A Phase I Trial of TB-403 in Relapsed Medulloblastoma, Neuroblastoma, Ewing Sarcoma, and Alveolar Rhabdomyosarcoma

Abstract

Purpose: Placental growth factor (PlGF) and its receptor neuropilin 1 are elevated in malignant embryonal tumors and mediate tumor progression by promoting cell proliferation, survival, and metastasis. TB-403 is a blocking monoclonal antibody against PlGF that inhibits tumor growth and increases survival in orthotopic medulloblastoma models.

Patients and methods: We conducted a phase I, open-label, multicenter, dose-escalation study of TB-403 in pediatric subjects with relapsed or refractory cancers. The study involved four dose levels (20 mg/kg, 50 mg/kg, 100 mg/kg, 175 mg/kg) using a 3 + 3 dose-escalation scheme. Subjects received two doses of TB-403 (days 1 and 15) per cycle. After cycle 1, temozolomide or etoposide could be added. The primary objective was to determine the maximum tolerated dose (MTD) of TB-403 monotherapy during a dose-limiting toxicity assessment period. The secondary and exploratory objectives included efficacy, drug pharmacokinetics, and detection of pharmacodynamic biomarkers.

Results: Fifteen subjects were treated in four dose levels. All subjects received two doses of TB-403 in cycle 1. Five serious treatment-emergent adverse events were reported in 3 subjects, but MTD was not reached. While no complete nor partial responses were observed, 7 of 11 relapsed subjects with medulloblastoma experienced stable disease, which persisted for more than 100 days in 4 of 7 subjects.

Conclusions: TB-403 was safe and well tolerated at all dose levels. No MTD was reached. The results look encouraging and therefore warrant further evaluation of efficacy in pediatric subjects with medulloblastoma.

Conflict of interest statement

Conflict of Interest Statement

GSS serves on the scientific advisory boards for Y-mAbs Therapeutics, Illumina, and California Cryobank. JK serves on the scientific advisory board for Y-mAbs Therapeutics. RKJ serves as a consultant for Elpis, Innocoll, SPARC, SynDevRx and Twenty-eight-Sevan, owns equity in Accurius, Enlight and SynDevRx and serves on the Boards of Trustees of Tekla Healthcare Investors, Tekla Life Sciences Investors, Tekla Healthcare Opportunities Fund and Tekla World Healthcare Fund and received a grant from Boehringer-Ingelheim. DGD received consultant fees from Innocoll and has research grants from Bayer, Exelixis, BMS and Surface Oncology. ADD and LG are employees of Oncurious NV. The remaining authors have no further disclosures.

©2022 American Association for Cancer Research.

Figures

FIGURE 1.. Design of phase I study of TB-403 in pediatric cancers.

(A) Study Design Diagram. (B) Dose-Escalation Schema 3+3 design for determination of DLT driven up to MTD or SMD (175 mg/kg). All indications: MB, NB, ES, ARMS (Cohorts 1–3); MB only (Cohort 4).

FIGURE 2.

Response over time, as assessed by Central Review, by subject.

FIGURE 3.. Pharmacokinetic/pharmacodynamics analyses of TB-403.

(A) Area under the Curve (AUC) of subjects at each dose level. (B) Minimum, Median and Mean dose concentrations at each dose level. (C) Plasma free PIGF levels detected over time.