preceding daily dose of vorinostat (T2 and T24). Individual vorinostat dose levels were 100 mg (D100), 200 mg (D200), 300 mg (D300), or 400 mg (D400).
2013-05-08 | E-GEOD-46703 | biostudies-arrayexpress
Project description:WXS files for Mullighan BiTE WXS paper titled "Tumor intrinsic and extrinsic mechanisms of response and resistance to blinatumomab in relapsed/refractory acute lymphoblastic leukemia"
| EGAD00001005730 | EGA
Project description:Immune checkpoint inhibitors such as anti-cytotoxic T-lymphocyte–associated antigen-4 and anti-programmed cell death-1 monoclonal antibodies (mAbs) agents or these combinations has improved outcomes of various cancers.However, still not a few patients fail to achieve clinical benefit, this highlights the importance of additional treatment to overcome its resistance. Previously, we showed that administration of the anti-CD4 mAb alone had strong anti-tumor effects that were superior to those elicited by CD25+ Treg depletion or other immune checkpoint mAbs in B16F10, Colon 26, or Lewis lung carcinoma subcutaneous tumor models. IT1208 (IDAC Theranostics, Tokyo, Japan) is a humanized anti-CD4 immunoglobulin G1 (IgG1) monoclonal antibody with a defucosylated Fc region, which markedly enhances antibody dependent cellular cytotoxicity. In a first-in-human, phase I, open-label, dose-escalation study, we performed T cell repertoire analysis of T cell subsets in the tumors and peripheral blood mononuclear cells (PBMCs) to clarify T cell responses against IT1208 monotherapy in patients with advanced solid tumors.
2019-08-06 | GSE120101 | GEO
Project description:Immune checkpoint inhibitors such as anti-cytotoxic T-lymphocyte–associated antigen-4 and anti-programmed cell death-1 monoclonal antibodies (mAbs) agents or these combinations has improved outcomes of various cancers.However, still not a few patients fail to achieve clinical benefit, this highlights the importance of additional treatment to overcome its resistance. Previously, we showed that administration of the anti-CD4 mAb alone had strong anti-tumor effects that were superior to those elicited by CD25+ Treg depletion or other immune checkpoint mAbs in B16F10, Colon 26, or Lewis lung carcinoma subcutaneous tumor models. IT1208 (IDAC Theranostics, Tokyo, Japan) is a humanized anti-CD4 immunoglobulin G1 (IgG1) monoclonal antibody with a defucosylated Fc region, which markedly enhances antibody dependent cellular cytotoxicity. In a first-in-human, phase I, open-label, dose-escalation study, we performed transcriptomic analysis of tumors to clarify molecular responses against IT1208 monotherapy in patients with advanced solid tumors.
2019-08-06 | GSE120028 | GEO