U01CA236220: SARC037: A Phase I Study to Evaluate the Safety of Trabectedin in Combination With Irinotecan in Ewing Sarcoma Patients

Study Details

Study Description

Brief Summary

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.

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

Detailed Description

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

45 participants

Allocation:

N/A

Intervention Model:

Sequential Assignment

Intervention Model Description:

This phase I study will follow a standard 3+3 design to determine the recommended dose of trabectedin given as a 1-hour infusion in combination with low dose irinotecan.This phase I study will follow a standard 3+3 design to determine the recommended dose of trabectedin given as a 1-hour infusion in combination with low dose irinotecan.

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

SARC037: A Phase I 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

Actual Study Start Date :

Jan 5, 2021

Anticipated Primary Completion Date :

Jun 30, 2023

Anticipated Study Completion Date :

Jun 30, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Trabectedin and Irinotecan 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] Patients with Ewing sarcoma will be administered trabectedin intravenously. Cycles are 21 days. Drug: Irinotecan Patients with Ewing sarcoma will be administered inirotecan intravenously. Cycles are 21 days. Diagnostic Test: tumor biopsy 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. Other: 3'-Deoxy-3'-18F Fluorothymidine (18F-FLT) Imaging Some patients will receive PET scans with the use of 18F-FLT, a radioactive tracer, performed at the National Institute of Health. Other Names: 18F-FLT Imaging

Arm

Intervention/Treatment

Experimental: Trabectedin and Irinotecan

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]

Patients with Ewing sarcoma will be administered trabectedin intravenously. Cycles are 21 days.

Drug: Irinotecan

Patients with Ewing sarcoma will be administered inirotecan intravenously. Cycles are 21 days.

Diagnostic Test: tumor biopsy

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.

Other: 3'-Deoxy-3'-18F Fluorothymidine (18F-FLT) Imaging

Some patients will receive PET scans with the use of 18F-FLT, a radioactive tracer, performed at the National Institute of Health.

Other Names:

18F-FLT Imaging

Outcome Measures

Primary Outcome Measures

The recommended dose (RD) of trabectedin administered in combination with low dose irinotecan [up to 36 months]
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).

Secondary Outcome Measures

Tumor response rate [up to 36 months]
The percentage of patients whose tumor shrinks or disappears after treatment (per RECIST 1.1)
18F-FLT PET Activity [up to 36 months]
18F-FLT PET avidity of Ewing sarcoma tumors.

Other Outcome Measures

Progression free survival [up to 5 years]
The time from starting treatment until disease progression
6- month Progression free survival [up to 36 months]
To determine the rate of disease progression at 6 months after starting treatment
Duration of Response [up to 5 years]
The time from tumor response to disease progression

Eligibility Criteria

Criteria

Ages Eligible for Study:

10 Years to 99 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Children's Hospital of Los Angeles	Los Angeles	California	United States	90027
2	National Cancer Institute	Bethesda	Maryland	United States	20892
3	Boston Children's Hospital / Dana Farber Cancer Institute	Boston	Massachusetts	United States	02215
4	University of Michigan	Ann Arbor	Michigan	United States	48106
5	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104
6	University of Pennsylvania	Philadelphia	Pennsylvania	United States	19105

Sponsors and Collaborators

Sarcoma Alliance for Research through Collaboration
Janssen Scientific Affairs, LLC
National Institutes of Health (NIH)
National Cancer Institute (NCI)

Investigators

Principal Investigator: Patrick Grohar, MD/PhD, Children's Hospital of Philadelphia
Study Director: John Glod, MD/PhD, National Cancer Institute (NCI)

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

Responsible Party:

Sarcoma Alliance for Research through Collaboration

ClinicalTrials.gov Identifier:

NCT04067115

Other Study ID Numbers:

SARC037
U01CA236220

First Posted:

Aug 26, 2019

Last Update Posted:

Aug 18, 2022

Last Verified:

Aug 1, 2022

Studies a U.S. FDA-regulated Drug Product:

Yes

Studies a U.S. FDA-regulated Device Product:

Additional relevant MeSH terms:

Study Results

No Results Posted as of Aug 18, 2022