Phase I/II Trial of Antagonism of HER in GI Cancer
Ontology highlight
ABSTRACT:
DISEASE(S): Metastatic Colorectal Cancer,Recurrent Colorectal Cancer,Colorectal Cancer,Colorectal Neoplasms
PROVIDER: 2145451 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:Background: The efficacy of FOLFIRI plus an antiangiogenesis biologic agent as 2nd line therapy for metastatic colorectal adenocarcinoma is limited. TAS-102 is a novel oral antimetabolite with a distinct mechanism of action from fluoropyrimidines. We evaluated the antitumor efficacy of TAS-102, irinotecan and bevacizumab in patients with pre-treated, advanced colorectal adenocarcinoma in a multicenter, phase II, single-arm study. Methods: Patients with advanced colorectal adenocarcinoma who had progressed after oxaliplatin and fluoropyrimidine and were eligible for treatment with bevacizumab were treated with irinotecan, bevacizumab, and TAS-102 in 28-day cycles. The primary endpoint was progression-free survival (PFS). Results: We enrolled 35 evaluable patients. The study was positive. The median PFS was 7.9 (90% CI 6.2-11.8) months (vs. 6 months in historical control, p=0.018). The median overall survival was 16.5 (90% CI 9.8-17.5) months. Sixty-seven percent of patients experienced grade 3 or higher treatment-related adverse events. The most common toxicities were hematological (neutropenia) and gastrointestinal (diarrhea, nausea, and vomiting). Conclusions: Irinotecan, TAS-102 and bevacizumab is an active 2nd line therapy for patients with metastatic colorectal adenocarcinoma. Neutropenia is common and can affect dose density/intensity mandating use of G-CSF. A randomized study versus standard of care therapy is warranted.
2024-08-26 | GSE275628 | GEO
Project description:We report here a phase I trial (NCT02208362) evaluating locoregional delivery of IL13Rα2-targeted CAR T cells in 65 patients with recurrent high-grade glioma, the majority being recurrent glioblastoma (rGBM). Primary objectives were to evaluate safety and feasibility, and secondary objectives were to assess therapy-related cytokine dynamics, CAR T cell persistence and clinical outcomes. Feasibility and safety were established for three routes of locoregional CAR T cell administration [intratumoral (ICT), intraventricular (ICV) and dual ICT/ICV], with IL13Rα2-CAR T cells being well-tolerated with clinically manageable adverse events at all dose levels. Stable disease or better was achieved in 50% of patients, with two partial responses, one complete response (CR), and a second CR after additional CAR T cycles off protocol therapy. Patients with rGBM treated on Arm 5, utilizing dual ICT/ICV delivery and an optimized manufacturing process exhibited the best overall survival of 10.2 months. . Central nervous system (CNS) increases in inflammatory cytokines, including IFNγ, CXCL9, and CXCL10, were associated with CAR T cell administration and bioactivity. Further, pre-treatment intratumoral CD3 T cell levels were positively associated with survival, suggesting an interplay between host immunity and CAR T cells as a determinant of outcomes. These findings advance our understanding of CAR T cell immunotherapy for malignant brain tumors. ClinicalTrials.gov Identifier: NCT02208362
2024-02-20 | GSE255850 | GEO
Project description:Devimistat is a novel TCA cycle inhibitor. A previously completed phase I study of devimistat in combination with cytarabine and mitoxantrone in patients with relapsed or refractory acute myeloid leukemia (AML) showed promising response rates. A single arm phase II study (NCT02484391) of AML patients to assess the feasibility of maintenance devimistat, response, survival and safety is now complete. A dose response was observed in older patients, but not younger patients. RNAseq analysis of pre-treatment bone marrow biopsies revealed an age-related decline in mitochondrial gene sets. Devimistat impairs ATP synthesis, and there is a direct correlation between mitochondrial membrane potential and chemotherapy sensitization. Devimistat induces mitochondrial reactive oxygen species and turnover consistent with mitophagy. Pharmacological or genetic inhibition of mitochondrial fission or autophagy sensitizes cells to devimistat. These data support a model where devimistat may benefit older patients as a consequence of age related decline in mitochondrial quality and autophagy.
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Project description:Mutations in RNA splicing factor genes (SF3B1, SRSF2, and U2AF1) are common in AML and MDS and recent studies demonstrate pharmacologic degradation of the RNA splicing factor RBM39 results in preferential killing of splicing factor mutant cells. We therefore conducted a phase II clinical trial (NCT05024994) of the oral RBM39 degrader E7820 at the recommended phase II dose in patients with R/R MDS/AML and a splicing factor mutation. No patients met the primary endpoint of overall response rate in the first 12 patients enrolled, leading to study termination. However, E7820 was well-tolerated and achieved >50% RBM39 degradation in blood and disruption of splicing. At the same time, the degree of splicing disruption was far less than seen with in vitro doses exhibiting preclinical efficacy, providing potential explanation for limited clinical efficacy. Overall, this study demonstrates on-target safety and feasibility of RBM39 degradation in patients and supports future combination therapies with E7820.
