Multiplexed Evaluation of Microdosed Antineoplastic Agents In Situ in the Tumor Microenvironment of Patients with Soft Tissue Sarcoma
Open Access
- 1 August 2020
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Clinical Cancer Research
- Vol. 26 (15), 3958-3968
- https://doi.org/10.1158/1078-0432.ccr-20-0614
Abstract
A persistent issue in cancer drug development is the discordance between robust antitumor drug activity observed in laboratory models and the limited benefit frequently observed when patients are treated with the same agents in clinical trials. Difficulties in accurately modeling the complexities of human tumors may underlie this problem. To address this issue, we developed Comparative In Vivo Oncology (CIVO), which enables in situ investigation of multiple microdosed drugs simultaneously in a patient's tumor. This study was designed to test CIVO's safety and feasibility in patients with soft tissue sarcoma (STS). We conducted a single arm, prospective, 13-patient pilot study. Patients scheduled for incisional biopsy or tumor resection were CIVO-injected 1 to 3 days prior to surgery. Saline or microdoses of anticancer agents were percutaneously injected into the tumor in a columnar fashion through each of eight needles. Following excision, drug responses were evaluated in the injected tissue. The primary objective was met, establishing CIVO's feasibility and safety. Device-related adverse events were limited to transient grade 1 nonserious events. In addition, biomarker evaluation of localized tumor response to CIVO microinjected drugs by IHC or with NanoString GeoMx Digital Spatial Profiler demonstrated consistency with known mechanisms of action of each drug, impact on the tumor microenvironment, and historic clinical activity. These results are an advance toward use of CIVO as a translational research tool for early evaluation of investigational agents and drug combinations in a novel approach to phase 0 trials. See related commentary by Sleijfer and Lolkema, p. 3897Keywords
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Funding Information
- ClinicalTrials.gov (NCT03056599)
This publication has 36 references indexed in Scilit:
- Phase II and Phase III attrition rates 2011–2012Nature Reviews Drug Discovery, 2013
- Role of Macrophage Targeting in the Antitumor Activity of TrabectedinCancer Cell, 2013
- Targeting the PDGF signaling pathway in tumor treatmentCell Communication and Signaling, 2013
- Efficacy of first-line doxorubicin and ifosfamide in myxoid liposarcomaClinical Sarcoma Research, 2012
- Macrophages and cathepsin proteases blunt chemotherapeutic response in breast cancerGenes & Development, 2011
- Leukocyte Complexity Predicts Breast Cancer Survival and Functionally Regulates Response to ChemotherapyCancer Discovery, 2011
- Phase 0 clinical trials: Recommendations from the task force on methodology for the development of innovative cancer therapiesEuropean Journal of Cancer, 2009
- Randomized Phase II Study of Gemcitabine and Docetaxel Compared With Gemcitabine Alone in Patients With Metastatic Soft Tissue Sarcomas: Results of Sarcoma Alliance for Research Through Collaboration Study 002Journal of Clinical Oncology, 2007
- Gemcitabine in advanced adult soft-tissue sarcomas. A phase II study of the EORTC Soft Tissue and Bone Sarcoma GroupEuropean Journal of Cancer, 2002
- Gemcitabine in soft tissue or bone sarcoma resistant to standard chemotherapy: a phase II studyCancer Chemotherapy and Pharmacology, 2000