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Project description:WES and RNAseq from tumor samples of patients treated on clinical trial
2021-08-20 | GSE174765 | GEO
Project description:Biopsy samples from 4 sites were collected for RNA-Seq and single-cell RNA-Seq from patients with HER2 positive tumors enrolled in a Phase 1 clinical trial of anti-HER2 CAR-macrophage cell therapy. Biopsies of solid tumors were aimed to be collected at screening, 8 days after treatment, and 4 weeks after treatment. Patients in Group 1 received dose escalation of intravenous administration of up to 500 million cells, 1.5 billion cells, and 3 billion cells, on Day 1, 3, and 5, respectively. Patients in Group 2 received their full dose of cells on Day 1. This trial aimed to determine the feasibility of manufacturing CAR-macrophages, as well as assess the safety and tolerability of CAR-macrophage therapy, and determine the severity of potential adverse events.
2025-03-01 | GSE285746 | GEO
Project description:BackgroundAcquired resistance to antiepidermal growth factor receptor (anti-EGFR) therapy may be caused by EGFR-v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2 (ErbB2) heterodimerization and pathway reactivation. In preclinical studies, inhibiting ErbB2 blocked this resistance mechanism and resensitized cells to anti-EGFR therapy. Cetuximab targets EGFR, whereas lapatinib inhibits both EGFR and ErbB2. The objective of this phase 1 trial was to assess the safety, dose-limiting toxicities (DLTs), and maximum tolerated doses (MTDs) of cetuximab and lapatinib in patients with solid tumors.MethodsPatients received standard weekly cetuximab with escalating lapatinib doses of 750 mg, 1000 mg, or 1250 mg daily in 3-week cycles. DLTs were monitored through the end of cycle 2. Pretreatment and post-treatment tumor biopsies and germline DNA samples were obtained for correlative studies.ResultsTwenty-two patients were enrolled, and 18 patients each were evaluable for toxicity and response. Fifty-nine percent of patients had received prior anti-EGFR therapy. Common toxicities included rash and diarrhea. No patient experienced a DLT at the highest dose level, and no grade 4 toxicity was observed. Response included no complete responses, 3 partial responses, 9 patients with stable disease, and 6 patients with disease progression, for an overall response rate of 17% and a clinical benefit rate of 67%. The clinical benefit rate in patients who had previously received anti-EGFR therapy was 70%. The mean treatment duration was 4.7 cycles (range, 1-14 cycles). Decreased expression of EGFR/ErbB2 pathway components after treatment was correlated with response, whereas increased expression in the PI3K, Jak/Stat, and MAPK pathways occurred in nonresponders.ConclusionsThe combination of cetuximab and lapatinib was well tolerated, had the expected toxicities, and exhibited notable clinical activity, including in patients who had received previous anti-EGFR therapy. Further clinical study of this combination is warranted.
| S-EPMC4424139 | biostudies-literature
Project description:BackgroundCombined inhibition of epidermal growth factor receptor (EGFR) and Src family kinases (SFK) may lead to improved therapeutic effects. We evaluated the combination of dasatinib, an inhibitor of SFK and other kinases, and cetuximab, an anti-EGFR monoclonal antibody.Patients and methodsPatients with advanced solid malignancies received cetuximab intravenously on a standard weekly schedule and dasatinib orally, once daily at 3 dose levels: (1) 100 mg, (2) 150 mg, (3) 200 mg. Pharmacokinetic and pharmacodynamic studies of dasatinib were performed prior to starting cetuximab and following 14 days of treatment.ResultsTwenty-five patients (3 dose level 1; 19 dose level 2; 3 dose level 3) were initially treated. Three patients developed dose-limiting toxicities: 1 at dose level 2 (headache) and 2 at dose level 3 (headache, nausea). Grade 3-4 toxicities in more than 2 patients included: dyspnea (4), vomiting (4), nausea (3), hypersensitivity reactions (3), headache (3) and anemia (3). Twenty-one patients developed headache (8 grade 1; 10 grade 2), which occurred after the loading of cetuximab and lasted 1-3 days. Six additional patients were treated with dasatinib starting 3 days after the loading dose of cetuximab; none developed headache after dasatinib. Dasatinib pharmacokinetics and a transient decrease in SFK PY416 levels in peripheral blood mononuclear cells were not altered by cetuximab. Patients with higher plasma TGF-alpha levels had worse progression-free survival.ConclusionsDasatinib 150 mg once daily plus weekly cetuximab is recommended for phase II studies. Early-onset headache was ameliorated by starting dasatinib after cetuximab.
