TK216 in Patients With Relapsed or Refractory Ewing Sarcoma

Study Overview
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Brief Summary
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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.

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

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

Conditions
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Sarcoma, Ewing

Intervention / Treatment
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* Drug: TK216


Participation Criteria
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Eligibility Criteria
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Willing and able to provide written IRB/IEC-approved Informed Consent. For patients < 18 years of age, their parents or legal guardians 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. Patients with metastatic disease who had standard chemotherapy at the time of diagnosis 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 computed tomography (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 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. Prior radiotherapy is allowed 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. 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 (see Concomitant Medications). Patients not requiring steroids or requiring steroids at stable dose (≤ 4 mg/day dexamethasone or equivalent) for at least 2 weeks are eligible. Resolution of all acute toxic effects (excluding alopecia) of any prior anti-cancer therapy to NCI CTCAE (Version 4.03) Grade < 1. Details can be provided by Sponsor. Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 2 in patients ≥17 years old; or Karnofsky/Lansky >50 in patients <16 years old. Life expectancy of at least 3 months.

Ages Eligible for Study
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Minimum Age: 8 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-limiting toxicities (DLTs) | Listing of dose-limiting toxicities by daily dose in mg/m^2 | 18 months | 
| Maximum tolerated dose (MTD) | Maximum daily dose in mg/m^2 | 18 months | 
| Biologically effective and recommended Phase 2 dose (RP2D) | Daily dose in mg/m^2 | 18 months | 
| Number of participants with treatment-related adverse events as assessed by CTCAE. | Daily dose of 175 mg/m2/day of TK216 administered intravenously via continuous infusion over 28-days | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | 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 |