On September 21, 2020 Oncternal Therapeutics, Inc. (Nasdaq: ONCT), a clinical-stage biopharmaceutical company focused on the development of novel oncology therapies, reported the presentation of interim clinical data from its ongoing Phase 1 clinical trial evaluating TK216, an investigational, potentially first-in-class, targeted small-molecule inhibitor of the E26 transformation-specific (ETS) family of oncoproteins, in patients with relapsed or refractory Ewing sarcoma (Press release, Oncternal Therapeutics, SEP 21, 2020, View Source [SID1234565438]). Joseph A Ludwig, M.D., Associate Professor in the Department of Sarcoma Medical Oncology at The University of Texas MD Anderson Cancer Center, presented the results in an oral presentation at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Virtual Congress 2020 on September 20, 2020.

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"I am very encouraged by the complete responses to TK216 in these two heavily pre-treated patients with Ewing sarcoma," said Dr. Ludwig. "Advanced, refractory Ewing sarcoma is a serious and devastating condition, with no approved therapies, and novel therapeutic approaches are desperately needed. These positive interim clinical results suggest that TK216 holds promise for patients with Ewing sarcoma with no alternatives and poor prognoses."

This ongoing clinical trial is a first-in-human, multicenter Phase 1 study of TK216 in patients with relapsed or refractory Ewing sarcoma. Trial objectives include the evaluation of safety, tolerability, pharmacokinetics, and tumor response. Patients entering the trial had previously been treated with a median of three, and as many as eleven prior lines of systemic therapy. TK216 has been generally well tolerated in this trial, with common side effects including myelosuppression, fatigue, nausea and alopecia. Dose limiting toxicities consisted of transient and manageable myelosuppression, primarily neutropenia. No unexpected off-target toxicities have been observed. The recommended Phase 2 dose (RP2D) has been established to be 200 mg/m2/day of TK216 for 14 days in combination with vincristine chemotherapy dosed at 0.75 mg/m2 on the first day of each treatment cycle.

Key Updates: The presentation included interim data for 15 evaluable patients treated at the RP2D as of the August 13, 2020 cut-off date. Two of the 15 patients have now achieved complete responses (CR), including one surgical CR. One of these patients was previously categorized as a partial responder after two treatment cycles and converted to a complete response after his 6th cycle. Five patients had stable disease (SD), for a disease control rate (CR, partial response or SD) of 47%.

The first patient achieving a CR initially presented with metastatic Ewing sarcoma involving the clavicle and lungs and had received four prior lines of systemic therapy as well as surgery and radiation and was progressing when he enrolled in this clinical trial. The patient experienced a deep and sustained partial clinical response following two cycles of TK216 alone, with resolution of all target lung metastases. After six months of treatment that included concomitant vincristine starting in the third cycle, a single 7 mm lung nodule was resected, resulting in a surgical complete remission. The patient remains on treatment, with no evidence of disease, at about 1.5 years in this clinical trial.

The second patient achieving a CR initially presented with metastatic Ewing sarcoma involving the kidney area and lungs. He relapsed following initial chemotherapy, radiation, and surgery before enrolling in this clinical trial. The patient achieved a partial response with a 90% reduction of all lesions following two cycles of therapy and achieved a complete response after six cycles. The patient remains on treatment, with no evidence of disease at about seven months in this clinical trial.

Pharmacokinetic data from the clinical trial showed that TK216 drug levels at the RP2D exceeded plasma levels associated with anti-tumor activity in preclinical models.

"We are excited by the deepening clinical responses over time, with now two complete responses reported for patients with Ewing sarcoma treated with TK216," said James Breitmeyer, M.D., Ph.D., President and CEO, Oncternal. "Enrollment in the expansion cohort of this clinical trial has accelerated despite the COVID-19 pandemic, and we plan to present additional data from over 16 patients with relapsed/refractory Ewing sarcoma treated at the RP2D at a scientific conference in the fourth quarter of 2020."

About TK216

TK216 is an investigational, potentially first-in-class, targeted small-molecule inhibitor of the E26 transformation-specific (ETS) family of oncoproteins including fusion proteins. Tumorigenic fusion proteins involving the EWS protein and an ETS protein can be found in most cases of Ewing sarcoma. ETS-related translocations or overexpression are also found in many other tumors such as prostate cancer and acute myeloid leukemia (AML). TK216 was developed based on discoveries in the laboratory of Jeffrey Toretsky, M.D., at Georgetown Lombardi Comprehensive Cancer Center, who discovered inhibitors of EWS-FLI1 using a novel chemical screening assay. In preclinical models, TK216 was observed to bind to EWS-FLI1, blocking the interaction between this fusion protein and other transcriptome proteins such as RNA helicase A, leading to tumor cell apoptosis and inhibiting tumor growth in animal models. The U.S. Food and Drug Administration (FDA) has granted Orphan Designation and Fast Track designation to TK216 for the treatment of Ewing sarcoma. TK216 is an investigational medication that has not been approved by the FDA for any indication.

About the Study

TK216 is being evaluated in a Phase 1 clinical study as a single agent and in combination with vincristine in patients with relapsed or refractory Ewing sarcoma, a rare pediatric cancer with no standard treatment available after first-line chemotherapy. The dose-finding portion of the study is complete, and patients are now being enrolled in the expansion cohort. This multi-center study is actively enrolling patients at nine clinical trial centers across the U.S. Additional information about the TK216 study may be accessed at ClinicalTrials.gov (NCT02657005).