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

Abstract

Background: Synovial 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.

Methods: Patients 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.

Results: From 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.

Conclusions: Radioimmunotherapy 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 registration: The study was registered on the NCT01469975 website with a registration code NCT01469975 on November the third, 2011.

Keywords: First-in-human trial; Radioimmunotherapy; Synovial sarcoma; Theranostic.

Conflict of interest statement

Ethics approval and consent to participate

This clinical trial protocol and amendments was approved by French competent Authority, ANSM on 12th October 2011 and by French Ethic committee (CPP Sud-Est IV, Lyon, France) on 13th September 2011 and conducted in accordance with International Conference on Harmonization for Good Clinical Practice, and local regulations (European Directive 2001/20/EC). All patients provided written informed consent. The study was registered on the clinicaltrial.gov website (NCT01469975).

Consent for publication

The manuscript does not contain data from any individual person and it is not applicable in this section.

Competing interests

Chicaco Iwao-Fukukawa; Masaharu Mori, Takuya Tsunoda, Toyomasa Katagiri, Yusuke Nakamura were/are employees of Oncotherapy Science (Japan).

Simon Baconnier was also an employee of OTS France.

The remaining authors declare no competing interest with the study data.

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Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1

Consort diagram

Fig. 2

111In-OTSA-101 visual uptake grading. Examples of 111In-OTSA-101 tumors uptake visualized in 3 patients on planar imaging (a) and assessed using visual scale applied on SPECT-CT acquisitions (b)

Fig. 3

111In-OTSA-101 whole body planar scintigraphy repeated over time for patient 8 showing increasing lesions uptake compare to mediastinal blood pool

Fig. 4

111In-OTSA-101 SPECT-CT images performed at H72 in patient 3 showing a grade 2 lesion in the right lower lung lobe (a) and a grade 4 lesion in the left lower lung lobe (b)

Fig. 5

Response to treatment assessed for each patient on time to disease progression in weeks after 90Y-OTSA-101 injection