FDA Grants Orphan Drug Status to TP-1287 for Ewing Sarcoma

The FDA granted an orphan drug designation for TP-1287, an investigational oral CDK9 inhibitor, for the treatment of patients with Ewing sarcoma, according to Sumitomo Pharma Oncology, Inc.¹

"TP-1287 exhibits potent inhibition of intracellular kinases including CDK9. Inhibition of CDK9 leads to downregulation of key antiapoptotic proteins such as MCL-1, which in turn has been shown to inhibit tumor growth in preclinical models of hematologic malignancies and several tumor types," said Jatin J. Shah, MD, chief medical officer of Sumitomo Pharma Oncology, Inc, in a press release.

TP-1287 is an investigational oral phosphate prodrug of the CDK9 inhibitor alvocidib and is hydrolyzed enzymatically to yield alvocidib. Alvocidib attaches at the ATP-binding site of CDK9 and stops phosphorylation by CDK9 which then prevents productive transcription and causes reduction of messenger RNA (mRNA) in genes, including c-MYC and MCL-1. In addition, the downregulationof c-MYC and MCL-1 transcription causes apoptosis in a variety of tumor cells.

Previously, the FDA also granted TP-1287 a rare pediatric disease designation for the treatment of patients with Ewing sarcoma.

Currently, an open-label, dose-escalation, dose-expansion, phase 1 study is assessing the safety, pharmacokinetics, and pharmacodynamics of treatment with TP-1287 by oral administration in patients with advanced metastatic or progressive solid tumors (NCT03604783).²

For the first part of the study, the dose-escalation portion, patients with a histologically confirmed diagnosis of advanced metastatic or progressive solid tumor who are refractory to, or intolerant of, established therapy known to provide clinical benefit for their condition will be included. In part 2, the dose-expansion portion, patients must have histologically confirmed locally advanced or metastatic unresectable Ewing sarcoma and have received at least 1 prior line, but no more than 5 prior lines of treatment, including an anthracycline. Enrollmetn in the trial for both parts is also open to patients with 1 or more measurable tumors, an ECOG performance status of 0-1, and acceptable liver function, renal function, hematologic status, and coagulation status.

During the dose-escalation portion of the study, investigators will determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of oral TP-1287 and establish the recommended phase 2 dose (RP2D) for future studies with TP-1287 as the primary end points. Secondary end points for this part of the trial are to assess pharmacokinetics, pharmacocdynamics, and evidence of antitumor activity.

Then in the second part of the study, the dose-expansion portion, primary end points are to evaluate the preliminary antitumor activity of TP-1287 in terms of objective response rate (ORR) when administered at the RP2D, and to evaluate the preliminary antitumor activity of TP-1287 in terms of clinical benefit rate (CBR) at week 16 when administered at the RP2D. The secondary end points in the dose-expansion portion are to determine the median progression-free survival rate and safety of TP-1287.

"We are delighted to have received this designation for TP-1287 which underscores the need for additional treatment options for patients with Ewing sarcoma," said Patricia S. Andrews, chief executive officer and global head of oncology, Sumitomo Pharma Oncology, Inc, in the press release. "We recognize the unmet need for novel treatments in this disease state and are excited to contribute to the advancement of this research with the goal of helping to improve patient outcomes."

REFERENCE:

1. Sumitomo pharma oncology receives orphan drug designation for TP-1287, an investigational oral CDK9 inhibitor for the treatment of ewing sarcoma. News release. Sumitomo Pharma Oncology, Inc. April 10, 2023. Accessed April 10, 2023. https://prn.to/3KOKhBm

2. Phase 1, first-in-human study of oral TP-1287 in patients with advanced solid tumors. ClinicalTrials.gov Updated December 13, 2023. Accessed April 10, 2023. https://clinicaltrials.gov/ct2/show/NCT03604783?term=NCT03604783&draw=2&rank=1