A first-in-human study investigating biodistribution, safety and recommended dose of a new radiolabeled MAb targeting FZD10 in metastatic synovial sarcoma patients

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.

Wnt signaling in cancer: therapeutic targeting of Wnt signaling beyond β-catenin and the destruction complex

“…OTSA101 is a humanized monoclonal antibody against FZD10. OTSA101-DTPA-90Y (NIH clinical trial number [clinicaltrials.gov] NCT01469975) is labeled with a β-radiation deliveringyttrium Y90 for OSTA101 84 . OTSA101-DTPA-90Y selectively killed cancer cells highly expressing FZD10.…”

Wnt signaling in breast cancer: biological mechanisms, challenges and opportunities

“…In addition, OTSA101-DTPA- 111 In and OTSA101-DTPA- 90 Y are humanized chimeric anti-Fzd10 antibodies (named OTSA-101) that are radiolabeled with Indium 111 and Yttrium 90, respectively. OTSA101-DTPA- 111 In is a promising Fzd10-targeted single-photon emission computed tomography (SPECT) imaging agent, while OTSA101-DTPA- 90 Y is a potent Fzd10-targeted agent for metastatic synovial sarcoma radiotherapy [ 420 , 421 ]. Salinomycin is an FDA-approved supplement in poultry feed and kills BCSCs selectively [ 424 ].…”

Feasibility of Targeting Traf2-and-Nck-Interacting Kinase in Synovial Sarcoma

“…Frizzled homolog 10 (FZD10) has attracted attention as a promising therapeutic target for synovial sarcoma [33], as its expression is limited to the cell membrane of synovial sarcoma and absent from vital organs [34]. A recent first-in-human clinical trial clarified the biodistribution, safety, and recommended dose of a radiolabeled humanized monoclonal antibody to FZD10 [35], but its efficacy has not been established.…”