TK216 in Patients With Relapsed or Refractory Ewing Sarcoma

A Phase 1 / 2, Dose Escalation Study of Intravenous TK216 in Patients With Relapsed or Refractory Ewing Sarcoma

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.

Study Overview

• Status: Terminated
• Conditions: Sarcoma, Ewing
• Intervention / Treatment: Drug: TK216

Detailed Description

The study has been expanded to explore single agent TK216 for longer treatment duration. Approximately 26 patients will be enrolled in this Cohort.

Please note: This study has been terminated and is no longer enrolling patients.

• Study Type: Interventional
• Enrollment (Actual): 85
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90095
      • UCLA Jonsson Comprehensive Cancer Center
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital of Colorado
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Children's National Hospital
  • New York
    • New York, New York, United States, 10174
      • Memorial Sloan Kettering Cancer Center
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke Cancer Institute
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Foundation
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science University
  • Texas
    • Houston, Texas, United States, 77030
      • UT MD Anderson Cancer Center
    • Houston, Texas, United States, 77030
      • Texas Children's Cancer & Hematology Centers, Baylor College

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 8 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

1. Major Inclusion Criteria (for all Study Parts or protocol versions unless specifically noted):

Patients who meet the following inclusion criteria will be eligible to participate in this study:

1. 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.

2. Have histologically or cytologically confirmed diagnosis of Ewing sarcoma (including ESFT) with relapsed or refractory disease

   1. who have failed standard therapy and for whom no known curative therapy exists (For Parts 1-3), OR
   2. 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.)
3. 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.
4. Must have a central venous catheter in place prior to initiating infusion of study drug.

5. Prior cancer therapy:

   1. Patients may have received any number of prior therapy regimens (For Parts 1-3) OR
   2. 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).

6. Prior radiotherapy is allowed

   1. 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
   2. 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).
7. Stem Cell Transplant or Rescue without TBI: No evidence of active graft vs. host disease and ≥ 3 months must have elapsed since transplant.
8. Patients with controlled asymptomatic CNS involvement are allowed.
9. Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 2 in patients ≥17 years old; or Karnofsky/Lansky >50 in patients <16 years old.

10. Age:

    a. Cohort 1: Patient's age >18 years old. b. Cohorts 2-6: Patients must be > 12 years old. c. Cohorts 7-10: Patients must be ≥ 10 years old. d. Cohort 11: Patient's age ≥ 8 years (For Part 4)

11. Life expectancy of at least 3 months.
12. Adequate organ function as measured by baseline laboratory values. 13. Cardiac ejection fraction > 50% or shortening fraction > 28%. 14. Females of child-bearing potential must have a negative pregnancy test (within 7-days of starting treatment) during screening and subjects must be willing to use effective contraception. be neither breastfeeding nor intending to become pregnant during study participation. Females of childbearing potential must agree to avoid pregnancy during the study and commit to abstinence from heterosexual intercourse or agree to use two methods of birth control (one highly effective method and one additional effective method) at least 4 weeks before the start of protocol therapy, for the duration of study participation, and for 6 months after the last dose of TK216. 15. Males with partner(s) of childbearing potential must take appropriate precautions to avoid fathering a child from the screening period until 90 days after receiving the last dose of TK216. They must commit to abstinence from heterosexual intercourse or agree to use appropriate barrier contraception.

16. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests and other study procedures.

Major Exclusion Criteria:

Patients will not be enrolled if they meet any one of the following exclusion criteria:

1. Current participation in another therapeutic clinical trial.
2. Symptomatic brain metastases.
3. 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.
4. 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.
5. 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

7. Use of concomitant medications that increase or possibly increase the risk to prolong the QTc interval and/or induce torsades de pointes ventricular arrhythmia.

8. 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: TK216 treatment; Dose escalation and expansion cohorts to determine dose-limiting toxicities, maximally tolerated dose, preliminary efficacy, and recommended phase 2 dose.	Drug: TK216; Inhibitor of protein-protein interactions of EWS-FLI1 fusion protein

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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

Secondary Outcome Measures

Outcome Measure	Time Frame
Adverse Events	18 months
Antitumor activity as measured by Overall Response Rate (ORR)	18 months
Antitumor activity as measured by Duration of Response (DOR)	18 months
Duration of Disease Control	18 months
Assay methods to detect EWS-FLI1 (or EWS-ERG and EWS-ets)	18 months
Pharmacokinetics: Maximum Plasma Concentration [Cmax]	18 months
Pharmacokinetics: Area Under the Curve [AUC]	18 months
Pharmacokinetics: Halflife [T1/2]	18 months
Pharmacodynamics: serum miRNA profile	18 months
Pharmacodynamics: tumor tissue RNA assays	18 months
Pharmacodynamics: tumor tissue protein assays	18 months

Collaborators and Investigators

• Sponsor: Oncternal Therapeutics, Inc
• Investigators: Study Director: James Breitmeyer, MD, Oncternal Therapeutics

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2016
• Primary Completion (Actual): May 1, 2022
• Study Completion (Actual): June 1, 2022

Study Registration Dates

• First Submitted: January 12, 2016
• First Submitted That Met QC Criteria: January 13, 2016
• First Posted (Estimated): January 15, 2016

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 29, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neoplasms, Connective and Soft Tissue; Neuroectodermal Tumors, Primitive; Osteosarcoma; Neoplasms, Bone Tissue; Neoplasms, Connective Tissue; Sarcoma, Ewing; Sarcoma; Neuroectodermal Tumors, Primitive, Peripheral
• Other Study ID Numbers: TK216-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO