Abstract
BackgroundSynovial Sarcomas (SS) are rare tumors occurring predominantly in adolescent and young adults with a dismal prognosis in advanced phases. We report a first-in-human phase I of monoclonal antibody (OTSA-101) targeting FZD10, overexpressed in most SS but not present in normal tissues, labelled with radioisotopes and used as a molecular vehicle to specifically deliver radiation to FZD10 expressing SS lesions.MethodsPatients with progressive advanced SS were included. In the first step of this trial, OTSA-101 in vivo bio-distribution and lesions uptake were evaluated by repeated whole body planar and SPECT-CT scintigraphies from H1 till H144 after IV injection of 187 MBq of 111In-OTSA-101. A 2D dosimetry study also evaluated the liver absorbed dose when using 90Y-OTSA-101. In the second step, those patients with significant tumor uptake were randomized between 370 MBq (Arm A) and 1110 MBq (Arm B) of 90Y-OTSA-101 for radionuclide therapy.ResultsFrom January 2012 to June 2015, 20 pts. (median age 43 years [21–67]) with advanced SS were enrolled. Even though 111In-OTSA-101 liver uptake appeared to be intense, estimated absorbed liver dose was less than 20 Gy for each patient. Tracer intensity was greater than mediastinum in 10 patients consistent with sufficient tumor uptake to proceed to treatment with 90Y-OTSA-101: 8 were randomized (Arm A: 3 patients and Arm B: 5 patients) and 2 were not randomized due to worsening PS. The most common Grade ≥ 3 AEs were reversible hematological disorders, which were more frequent in Arm B. No objective response was observed. Best response was stable disease in 3/8 patients lasting up to 21 weeks for 1 patient.ConclusionsRadioimmunotherapy targeting FZD10 is feasible in SS patients as all patients presented at least one lesion with 111In-OTSA-101 uptake. Tumor uptake was heterogeneous but sufficient to select 50% of pts. for 90Y-OTSA-101 treatment. The recommended activity for further clinical investigations is 1110 MBq of 90Y-OTSA-101. However, because of hematological toxicity, less energetic particle emitter radioisopotes such as Lutetium 177 may be a better option to wider the therapeutic index.Trial registrationThe study was registered on the NCT01469975 website with a registration code NCT01469975 on November the third, 2011.
Highlights
Synovial Sarcomas (SS) are rare tumors occurring predominantly in adolescent and young adults with a dismal prognosis in advanced phases
Radioimmunotherapy targeting Frizzled homologue 10 (FZD10) is feasible in SS patients as all patients presented at least one lesion with 111In-OncoTherapy Science Antigen (OTSA)-101 uptake
We describe the results of a FIH, first in class phase I study evaluating the use of 111In-OTSA-101 and 90Y-OTSA-101 in patients with advanced synovial sarcoma following a theranostic approach
Summary
Synovial Sarcomas (SS) are rare tumors occurring predominantly in adolescent and young adults with a dismal prognosis in advanced phases. Synovial Sarcomas (SS) account for 2.5–5% of all soft tissue sarcoma and affect all ages, but is most prevalent among adolescents and young adults (15–40 years of age) [1]. Therapy for patients with localized disease is based on surgery followed by external radiotherapy. Five-year overall survival rates range from 36 to 76%. Survival is better in children, possibly because of major biological differences between SS of adults and children [2]. In the setting of advanced disease, systemic chemotherapy with doxorubicin and/or ifosfamide is the standard of care. Median overall survival becomes close to 12–18 months [3, 4]. Therapeutic options in advanced SS remain an unmet clinical need
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