TK216 in Patients With Relapsed or Refractory Ewing Sarcoma

NCT02657005 | Terminated Phase 1 Results

• 1 other identifier: TK216-01
• Study Type: interventional
• Target: 85
• Locations: 1 country
• Sites: 9

Brief Summary

Ewing sarcoma is characterized by genomic rearrangements resulting in over-expression of ets family transcription factors driving tumor progression. TK216 is designed to inhibit this effect by inhibiting downstream effects of the EWS-FLI1 transcription factor. This study is a first in human study of TK216 in subjects with Ewing sarcoma. The study is designed to establish initial safety and efficacy data in monotherapy and in combination with vincristine to assess the potential of TK216 for further development.

Conditions

Sarcoma, Ewing

Outcome Measures

Primary Outcomes (1)

• Overall Response Rate

  Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions and pathologic lymph nodes; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions, no new lesions, and no progression of non-target lesions; Overall Response (OR) = CR + PR.

  36 months

Study Arms (1)

TK216 treatment

EXPERIMENTAL

Dose escalation and expansion cohorts to determine dose-limiting toxicities, maximally tolerated dose, preliminary efficacy, and recommended phase 2 dose.

Drug: TK216

Interventions

TK216 DRUG

Inhibitor of protein-protein interactions of EWS-FLI1 fusion protein

TK216 treatment

Eligibility Criteria

• Age: 8 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Willing and able to provide written IRB/IEC-approved Informed Consent. For patients \< 18 years of age, their parent or legal guardian must sign a written informed consent. Assent, when appropriate, will be obtained according to institutional guidelines.
• Have histologically or cytologically confirmed diagnosis of Ewing sarcoma (including ESFT) with relapsed or refractory disease
• who have failed standard therapy and for whom no known curative therapy exists (For Parts 1-3), OR
• patients with metastatic disease who had standard chemotherapy at the time of diagnosis (For Part 4) (NOTE: as of Protocol version 7, pathology reports and slides or blocks should be available for review or additional testing. If not available, site must discuss with Sponsor.)
• Measurable disease according to RECIST version 1.1. Measurable disease can be verified from a previously documented CT scan or MRI as long as no anti-cancer treatments have been administered in the interim.
• Must have a central venous catheter in place prior to initiating infusion of study drug.
• Prior cancer therapy:
• Patients may have received any number of prior therapy regimens (For Parts 1-3) OR
• Patients may have received no more than 5 prior systemic regimens. At the time of treatment initiation, at least 2 weeks or 5 half-lives, whichever is longer, must have elapsed since prior cytotoxic chemotherapy. At least 7 days must have elapsed since completion of any prior non-cytotoxic cancer therapy (For Part 4).
• Prior radiotherapy is allowed
• If ≥ 2 weeks have elapsed for local palliative XRT (small port); ≥ 6 months must have elapsed if prior total body irradiation, craniospinal XRT or if \> 50% radiation of the pelvis; \> 6 weeks must have elapsed if other substantial bone marrow radiation. Patients who have received brain irradiation must have completed whole brain radiotherapy and/or gamma knife at least 4 weeks prior to enrollment (For Parts 1-3) OR
• If ≥ 4 weeks has elapsed for radiation therapy (RT); ≥ 6 months must have elapsed if prior total body irradiation, craniospinal RT or if \> 50% radiation of the pelvis; \> 6 weeks must have elapsed if other substantial bone marrow radiation. Patients who have received brain irradiation must have completed whole brain radiotherapy and/or gamma knife at least 4 weeks prior to enrollment (For Part 4).
• Stem Cell Transplant or Rescue without TBI: No evidence of active graft vs. host disease and ≥ 3 months must have elapsed since transplant.
• Patients with controlled asymptomatic CNS involvement are allowed.
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 2 in patients ≥17 years old; or Karnofsky/Lansky \>50 in patients \<16 years old.

You may not qualify if:

• Current participation in another therapeutic clinical trial.
• Symptomatic brain metastases.
• History of previous cancer (non ES), except squamous cell or basal-cell carcinoma of the skin or any in situ carcinoma that has been completely resected, which required therapy within the previous 3 years.
• Any of the following in the past 6 months: symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack, pulmonary embolism, deep vein thrombosis, symptomatic bradycardia, requirement for antiarrhythmic medication.
• History of prolonged QTc interval (e.g., repeated demonstration of a QTc interval \> 450 milliseconds, unless associated with the use of medications known to prolong the QTc interval). (NOTE: For Part 4, repeated demonstration of a QTc interval \> 470 milliseconds) 6. History of additional risk factors for torsade de pointes (e.g., heart failure, family history of long QT syndrome
• \. Use of concomitant medications that increase or possibly increase the risk to prolong the QTc interval and/or induce torsades de pointes ventricular arrhythmia.
• \. Females who are breastfeeding/lactating. 9. Known active infections (bacterial, fungal, viral including hepatitis and HIV positivity). 10. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the patient inappropriate for entry into this study or could compromise protocol objectives in the opinion of the Investigator and/or the Sponsor.

Sponsors & Collaborators

• Oncternal Therapeutics, Inc: lead

Study Sites (9)

UCLA Jonsson Comprehensive Cancer Center

Los Angeles, California, 90095, United States

Location

Children's Hospital of Colorado

Aurora, Colorado, 80045, United States

Location

Children's National Hospital

Washington D.C., District of Columbia, 20010, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10174, United States

Location

Duke Cancer Institute

Durham, North Carolina, 27710, United States

Location

Cleveland Clinic Foundation

Cleveland, Ohio, 44195, United States

Location

Oregon Health & Science University

Portland, Oregon, 97239, United States

Location

Texas Children's Cancer & Hematology Centers, Baylor College

Houston, Texas, 77030, United States

Location

UT MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Related Publications (1)

• Meyers PA, Federman N, Daw N, Anderson PM, Davis LE, Kim A, Macy ME, Pietrofeso A, Ratan R, Riedel RF, Trucco M, Breitmeyer JB, Toretsky JA, Ludwig JA. Open-Label, Multicenter, Phase I/II, First-in-Human Trial of TK216: A First-Generation EWS::FLI1 Fusion Protein Antagonist in Ewing Sarcoma. J Clin Oncol. 2024 Nov;42(31):3725-3734. doi: 10.1200/JCO.24.00020. Epub 2024 Jul 2.

  PMID: 38954782 RESULT

MeSH Terms

Conditions

Sarcoma, Ewing

Condition Hierarchy (Ancestors)

Osteosarcoma; Neoplasms, Bone Tissue; Neoplasms, Connective Tissue; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Sarcoma

Limitations and Caveats

TK216 was advanced as a novel inhibitor of EWS::FLI1 despite pharmacologic challenges to creating an oral formulation. In vivo studies showed that continuous exposure to TK216 was required for optimal efficacy.47 This continuous infusion was a logistical challenge and negatively affected study enrollment rates. Another limitation of this study was the lack of a pharmacodynamic readout of TK216 activity.

Results Point of Contact

• Title: Mary Breitmeyer
• Organization: Oncternal Therapeutics

clinical@oncternal.com

858-434-1113

Study Officials

• James Breitmeyer, MD

  Oncternal Therapeutics

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 12, 2016
• First Posted: January 15, 2016
• Study Start: August 1, 2016
• Primary Completion: May 1, 2022
• Study Completion: June 1, 2022
• Last Updated: February 12, 2025
• Results First Posted: November 7, 2024

Record last verified: 2025-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (9)