Pilot Study of Recurrent Ewing's Sarcoma Management with Vigil/Temozolomide/Irinotecan and Assessment of Circulating Tumor (ct) DNA

Abstract

Purpose: Treatment options for recurrent or refractory Ewing's sarcoma (ES) are limited. Vigil is a novel autologous tumor cell therapy expressing bi-shRNA furin/GMCSF plasmid, which previously demonstrated monotherapy activity in advanced ES. Herein we report safety and evidence of benefit to Vigil for ES as potential treatment.

Patients and methods: In this pilot trial, eligible patients with recurrent or refractory ES who failed initial standard-of-care therapy received treatment with temozolomide (TEM) 100 mg/m2/day oral and irinotecan (IRI) 50 mg/m2/day oral, Days 1 to 5, in combination with Vigil (1 × 106-107 cells/mL/day intradermal, Day 15), every 21 days (Vigil/TEM/IRI). Objective response rate (ORR) by RECIST v1.1, progression-free survival (PFS), and overall survival (OS) were assessed. Circulating tumor (ct) DNA analysis was done by patient-specific droplet digital PCR on baseline and serially collected on-treatment samples.

Results: Eight of 10 enrolled patients were evaluable for safety and efficacy (mean age 24.6; 12.6-46.1 years old); 2 did not receive Vigil. Seven of 8 patients previously received TEM/IRI. No Vigil-related adverse events were reported. Common ≥Grade 3 chemotherapy-related toxicity included neutropenia (50%) and thrombocytopenia (38%). We observed two partial response patients by RECIST; both showed histologic complete response without additional cancer therapy. Median PFS was 8.2 months (95% confidence interval, 4.3-NA). Five patients showed stable disease or better for ≥6 months. Patient-specific EWS/FLI1 ctDNA was detectable in all 8 evaluable patients at baseline. Changes in ctDNA levels corresponded to changes in disease burden.

Conclusions: Results demonstrated safety of combination Vigil/TEM/IRI.

Figure 1.

Swimmers plot of all patients (n = 8). Yellow arrows indicate patients who are still alive.

Figure 2.

Monitoring of ctDNA percent levels (black) and tumor burden volume (blue) during the treatment course for all patients. Correlation of tumor response was demonstrated with ctDNA reduction and image (PET/CT) guidance. Vigil was administered on day 1 of each cycle. EOT, end of treatment; FU, 3-month follow up; Rx, palliative radiotherapy.

Figure 3.

Monitoring of tumor burden (PET/CT) in EW-167–3006. Target lesions in PET/CT scans are marked with white arrows. Tumor volumes in the left upper lung (A–D) and left diaphragm (E–H) are shown at baseline (A, E), month 3 (B, F), month 6 (C, G), and end of treatment (EOT; D, H). The biopsy of the bony pelvic lesion (I) showed a histologic CR with necrotic tissue and without any evidence of live tumor cells (J). Tumor volumes of all target lesions are shown in K.

Figure 4.

Monitoring of tumor burden (CT and PET/CT) in EW-167–3003. Right lower lung lesions (A–C) are marked with yellow arrows in CT scans at baseline (A), month 3 (B), and month 6 (C) of treatment. Posterior chest wall/spleen lesions (D–H) are also marked with yellow arrows in CT scans (D, F, H) or yellow arrows in PET/CT scans (E, G) at baseline (D, E), month 3 (F, G), and month 6 (H) of treatment. Tumor volumes of target lesions are shown in I. Autopsy report showed a histological CR without any evidence of live tumor cells.