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

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ClinicalTrials.gov Identifier: NCT04067115
Recruitment Status : Recruiting
First Posted : August 26, 2019
Last Update Posted : May 7, 2021
Sponsor:
Collaborators:
Janssen Scientific Affairs, LLC
National Institutes of Health (NIH)
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Sarcoma Alliance for Research through Collaboration

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 45 participants
Allocation: Non-Randomized
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.
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 : January 5, 2021
Estimated Primary Completion Date : June 30, 2023
Estimated Study Completion Date : June 30, 2023


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 Name: 18F-FLT Imaging




Primary Outcome Measures :
  1. The recommended dose (RD) of trabectedin administered in combination with low dose irinotecan [ Time Frame: 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 :
  1. Tumor response rate [ Time Frame: up to 36 months ]
    The percentage of patients whose tumor shrinks or disappears after treatment (per RECIST 1.1)

  2. 18F-FLT PET avidity of Ewing sarcoma tumors. [ Time Frame: up to 36 months ]

Other Outcome Measures:
  1. Progression free survival [ Time Frame: up to 5 years ]
    The time from starting treatment until disease progression

  2. 6- month Progression free survival [ Time Frame: up to 36 months ]
    To determine the rate of disease progression at 6 months after starting treatment

  3. Duration of Response [ Time Frame: up to 5 years ]
    The time from tumor response to disease progression



Information from the National Library of Medicine

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Ages Eligible for Study:   10 Years to 99 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04067115


Contacts
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Contact: SARC 7349307600 sarc@sarctrials.org

Locations
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United States, California
Children's Hospital of Los Angeles Recruiting
Los Angeles, California, United States, 90027
Contact: Abe Levi, CRSO    323-361-6686      
Principal Investigator: Leo Mascarenhas, MD         
United States, Maryland
National Cancer Institute Recruiting
Bethesda, Maryland, United States, 20892
Principal Investigator: John Glod, MD         
United States, Massachusetts
Boston Children's Hospital / Dana Farber Cancer Institute Not yet recruiting
Boston, Massachusetts, United States, 02215
Principal Investigator: Steven Dubois, MD         
United States, Michigan
University of Michigan Recruiting
Ann Arbor, Michigan, United States, 48106
Principal Investigator: Rashmi Chugh, MD         
United States, Pennsylvania
Children's Hospital of Philadelphia Recruiting
Philadelphia, Pennsylvania, United States, 19104
Principal Investigator: Patrick Grohar, MD/PhD         
Sponsors and Collaborators
Sarcoma Alliance for Research through Collaboration
Janssen Scientific Affairs, LLC
National Institutes of Health (NIH)
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Patrick Grohar, MD/PhD Children's Hospital of Philadelphia
Study Director: John Glod, MD/PhD National Cancer Institute (NCI)
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Responsible Party: Sarcoma Alliance for Research through Collaboration
ClinicalTrials.gov Identifier: NCT04067115    
Other Study ID Numbers: SARC037
U01CA236220 ( U.S. NIH Grant/Contract )
First Posted: August 26, 2019    Key Record Dates
Last Update Posted: May 7, 2021
Last Verified: May 2021

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Sarcoma
Sarcoma, Ewing
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms
Osteosarcoma
Neoplasms, Bone Tissue
Neoplasms, Connective Tissue
Alovudine
Irinotecan
Trabectedin
Topoisomerase I Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Antiviral Agents
Anti-Infective Agents