| S-EPMC3402509 | biostudies-literature
Project description:Phase 1 Study of Ulixertinib (BVD 523) in Patients with Advanced Solid Malignancies
| PRJNA882457 | ENA
Project description:Angiogenesis is a hallmark of cancer development. This study sought to determine the recommended dose of aflibercept, a recombinant fusion protein targeting VEGF-A, VEGF-B and placental growth factor (PlGF), combined with docetaxel in Japanese patients with advanced solid malignancies. This phase I study was planned to include 12 patients following a 3 + 3 algorithm to determine the maximum tolerated dose of aflibercept combined with docetaxel in patients with metastatic or unresectable solid tumors (trial registration: NCT00545246). Docetaxel (75 mg/m2 every 3 weeks or 60 mg/m2 after protocol amendment) was combined with escalating doses of aflibercept (2, 4 and 6 mg/kg every 4 weeks). Free and VEGF-bound aflibercept were measured to assess free aflibercept in excess of the VEGF-bound form. At the starting dose of the combination, 3 of 6 patients treated experienced febrile neutropenia. After reducing the docetaxel dose to 60 mg/m2 in step 2 and permitting therapeutic granulocyte colony-stimulating factor (G-CSF) use, 2 of 3 patients in both cohorts experienced febrile neutropenia. Five patients (42%) had a partial response and 4 patients had stable disease (33%). Free aflibercept in excess of the VEGF-bound form was not maintained at this dose level. The dose limiting toxicity (DLT) of aflibercept combined with docetaxel was febrile neutropenia, which occurred in 2 of 3 Japanese patients at the lowest aflibercept dose level (2 mg/kg) combined with docetaxel (60 mg/m2) and therapeutic G-CSF use. A recommended dose for further studies was not determined because of the DLT at the starting dose.
| S-EPMC9395466 | biostudies-literature
Project description:BackgroundThe safety, efficacy, pharmacokinetics, and pharmacodynamics of the anti-programmed cell death-1 antibody MEDI0680 were evaluated in a phase I, multicenter, dose-escalation study in advanced solid malignancies.MethodsMEDI0680 was administered intravenously once every 2 weeks (Q2W) or once every 3 weeks at 0.1, 0.5, 2.5, 10 or 20 mg/kg. Two cohorts received 20 mg/kg once a week for 2 or 4 weeks, then 20 mg/kg Q2W. All were treated for 12 months or until progression. The primary endpoint was safety. Secondary endpoints were efficacy and pharmacokinetics. Exploratory endpoints included pharmacodynamics.ResultsFifty-eight patients were treated. Median age was 62.5 years and 81% were male. Most had kidney cancer (n = 36) or melanoma (n = 9). There were no dose-limiting toxicities. Treatment-related adverse events occurred in 83% and were grade ≥ 3 in 21%. Objective clinical responses occurred in 8/58 patients (14%): 5 with kidney cancer, including 1 with a complete response, and 3 with melanoma. The relationship between dose and serum levels was predictable and linear, with apparent receptor saturation at 10 mg/kg Q2W and all 20 mg/kg cohorts.ConclusionsMEDI0680 induced peripheral T-cell proliferation and increased plasma IFNγ and associated chemokines regardless of clinical response. CD8+ T-cell tumor infiltration and tumoral gene expression of IFNG, CD8A, CXCL9, and granzyme K (GZMK) were also increased following MEDI0680 administration.Trial registrationNCT02013804 ; date of registration December 12, 2013.
