ESTRO 2020 Abstract book

S338 ESTRO 2020

100 mg/kg) in combination with whole brain radiation therapy (30 Gy, 10 Fr of 3 Gy) for patients with multiple brain metastases. AGuIX was intravenous injected at 100 mg/mL with 1 mL/min rate flow. A multiparametric MRI was performed 2 hours after injection to visualize the distribution of AGuIX in brain metastases and surrounding healthy tissues. Radiotherapy was started 4 hours after injection. Secondary objectives are the pharmacokinetics, distribution of AGuIX by MRI, intracranial progression-free survival and overall survival. Safety was evaluated using NCI-CTCAE v 4.03 and tumoral response was assessed using RECIST 1.1. Results The first human administration was performed on July 2016 and the last patient (n=15) was included on February 2018. Median age is 60 [37-79], median number of brain metastases is 24 [4-50]. An efficient metastases targeting (T 1 MRI enhancement) and a persistence of AGuIX one week after administration was observed in all metastases, whatever the histological type (lung, melanoma, breast and colon). The concentration of AGuIX in metastases was proportional to the injected dose and ranged from 20 to 60 mg/L 2 hours after administration. The average elimination blood half-life is 77.2 min (±31min) and mean urinary excretion is 54 % during the first 24 hours. No dose- limiting toxic effects were observed with a dose escalation up to 100 mg/kg and will be the dose selected for further clinical trials. Of the 14 evaluable patients, 12 had a clinical benefit of treatment with a decrease in tumor volume. Conclusion These results are promising in terms of safety, distribution and efficacy of AGuIX with efficient targeting and persistence of the nano-drug into different histological types. Evidences of radiosensitizing effects should be confirmed by the randomized multicenter Phase 2 study started in March 2019 (NCT03818386) OC-0562 Exploiting tumor DNA repair status and hypoxia with CP-506, a novel hypoxia-activated prodrug A. Van der Wiel 1 , D. Marcus 1 , R. Niemans 1 , A. Yaromina 1 , J. Theys 1 , A. Mowday 1 , A. Ashoorzadeh 2 , R. Anderson 2 , M. Bull 2 , M. Abbattista 2 , A. Heyerick 3 , C. Guise 2 , J. Smaill 2 , A. Patterson 2 , L. Dubois 1 , P. Lambin 1 1 GROW – School for Oncology and Developmental Biology- Maastricht Comprehensive Cancer Center- Maastricht University Medical Centre, Department of Precision Medicine- The M-Lab, Maastricht, The Netherlands ; 2 University of Auckland, Auckland Cancer Society Research Centre, Auckland, New Zealand ; 3 Convert Pharmaceuticals, Convert Pharmaceuticals, Liège, Belgium Purpose or Objective Hypoxia-activated prodrugs (HAPs) are a promising class of anticancer agents that selectively target hypoxic tumor regions associated with malignancy and treatment resistance. However, the majority of HAP clinical trials yielded disappointing results. As gaining mechanistic understanding is crucial for successful clinical implementation, the present study aimed to identify key factors contributing to the antitumor effects of CP-506: a novel hypoxia-activated DNA crosslinking agent designed to have a large bystander effect, aqueous solubility, and oral bioavailability, without off-mechanism aerobic activation by human aerobic reductases. Material and Methods

Cell viability was assessed under normoxic and anoxic (≤0.02% O 2 ) conditions in 2D cultures of a panel of tumor cell lines (n=25), some deficient in DNA repair pathways. Normoxic and hypoxic 3D spheroids were exposed to CP- 506 and growth and clonogenic survival were assessed. Mice bearing a range of tumor xenografts (n=11) received a single dose of CP-506 (800 mg/kg) for 5 consecutive days (QD5) at a tumor volume of ca. 200 mm 3 . To alter tumor oxygenation, animals bearing MDA-MB-468 xenografts were exposed to 7% O 2 , 21% O 2 , or carbogen (95% O 2 , 5% CO 2 ) plus nicotinamide (CarbN) breathing conditions for 2.5 h during which CP-506 (600 mg/kg) was administered (QD1). Tumor response was quantified as tumor growth delay (TGD) defined as mean time to reach four times starting volume (T4XSV). Baseline tumor hypoxic fraction (HF) was assessed using the markers pimonidazole and EF5. Results In all cell lines, IC 50 values were lower in anoxia than normoxia resulting in hypoxia cytotoxicity ratios ranging from >2.3 to >38.5. CP-506 exhibited a concentration- dependent growth inhibition and decrease in clonogenic survival in hypoxic spheroids only. Cell lines deficient in homologous recombination and the Fanconi anemia pathway, but not in non-homologous end joining, demonstrated greatly enhanced sensitivity to CP-506 in both 2D and 3D models. CP-506 resulted in TGD in all models and increased T4XSV 1.3 to 3.4 fold. In MDA-MB- 468 tumors, exposure to 7% O 2 during treatment increased T4XSV compared to 21% O 2 and CarbN breathing conditions (101.9 vs. 84.7 and 74.7 days respectively). When comparing multiple xenograft models, no correlation between baseline HF and antitumor effects of CP-506 was observed. Conclusion CP-506 is a novel HAP with highly favorable properties. CP- 506 selectively kills hypoxic tumor cells in vitro and inhibits growth of a wide range of xenografts in vivo . Even though a causal relationship between tumor oxygenation and antitumor effects of CP-506 was established within one tumor model, our data demonstrate that hypoxia is not the only or even most important factor in determining its antitumor effects. Our in vitro data indeed indicate that DNA repair mutational status greatly influences the cytotoxicity of CP-506. Our findings can lead to the identification of biomarkers crucial for successful clinical implementation of CP-506. OC-0563 Hypoxia suppresses radiation-induced tumor immunogenicity in 3D breast cancer models S. Gruber 1 , M. Charpentier 2 , E. Wennerberg 2 , S. Van Nest 2 , S. Demaria 2 1 Medizinische Universität Wien, Univ.Klinik f. Strahlentherapie, Vienna, Austria ; 2 Weill Cornell Medicine, Radiation Oncology, New York, USA Purpose or Objective Immune checkpoint blockade therapy (ICB) has achieved remarkable successes in a subset of cancer patients across different malignancies, but responses are limited in breast cancer (BC), prompting investigations into combination therapies that can synergize with ICB. In pre-clinical models focal radiotherapy has been shown to induce systemic responses when combined with ICB in otherwise unresponsive tumors. Mechanistically, the DNA damage response induced by radiation is coupled with the accumulation of DNA in the cytosol of the cancer cells and leads to the production of interferon type I (IFN-I) in the tumor microenvironment (TME). IFN-I and IFN-stimulated genes (ISGs) orchestrate the recruitment and activation of