Volasertib

Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma. There are two main histological subtypes of pediatric RMS, alveolar RMS accounting for approximately 30% of RMS and embryonal RMS (approx. 70%).  A gene fusion between the PAX3 or PAX7 and FOXO1 genes is found in the majority of cases with alveolar RMS, and these fusion-positive diseases tend to be more aggressive and less amenable to treatment. Generally, these patients face a very poor prognosis and there is an urgent need for new therapeutic agents for this pediatric cancer. 

Volasertib is a highly potent Polo-like kinase 1 (PLK-1) inhibitor. PLK-1 is a key regulator of the cell cycle, is over-expressed in many cancers, and has been associated with poor survival. Volasertib has been studied as a single agent in Phase I in children with leukemia and refractory solid tumors. The recommended Phase 2 dose (RP2D) for children has been defined and lies above the adult RP2D. 

There is substantial preclinical evidence suggesting that volasertib might be an effective therapeutic agent against RMS. 

Two key novel mechanisms of action for PLK-1 inhibition have been identified for RMS:

  • PLK-1 inhibition directly reduces the activity and stability of the PAX3/7- FOXO1 fusion protein. Potential biomarkers of efficacy within the PAX3/7-FOXO1 fusion-positive cell line models have been identified

  • PLK-1 inhibition is synergistic in combination with microtubule-destabilizing agents such as vincristine. This synergism has been demonstrated in vitro for both fusion gene-positive and negative RMS

Oncoheroes is currently planning the clinical evaluation of volasertib in RMS and other pediatric indications in collaboration with international pediatric oncology networks. Clinical studies are expected to be launched in 2024.

Volasertib received Rare Pediatric Disease Designation (RPDD) and Orphan Drug Designation (ODD) from the United States Food and Drug Administration (FDA) in 2020.

  • RPDD: This designation qualifies Oncoheroes to receive fast track review, and a priority review voucher (PRV) at the time of marketing approval of volasertib. PRV holders can benefit from an expedited six-month review of a new drug application for any disease by the FDA.

  • ODD: FDA awards ODD to potential therapies addressing unmet needs of underserved patients with rare diseases. ODD may enable Oncoheroes to retain seven years of U.S. market exclusivity upon marketing approval and obtain partial tax credits for clinical trial expenditures.

References

Polo-like Kinase Inhibitor Volasertib Exhibits Antitumor Activity and Synergy with Vincristine in Pediatric Malignancies. Abbou S, Lanvers-Kaminsky C, Daudigeos-Dubus E, LE Dret L, Laplace-Builhe C, Molenaar J, Vassal G, Geoerger B; within the ITCC Biology and Preclinical Evaluation Committee. Anticancer Res. 2016 Feb;36(2):599-609. https://www.ncbi.nlm.nih.gov/pubmed/26851014 

Identification of synthetic lethality of PLK1 inhibition and microtubule-destabilizing drugs. Hugle M, Belz K, Fulda S. Cell Death Differ. 2015 Dec;22(12):1946-56. doi: 10.1038/cdd.2015.59. Epub 2015 May 29. https://www.ncbi.nlm.nih.gov/pubmed/26024389 

Initial testing (stage 1) of the Polo-like kinase inhibitor volasertib (BI 6727), by the Pediatric Preclinical Testing Program. Gorlick R, Kolb EA, Keir ST, Maris JM, Reynolds CP, Kang MH, Carol H, Lock R, Billups CA, Kurmasheva RT, Houghton PJ, Smith MA. Pediatr Blood Cancer. 2014 Jan;61(1):158-64. doi: 10.1002/pbc.24616. Epub 2013 Aug 19. https://www.ncbi.nlm.nih.gov/pubmed/23956067