SARC037: A Phase I/II Study to Evaluate the Safety of Trabectedin in Combination With Irinotecan in Ewing Sarcoma Patients

Study Overview
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Brief Summary
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This study evaluates the trabectedin and irinotecan in the treatment of Ewings sarcoma, with a EWS-FLI1 mutation. Patients will also receive an infusion of 18F-FLT in combination with a Positron Emission Tomography (PET) scan to help evaluate the effect of treatment. Phase I was completed on 11/16/2022. Phase II is actively recruiting.

Detailed Description
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Trabectedin and Irinotecan may inhibit the activity of this Ewing sarcoma mutation. Trabectedin may suppress the proliferation of the gene involved in DNA damage response. It blocks EWS-FLI1 by inactivating the fusion protein and silences the target genes. Irinotecan also suppresses the genes regulating the tumor cells, generating DNA damage. Together, these drugs work in combination to suppress the gene regulating the tumor cells. This combination may suppress the activity of the tumor regulating genes, disrupting the activity of the genes. The infusion of 18F-FLT in combination with a Positron Emission Tomography (PET) scan will demonstrate whether the target cells have been suppressed.

Official Title
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SARC037: A Phase I/II Study to Evaluate the Safety of Trabectedin Administered as a 1-Hour Infusion in Ewing Sarcoma Patients in Combination With Low Dose Irinotecan and 3'-Deoxy-3'-18F Fluorothymidine (18F-FLT) Imaging

Conditions
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Ewing Sarcoma

Intervention / Treatment
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* Drug: Trabectedin 1 MG [Yondelis]
* Drug: Irinotecan
* Diagnostic Test: tumor biopsy
* Other: 3'-Deoxy-3'-18F Fluorothymidine (18F-FLT) Imaging


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: diagnosis of relapsed and refractory Ewing sarcoma with EWS-FLI1 fusion type for which there is no known therapy proving to prolong survival measurable disease ECOG Performance Status of 0-2 or Lansky of 50 adequate organ function written, voluntary consent willing to undergo tumor biopsy negative hepatitis infection Exclusion Criteria: prior therapy with trabectedin or lurbinectedin known history of hypersensitivity to irinotecan or topotecan or their excipients. known brain metastases known bleeding diathesis pregnant or breastfeeding currently receiving other investigational drugs or anticancer agents clinically significant unrelated illness or uncontrolled infection unable to comply with the safety monitoring requirements

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 99 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: Sequential Assignment
Interventional Model Description: This phase I study will follow a standard 3+3 design and the Phase II study will be a single-arm, mini-max Simon two-stage design.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Trabectedin and Irinotecan<br>Trabectedin will be delivered by infusion on day 1 followed by 2 doses on irinotecan delivered by infusion for one hour on day 2 and day 4 of 21 day cycles. Some patients will receive an 18F-FLT Imaging scan prior to the first administration of trabectedin and once after administration of trabectedin. | Drug: Trabectedin 1 MG [Yondelis]<br>* Patients with Ewing sarcoma will be administered trabectedin intravenously. Cycles are 21 days.<br>Drug: Irinotecan<br>* Patients with Ewing sarcoma will be administered inirotecan intravenously. Cycles are 21 days.<br>Diagnostic Test: tumor biopsy<br>* Tumor tissue samples will be collected collected at two timepoints. The first biopsy will be prior to treatment. If a biopsy is not possible archival tissue may be submitted. A second tumor biopsy will be taken fro consenting patients when possible after the first administration of Trabectedin to evaluate the effect on the tumor cells.<br>Other: 3'-Deoxy-3'-18F Fluorothymidine (18F-FLT) Imaging<br>* Some patients will receive PET scans with the use of 18F-FLT, a radioactive tracer, performed at the National Institute of Health.<br>* Other names: 18F-FLT Imaging;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase I The recommended dose (RD) of trabectedin administered in combination with low dose irinotecan | The recommended dose will be established by enrolling patients at the lowest dose and observing them for dose limiting toxicity. Dose limiting toxicity describes side effects of a drug or other treatment that are serious enough to prevent an increase in dose or level of that treatment. The maximum tolerated dose is the highest dose of a drug or treatment that does not cause unacceptable side effects. If 0 of the first 3 subjects experience DLT, the study will proceed to the next dose level. If 1 subject experiences a DLT, that dose level cohort will be expanded to 6 total subjects. If no additional subjects experience DLTs at that dose level cohort, the study will proceed to enroll the next dose level cohort. If ≥ 2 of 6 subjects experience DLT, then that dose level is the recommended dose of trabectedin (RD). The study will proceed to the same process for the irinotecan escalation. If 2 or all 3 subjects experience DLT, that dose level is the recommended dose of trabectedin (RD). | up to 36 months | 
| Phase I Tumor response rate | The anti-tumor activity of the combination of trabectedin and low-dose irinotecan as measured by the tumor objective response rate (ORR) assessed by RECIST v1.1 | up to 36 months | 
| Phase 2 To determine anti-tumor activity of the combination trabectedin and low-dose irinotecan | Tumor objective response rate (ORR) assessed by RECIST v1.1. | up to 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase I/Phase 2 Tumor response rate, progression-free survival (PFS), duration of response, and 6-month PFS rate of patients with ES treated with trabectedin and irinotecan. | The percentage of patients whose tumor shrinks or disappears after treatment (per RECIST 1.1), progression-free survival (PFS) of patients with ES treated with trabectedin and irinotecan. | up to 36 months | 
| Phase I monitor the avidity of Ewing sarcoma tumors of EWS-FLI1 12-24 hours after trabectedin administration and before irinotecan is administered and before 18F-FLT PET scans | 18F-FLT PET avidity of Ewing sarcoma tumors. | up to 36 months | 
| Phase 2 To determine anti-tumor activity of the combination trabectedin and low-dose irinotecan | The anti-tumor activity of the combination of trabectedin and low-dose irinotecan as measured by the tumor objective response rate (ORR) assessed by RECIST v1.1 | up to 36 months | 
| Phase I/Phase 2 Tumor response rate, progression-free survival (PFS), duration of response, and 6-month PFS rate of patients with ES treated with trabectedin and irinotecan. | The percentage of patients whose tumor shrinks or disappears after treatment (per RECIST 1.1) duration of response of patients with ES treated with trabectedin and irinotecan. | up to 36 months | 
| Phase I/Phase 2 Tumor response rate, progression-free survival (PFS), duration of response, and 6-month PFS rate of patients with ES treated with trabectedin and irinotecan. | The percentage of patients whose tumor shrinks or disappears after treatment (per RECIST 1.1) duration of 6-month PFS rate ES treated with trabectedin and irinotecan. | up to 36 months |