2024-09-30 | GSE227343 | GEO
Project description:Cutaneous basal cell carcinoma (BCC) is the most common cancer worldwide. We present a single arm, phase II neoadjuvant trial with the oncolytic virus Talimogene laherparepvec (T-VEC) in 18 patients with difficult-to-resect basal cell carcinomas. Six cycles of T-VEC were applied intralesionally. The primary endpoint of the study, defined as the proportion of patients, who after six cycles of T-VEC (13 weeks) at the time point of surgery, become resectable with primary wound closure without the need for plastic reconstructive surgery like skin flaps or skin grafts, was already achieved after stage I (9/18 patients; 50.0%), thus the study was discontinued for early success. The objective response rate was 55.6% and the complete pathological response rate was 33.3%. Only mild adverse events occurred. The 6-months RFS and OS rates were 100%. T-VEC led to a significant increase of cytotoxic T cells, B cells and myeloid cells, and a decrease of Tregs within the tumor microenvironment. We observed a potent induction of T cell receptor clones of antitumoral and antiviral origin, as well as a strong humoral immune response. Together, neoadjuvant T-VEC represents a viable treatment option for patients with difficult-to-resect BCCs (EudraCT Number 2018-002165-19).
2024-09-11 | GSE268728 | GEO
Project description:Endocrine therapy in patients with breast cancer can be limited by the problem of resistance. Preclinical studies suggest that complete blockade of the estrogen receptor (ER) combined with inhibition of the epidermal growth factor receptor (EGFR) can overcome endocrine resistance. We tested this hypothesis in a phase II neoadjuvant trial of anastrozole and fulvestrant combined with gefitinib in postmenopausal women with newly diagnosed ER-positive breast cancer. After a baseline tumor core biopsy, patients were randomized to receive anastrozole and fulvestrant (AF) or anastrozole, fulvestrant, and gefitinib (AFG) for 3 weeks. After a second biopsy at 3 weeks, all patients received AFG for 4 months and surgery was done if the tumor was operable. The primary endpoint was best clinical response by RECIST criteria and secondary endpoints were toxicity and change in biomarkers. The study closed after 15 patients were enrolled because of slow accrual. Median patient age was 67 years and median clinical tumor size was 7 cm. Four patients had metastatic disease present. Three patients withdrew before response was assessed. In the remaining twelve patients, there were two complete clinical responses (17%), three partial responses (25%), five had stable disease (41%), and two (17%) had progressive disease. Most common adverse events were rash in four patients, diarrhea in four, joint symptoms in three, and abnormal liver function tests in three. There were no grade 4 toxicities and all toxicities were reversible. At 3 weeks, cell proliferation as measured by Ki-67 was significantly reduced in the AFG group (p value= 0.01) with a parallel reduction in the expression of the Cyclin D1 (p value=0.02). RNA microarray data showed a corresponding decrease in the expression of cell cycle genes. These results suggest that AFG was an effective neoadjuvant therapy and consistently reduced proliferation in ER-positive tumors.
2011-12-20 | GSE33658 | GEO
Project description:In this open-label randomized controlled phase I/II trial, 20 stable peritoneal dialysis patients underwent two 4 h dwells with acidic glucose-based PDF, with and without 8 mM alanyl-glutamine (AlaGln) in a cross-over design. Unsupervised hierarchical clustering of transcriptomics data suggested specific effects of AlaGln in patients who had previously suffered from peritonitis.
2020-01-24 | GSE57070 | 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.
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2022-01-07 | GSE193157 | GEO
Project description:Immune checkpoint blockade has limited efficacy in microsatellite stable (MSS) colorectal (CRC) and pancreatic (PDAC) cancer. Preclinical models have demonstrated the use of radiation to activate the innate immune response and stimulate responsiveness to immune checkpoint blockade. Here, we describe a Phase 2 trial of radiation therapy combined with combined anti-CTLA4 (ipilimumab) and anti-PD1 (nivolumab) antibodies in MSS CRC and PDAC. In the per protocol analysis disease control rate was 37% (10/27) in CRC and 29% (5/17) in PDAC with an overall response rate of 15% (4/27) and 18% (3/17), respectively. Whole exome and RNA sequencing of biopsies from 17 patients revealed low tumor mutational burden in all tumors, but a notable upregulation of interferon stimulated genes with concordant high expression of multiple repeat RNA transcripts in responders. Altogether, this study provides foundational human proof of concept of radiation with combination immune checkpoint blockade therapy in otherwise immunotherapy resistant cancers.
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