| S-EPMC6704567 | biostudies-literature
Project description:BackgroundSynergistic cytotoxicity with high-dose statins and erlotinib has been demonstrated in preclinical models across a number of tumour types. In this phase I study, we evaluated the safety and potential anti-tumour activity of escalating doses of rosuvastatin in combination with the standard clinical dose of erlotinib in heavily pretreated patients with advanced solid tumours.MethodsThis was a single-center, phase I open-label study to determine the safety and recommended phase two dose (RPTD) of rosuvastatin in combination with 150 mg/day standard dose of erlotinib. Using a 3 + 3 study design and 28-day cycle, escalating doses of rosuvastatin from 1 to 8 mg/kg/day × 2 weeks (cycle 1) and 3 weeks (subsequent cycles) given concurrently with erlotinib were evaluated. In order to expand the experience and to gain additional safety and pharmacokinetic data, two expansions cohorts using concurrent or alternating weekly dosing regimens at the RPTD were also evaluated.ResultsAll 24 patients enrolled were evaluable for toxicity, and 22 for response. The dose-limiting toxicity (DLT) of reversible muscle toxicity was seen at the 2 mg/kg/day dose level. Maximal tolerated dose (MTD) was determined to be 1 mg/kg/day. Thirty-three percent of patients developed at least 1 ≥ grade 2 muscle toxicity (rhabdomyolysis: 1/24, myalgia: 7/24) resulting in one study-related death. Durable stable disease for more than 170 days was seen in 25 % of patients that received concurrent treatment and were evaluable for response (n = 16). Plasma erlotinib levels on study were unaffected by the addition of rosuvastatin.ConclusionsThe observed disease stabilization rate of 25 % with combination therapy in this heavily pretreated population is encouraging, however, the high levels of muscle toxicities observed limited this combination strategy.
| S-EPMC4815068 | biostudies-literature
Project description:In a post-hoc exploratory analysis of the KING trial to seek molecular markers of outcome, RNAseq was performed on resected tumor specimens at the time of diagnostic surgery before the recurrence from 57 study patients from all arms with adequate selinexor exposure and evidence of either clinical benefit or resistance defined above. RNAseq data were used to infer the activity for 6,203 master regulator proteins using the VIPER algorithm.
2021-12-01 | GSE186332 | GEO
Project description:PurposeImaradenant is a novel potent and selective adenosine A2A receptor antagonist that is hypothesized to reduce immune suppression in the tumor microenvironment. This phase I, open-label, dose-escalation study evaluated the safety, pharmacokinetics, and anti-tumor activity of imaradenant.MethodsJapanese patients with advanced solid malignancies received imaradenant 50 mg (n = 3) or 75 mg (n = 7) once daily (QD). The primary objective was safety and tolerability, and the secondary objectives were pharmacokinetics and anti-tumor activity.ResultsThe median treatment duration was 2.10 months and 2.14 months for the 50- and 75-mg QD cohorts, respectively. The most common adverse events were nausea, malaise, decreased appetite, and vomiting. Five patients (50%) reported adverse events that were considered causally related to imaradenant; three patients had Grade 2 adverse events of malaise, nausea, and diarrhea. No deaths or serious adverse events occurred. The median times of maximum observed concentrations sampled after a single dose in the 50- and 75-mg QD cohorts were 1.08 h (range, 0.95-1.95) and 2.00 h (range, 0.92-5.52), respectively. There was little accumulation after multiple dosing, with geometric mean accumulation ratios of maximum concentration of 1.3 (50-mg QD) to 1.4 (75-mg QD) and area under the concentration-time curve 0-24 of 1.4 (50-mg QD) to 1.5 (75-mg QD). The best objective response was stable disease (3/10).ConclusionNo new or unexpected safety concerns were identified, and imaradenant had an acceptable safety profile at both 50- and 75-mg QD.Clinicaltrialsgov identifier NCT03980821 (June 10, 2019).
| S-EPMC10950984 | biostudies-literature