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Phase I trial evaluating safety and efficacy of intratumorally administered inflammatory allogeneic dendritic cells (ilixadencel) in advanced gastrointestinal stromal tumors.

ABSTRACT: BACKGROUND:The majority of patients with advanced gastrointestinal stromal tumor (GIST) develop resistance to imatinib, and subsequent treatments have limited efficacy. Ilixadencel (allogeneic inflammatory dendritic cells) is a cell-based immune primer injected intratumorally that previously has been clinically investigated in metastatic renal cell carcinoma and hepatocellular carcinoma. METHODS:The trial was a single arm phase I trial assessing safety and efficacy of ilixadencel in subjects with progressing advanced/metastatic GIST despite ongoing treatment with second or later lines of tyrosine kinase inhibitors (TKI). Three patients were progressing while on sunitinib (second line), one on regorafenib (third line), and two on pazopanib (fourth line). TKI treatment was maintained throughout, while two intratumoral injections of ilixadencel (10?×?106 viable and HLA-DR expressing cells per dose) were administered. RESULTS:No severe adverse events were found to be related to ilixadencel administration. Four patients showed continued tumor progression at 3 months per RECIST 1.1 and Choi criteria. One patient (on third line regorafenib) had stable disease for 9 months and another patient (on second line sunitinib) had stable disease at end of study (12 months) as per RECIST 1.1. These two patients developed a partial response as per Choi criteria with a duration of 3 and 6 months, respectively. The median progression-free survival (PFS) was 4.0 months. CONCLUSION:Ilixadencel treatment presented an acceptable safety profile among advanced GIST patients who developed resistance to TKI. Encouraging radiological tumor responses were detected in 33% of treated patients, supporting further investigation. Clinical trial registration www.clinicaltrials.gov ; NCT: 02432846; registration date: February 22, 2016.

SUBMITTER: Frobom R

PROVIDER: S-EPMC7568699 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Phase I trial evaluating safety and efficacy of intratumorally administered inflammatory allogeneic dendritic cells (ilixadencel) in advanced gastrointestinal stromal tumors.

Fröbom Robin R Berglund Erik E Berglund David D Nilsson Inga-Lena IL Åhlén Jan J von Sivers Karin K Linder-Stragliotto Christina C Suenaert Peter P Karlsson-Parra Alex A Bränström Robert R

Cancer immunology, immunotherapy : CII 20200613 11

<h4>Background</h4>The majority of patients with advanced gastrointestinal stromal tumor (GIST) develop resistance to imatinib, and subsequent treatments have limited efficacy. Ilixadencel (allogeneic inflammatory dendritic cells) is a cell-based immune primer injected intratumorally that previously has been clinically investigated in metastatic renal cell carcinoma and hepatocellular carcinoma.<h4>Methods</h4>The trial was a single arm phase I trial assessing safety and efficacy of ilixadencel ...[more]

PMID: 32535637

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Project description:BackgroundThe objectives of this study were to provide sunitinib to patients with gastrointestinal stromal tumor (GIST) who were otherwise unable to obtain it and to collect broad safety and efficacy data from a large population of patients with advanced GIST after imatinib failure. (ClinicalTrials.gov identifier NCT00094029).MethodsImatinib-resistant/intolerant patients with advanced GIST received sunitinib on an initial dosing schedule of 50 mg daily in 6-week cycles (4 weeks on treatment, 2 weeks off treatment). Tumor assessment frequency was according to local practice, and response was assessed by investigators according to Response Evaluation Criteria in Solid Tumors version 1.0. Overall survival (OS) and safety were assessed regularly. Post hoc analyses evaluated different patterns of treatment management.ResultsAt final data cutoff, 1124 patients comprised the intent-to-treat population, and 15% of these patients had a baseline Eastern Cooperative Oncology Group performance status ≥2. The median treatment duration was 7.0 months. The median time to tumor progression was 8.3 months (95% confidence interval [CI], 8.0-9.4 months), the median OS was 16.6 months (95% CI, 14.9-18.0 months), and 36% of patients were alive at the time of analysis. Patients for whom the initial dosing schedule was modified exhibited longer median OS (23.5 months) than those who were treated strictly according to the initial dosing schedule (11.1 months). The most common treatment-related grade 3 and 4 adverse events were hand-foot syndrome (11%), fatigue (9%), neutropenia (8%), hypertension (7%), and thrombocytopenia (6%). Treatment-related adverse events associated with cardiac function (eg, congestive heart failure and myocardial infarction) were reported at frequencies of ≤1% each.ConclusionsThis treatment-use study confirms the long-term safety and efficacy of sunitinib in a large international population of patients with advanced GIST after imatinib failure.

Project description:AimTo evaluate endoscopic ultrasound (EUS)-guided biopsies for the pretreatment characterization of gastrointestinal stromal tumors (GIST) to personalize the management of patients.MethodsAll patients with lesions suspected to be GIST who were referred for EUS-sampling at a tertiary Swedish center were eligible for inclusion 2006-2015. During the observational study phase (2006-2011), routine fine-needle-aspiration (EUS-FNA) was performed. In 2012-2015, we converted to an interventional, randomized protocol with dual sampling EUS-FNA and fine-needle-biopsy-sampling (EUS-FNB) for all lesions. c-KIT- and DOG-1-immunostaining was attempted in all samples and a manual count of the Ki-67-index was performed. FNB-sampled tissue and the resected specimens were subjected to Sanger sequencing of the KIT and platelet-derived growth factor alpha (PDGFRA) genes.ResultsIn all, 64 unique patients with GIST were included, and of these, 38 were subjected to pretreatment dual sampling. EUS-FNB had a higher diagnostic sensitivity when compared head-to-head with EUS-FNA (98% vs 58%, P < 0.001) and was more adequate for Ki-67-indexing (Ki-67EUS) (92% vs 40%, P < 0.001). Sequencing of EUS-biopsies was successful in 43/44 (98%) patients, and the mutation profiles (KIT-mutation 73%, PDGFRA-mutation 18%, wild-type 7%) were fully congruent with those detected in the corresponding resected specimens. In imatinib-naïve patients, the Ki-67EUS was comparable with the Ki-67-index in the corresponding surgical specimens (Ki-67SURG) (2.7% vs 2.9%, P = 0.68). In patients treated with neoadjuvant imatinib who also carried mutations indicating sensitivity, the Ki-67EUS was higher than the Ki-67SURG (2.5% vs 0.2%, P = 0.005), with a significant reduction in the Ki-67-index of -91.5% (95%CI: -82.4 to -96.0, P = 0.005).ConclusionEUS-guided biopsy sampling is accurate for the pretreatment diagnosis and characterization of GISTs and allows the prediction and evaluation of tumor response to neoadjuvant imatinib therapy.

Dataset Information

Phase I trial evaluating safety and efficacy of intratumorally administered inflammatory allogeneic dendritic cells (ilixadencel) in advanced gastrointestinal stromal tumors.

Publications

Phase I trial evaluating safety and efficacy of intratumorally administered inflammatory allogeneic dendritic cells (ilixadencel) in advanced gastrointestinal stromal tumors.

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