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

FDA

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

TP-1287 is currently being evaluated in a first-in-human phase 1 trial (NCT03604783) in patients with advanced metastatic or progressive solid tumors who are refractory to, or intolerant of, standard therapy associated with clinical benefit.²

“We are delighted to have received this designation for TP-1287 which underscores the need for additional treatment options for patients with Ewing sarcoma,” Patricia S. Andrews, chief executive officer and global head of oncology at Sumitomo Pharma Oncology, Inc., said in a press release.¹ “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.”

TP-1287 is an investigational oral phosphate prodrug of the CDK9 inhibitor alvocidib. TP-1287 is hydrolyzed enzymatically to produce alvocidib, which binds at the ATP-binding site of CDK9, inhibiting phosphorylation by CDK9. This binding stops productive transcription, leading to reduced messenger RNA in genes such as c-MYC and MCL-1. Downregulation of c-MYC and MCL-1 transcription leads to tumor cell death.

Previously reported data from the first-in-human phase 1 trials showed that TP-1287 demonstrated tolerability as a single agent in patients with heavily pretreated, relapsed/refractory solid tumors.² A total of 22 patients who were enrolled between December 2018 and January 2020 received TP-1287 at doses ranging from 1 mg once daily to 11 mg twice daily across 7 cohorts.

Of the 20 patients evaluable for analysis at data cutoff, investigators showed that plasma pharmacokinetic C_max and area under the curve (AUC) increased in almost linear fashion in cohorts 1 through 6, reaching 80 ng/mL and 499.3 ng*h/mL in cohort 6 for C_max and AUC, respectively. Additionally, treatment with TP-1287 led to dose-dependent reductions of phospho-RNA Pol II, consistent with CDK9 inhibition, as measured by a flow cytometric assay assessing pharmacodynamic changes in phosphorylation state in peripheral blood mononuclear cells.

Regarding safety, the most common grade 3 adverse effect (AE) was unrelated anemia in 2 patients. All other grade 3 (n = 9) and grade 4 (n = 1) AEs were also deemed unlikely related or unrelated to TP-1287.

Clinical benefit was seen in one patient with sarcoma who experienced partial response with 15+ cycles, one patient with renal cell carcinoma who experienced stable disease (SD) with 7+ cycles, and 2 patients with bladder cancer who experienced SD with 6 and 8 cycles, respectively.

The open-label, dose-escalation, dose-expansion trial is evaluating the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of oral TP-1287 in patients with advanced metastatic or progressive solid tumors who are refractory to, or intolerant of, established therapy known to provide clinical benefit for their disease.

To be eligible for inclusion in the dose-escalation phase, patients must have a histologically confirmed diagnosis of advanced metastatic or progressive solid tumor excluding tumor types with rapid cell turnover including lung and extra pulmonary small cell cancer, inflammatory breast cancer, medulloblastoma, neuroblastoma, and melanoma with extensive liver metastasis with at least 50% liver involvement. Patients with melanoma and metastasis to less than 50% of the liver are eligible.³

For inclusion in the dose-expansion phase, patients must have histologically confirmed locally advanced or metastatic unresectable Ewing sarcoma and have received at least 1 but no more than 5 prior lines of therapy including an anthracycline. Additionally, patients must have measurable disease per RECIST v1.1 criteria, an ECOG performance status of 0 or 1, a life expectancy of at least 3 months, and acceptable liver, renal, hematologic, and coagulation function.

In November 2021, Sumitomo announced that the first patient had been dosed in the phase 1 dose-expansion portion of the trial.4 The primary objective of the phase 1 dose-expansion portion of the study is to evaluate the preliminary antitumor activity of TP-1287 measured by objective response rate at the recommended phase 2 dose (RP2D) in patients with different subtypes of sarcoma. The secondary objectives are to determine the progression-free survival and evaluate the safety of TP-1287 when administered at the RP2D in this population.

“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.¹

References

1. Sumitomo Pharma Oncology receives orphan drug designation for TP-1287, an investigational rral CDK9 inhibitor for the treatment of Ewing sarcoma. News release. April 10, 2023. Accessed April 14, 2023. https://oncology.sumitomo-pharma.com/news-media/20230410/
2. George B, Richards DA, Edenfield WJ, et al. A phase I, first-in-human, open-label, dose-escalation, safety, pharmacokinetic, and pharmacodynamic study of oral TP-1287 administered daily to patients with advanced solid tumors. J Clin Oncol. 2020;38(suppl 15):3611. doi:10.1200/JCO.2020.38.15_suppl.3611
3. Phase 1, first-in-human study of oral TP-1287 in patients with advanced solid tumors. ClinicalTrials.gov. Updated December 13, 2022. Accessed April 14, 2023. https://www.clinicaltrials.gov/ct2/show/NCT03604783
4. Sumitomo Dainippon Pharma Oncology announces first patient dosed in phase 1 dose expansion study of TP-1287 in patients with sarcoma. News release. Sumitomo Dainippon Pharma Oncology. November 3, 2021. Accessed April 14, 2023. https://oncology.sumitomo-pharma.com/news-media/20211103/