Silmitasertib Gets Fast Track Status for Recurrent Sonic Hedgehog–Driven Medulloblastoma

FDA

The FDA has granted a fast track designation to the highly selective CK2 inhibitor silmitasertib (CX-4945) as a potential therapeutic option for patients with recurrent sonic hedgehog (SHH)–driven medulloblastoma, according to an announcement from Senhwa Biosciences, Inc.¹

CK2 is a protein kinase that has elevated activity in several cancers and a key role in DNA damage repair.² It is known that DNA repair pathways permit cancer cells to survive damage from treatment with chemotherapy drugs. As such, inhibitors of this pathway have been found to boost the efficacy experienced with DNA-damaging chemotherapeutics when used in combination regimens.

Data from prior studies have shown that silmitasertib has favorable safety, pharmacokinetic characteristics, and pharmacodynamics responses. The agent targets CK2 and has been shown to control the expected pathways without toxicity. Silmitasertib has produced clinical benefit as a monotherapy and in combination with drugs such as gemcitabine and cisplatin. The drug acts synergistically to improve the efficacy reported with these DNA-damaging agents.

“We are delighted to receive fast track designation and look forward to working closely with the FDA to accelerate the development of silmitasertib, aiming to promptly bring a meaningful treatment to patients with recurrent SHH-driven medulloblastoma,” Tai-Sen Soong, chief executive officer of Senhwa Biosciences, Inc., stated in a press release.

The agent is under examination in a Pediatric Brain Tumor Consortium–sponsored multicenter phase 1/2 trial (NCT03904862) in children and adult patients with recurrent medulloblastoma who may or may not undergo surgery.³

To be eligible for inclusion on the phase 1 portion of the trial, patients need to be skeletally immature at the time of enrollment; this means females need to have a bone age of less than 14 years and males need to have a bone age of less than 16 years. Patients must be at least 3 years and as old as 18 years.⁴ Investigators seek to enroll 6 to 10 skeletally immature patients per year.

The primary goal of this portion of the research is to estimate the maximum-tolerated dose (MTD) and/or the recommended phase 2 dose (RP2D), to describe the safety profile and define the dose-limiting toxicities, and to characterize the pharmacokinetics profile. A key secondary end point will focus on documenting preliminary antitumor activity.

The surgical cohort of the trial is anticipated to ensure 2 to 3 patients annually. To eligible for enrollment, patients need to be clinically indicated for surgical resection, be at least 3 years of age, and be amenable to receiving silmitasertib for 5 to 7 days before the procedure.

Here, the primary end point is to characterize the concentrations of the drug in the tumor following administration of the agent and surgical resection. An important secondary focus is to evaluate the ability of silmitasertib at the MTD and/or RP2D to inhibit CK2-mediated signaling in the tumor.

The phase 2 portion of the research will enroll 10 to 12 skeletally mature patients annually. Skeletal maturity is defined as females with a bone age of 14 years or older and males with a bone age of 16 years or older, or a chronological age of over 18 years. Patients must also have bi-dimensionally measurable disease.

Here, investigators will establish the safety of the agent when given at a twice-daily dose of 1000 mg/m² and to examine the objective response rate achieved in these patients. Investigators will also characterize the pharmacokinetics of the drug and to conduct genomic analyses.

References

1. Senhwa’s silmitasertib receives US FDA fast track designation for the treatment of recurrent sonic hedgehog driven medulloblastoma. News release. August 18, 2021. Accessed August 25, 2021. https://prn.to/3gxUjax
2. Silmiasedrtib CX-4945. Senhwa Biosciences, Inc. Accessed August 25, 2021. https://bit.ly/3zhOyW5
3. Silmitasertib: CX-4945-MB. Senhwa Biosciences, Inc. Accessed August 25, 2021. https://bit.ly/3gyD2ht
4. Testing the safety and tolerability of CX-4945 in patients with recurrent medulloblastoma who may or may not have surgery. ClinicalTrials.gov. Updated June 22, 2020. Accessed August 25, 2021. https://clinicaltrials.gov/ct2/show/NCT03904862