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.

• Authors: Giselle Saulnier-Sholler, Dan G Duda, Genevieve Bergendahl, David Ebb, Matija Snuderl, Theodore W Laetsch, Jennifer Michlitsch, Derek Hanson, Michael S Isakoff, Kevin Bielamowicz, Jacqueline M Kraveka, William Ferguson, Peter Carmeliet, A De Deene, Lore Gijsen, Rakesh K Jain
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 28 Issue 18 Pg. 3950-3957 (09 15 2022) ISSN: 1557-3265 [Electronic] United States
• PMID: 35833850 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: ©2022 American Association for Cancer Research.

Chemical References

• Antibodies, Monoclonal, Humanized
• Placenta Growth Factor
• TB-403

Topics

• Antibodies, Monoclonal, Humanized
• Brain Neoplasms
• Cerebellar Neoplasms
• Child
• Female
• Humans
• Maximum Tolerated Dose
• Medulloblastoma (drug therapy, pathology)
• Neuroblastoma (drug therapy)
• Placenta Growth Factor
• Rhabdomyosarcoma, Alveolar
• Sarcoma, Ewing