Lurbinectedin in FET-Fused Tumors

NCT ID: NCT05918640

Last Updated: 2025-11-21

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

RECRUITING

Clinical Phase

PHASE1/PHASE2

Total Enrollment

63 participants

Study Classification

INTERVENTIONAL

Study Start Date

2023-07-27

Study Completion Date

2028-07-30

Brief Summary

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The purpose of this study is to find out if a drug called lurbinectedin (the "study drug") is safe and effective at treating people with recurrent or relapsed solid tumors, including Ewing sarcoma.

Detailed Description

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In this study, the investigators will test the activity of lurbinectedin as a targeted therapy for FET (FUS, Ewing Sarcoma Breakpoint Region 1 (EWRS1), TATA-Box-Binding Protein Associated Factor 15 (TAF15)). Ewing sarcoma is driven by the Ewing Sarcoma-Friend Leukemia Integration 1 Transcription Factor (EWS-FLI1). Lurbinectedin has been shown to inhibit EWS-FLI1 and Ewing Sarcoma-Wilms' Tumor Gene 1 (EWS-WT1) in preclinical models. Therefore, the goal of this study is to see if Lurbinectedin can be used to inhibit EWS-FLI1, EWS-WT1, or other FET fusion proteins to drive tumor responses in patients.

Conditions

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Ewing Sarcoma Desmoplastic Small Round Cell Tumor Pediatric Cancer Undifferentiated Sarcoma

Study Design

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Allocation Method

NA

Intervention Model

SINGLE_GROUP

The first part of this study is a standard 3+3 design to test the safety, tolerability and pharmacokinetic profile of lurbinectedin administered on a day 1, 4 schedule in patients with FET-fusion tumors. The second part of this study is a single-stage phase 2 design and will accrue 17 patients in parallel to the exploratory cohort after the Recommended Phase 2 Dose (RP2D) is determined.
Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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Ewing Sarcoma

The first part of this study is a standard 3+3 design to test the safety, tolerability and pharmacokinetic profile of lurbinectedin administered on a day 1, 4 schedule in patients with FET-fusion tumors.

Group Type EXPERIMENTAL

Lurbinectedin

Intervention Type DRUG

Lurbinectedin will be administered on a Day 1, Day 4 schedule every 21 days. Doses will be determined in the phase 1 portion of the trial.

Interventions

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Lurbinectedin

Lurbinectedin will be administered on a Day 1, Day 4 schedule every 21 days. Doses will be determined in the phase 1 portion of the trial.

Intervention Type DRUG

Eligibility Criteria

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Inclusion Criteria

1. Age ≥ 10 years.
2. Phase 1: Histological confirmed diagnosis of recurrent or relapsed solid tumor failing primary therapy. Patients must have a known FET fusion (fusion that contains EWSR1, FUS, or TAF15) as documented by next generation sequencing, polymerase chain reaction (PCR) or Fluorescence in situ hybridization (FISH). Patients with a histological diagnosis of Ewing sarcoma with EWS-FLI1 are eligible for dose escalation but not for the exploratory cohort. Please note patients with Ewing sarcoma and alternative FET-ETS fusions (including but not limited to EWS-ERG, EWS-ETV1, EWS-ETV4, EWS-FEV, FUS-ERG, FUS-FEV) are eligible for the exploratory cohort.
3. Phase 2: Histologically confirmed diagnosis of recurrent or relapsed Ewing sarcoma failing primary therapy with confirmation of EWS-FLI1 fusion and breakpoint by Next generation sequencing or PCR or EWSR1 rearrangement confirmed by FISH and available tissue for central confirmation of EWS-FLI1 fusion and breakpoint.
4. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2 (age ≥16 years) or Lansky of at least 60 (age \<16 years).
5. Disease status (baseline imaging must be performed within 28 days of Day 1 of study treatment):

1. Phase 1: At least one site of measurable disease on CT or MRI as defined by RECIST 1.1 OR evaluable disease with at least one site of disease that has not been previously radiated
2. Phase 2: At least one site of measurable disease on CT or MRI as defined by RECIST 1.1
6. Meets organ function requirements as outlined below:

1. Liver:

Alanine aminotransferase (ALT) ≤ 2.5X upper limit of normal. For the purposes of this study the upper limit of normal for ALT is 45 U/L. Aspartate aminotransferase (AST) ≤ 2.5X upper limit of normal. For the purposes of this study the upper limit of normal for AST is 50 U/L. Total bilirubin ≤ 1.5X institutional upper limit of normal with the exception of patients with Gilbert's syndrome who must have bilirubin \<3X institutional upper limit of normal.
2. Renal:

Creatinine Calculated creatinine clearance (by the Schwartz equation for patients \<18 years of age and Cockroft-Gault formula (Appendix B) for patients ≥18 years of age) or radionuclide glomerular filtration rate (GFR) ≥ 50 mL/min /m2 or a serum creatinine less than or equal to the age/gender valued below:

Age Maximum Serum Creatinine (mg/dL) Male Female 10 to \< 13 years 1.2 1.2 13 to \< 16 years 1.5 1.4

≥ 16 years 1.7 1.4
3. Bone marrow:

Absolute Neutrophil Count (ANC) ≥ 1,000/µL (\>one week since last dose of short acting medications (e.g. filgrastim) and \> two weeks since last dose of long acting medications (e.g. peg-filgrastim)) Platelet Count (PLTs) ≥ 100,000/ µL (\>two weeks since last dose of thrombopoietin receptor agonist such as romiplostim and without platelet transfusion within previous 7 days of screening laboratories) Patients with a history of bone marrow involvement are required to have bilateral bone marrow aspirates and biopsies at baseline. Subjects with bone marrow disease are eligible as long as they meet the hematologic requirements above and are not known to be refractory to red cell or platelet transfusions.
4. Cardiac:

Creatine phosphokinase ≤ 2.5 x institutional upper limit of normal, Left ventricular ejection fraction (LVEF) or shortening fraction (SF) per institutional norm LVEF \> 50% OR SF \>28%.
7. Written, voluntary informed consent
8. Fertile males and females of childbearing potential must agree to use an effective method of birth control from screening, through 6 months after last study drug administration for females and 4 months for males. Women of childbearing potential must have a negative pregnancy test during screening procedures. Effective methods of birth control include: double barrier method (condom, diaphragm), abstinence, an intrauterine device (IUD), levonorgestrol implants, medroxyprogesterone acetate injections, or oral contraception. For those subjects whose preferred and usual lifestyle employs abstinence, refraining from heterosexual intercourse must be practiced during the entire active phase of the trial.
9. Patients ≥18 years must be willing to undergo tumor biopsy at study entry. Patients with Ewing sarcoma or DSRCT must be willing to undergo biopsy post-treatment. If biopsy is contraindicated, enrollment must be approved by study PI and archival tissue must be available.
10. Time elapsed from previous therapy:

1. Must be ≥ 3 weeks for systemic myelosuppressive therapy
2. ≥ 2 weeks for local radiation therapy (small field), ≥ 150 days after thyrotropin binding inhibition (TBI), craniospinal external beam radiotherapy (XRT) or radiation to ≥50% of the pelvis
3. ≥ 2 weeks for major surgery
4. ≥ 2 weeks for monoclonal antibodies and oral kinase inhibitors.
5. ≥ 6 weeks for autologous stem cell transplant. 6 months for allogeneic stem cell transplant.
6. ≥ 6 weeks for any type of cellular therapy
11. Patients must be recovered to baseline or Grade ≤1from the acute adverse effects of prior treatments, with the exception of alopecia and decreased deep tendon reflexes.

Exclusion Criteria

1. Prior therapy with trabectedin or lurbinectedin.
2. Subjects with known brain metastases.
3. Subjects with a known bleeding diathesis.
4. Subjects who are pregnant or breastfeeding.
5. Concurrent therapy:

1. Patients who are currently receiving an investigational drug or another anticancer agent
2. Patients receiving over the counter or herbal supplement with significant potential hepatotoxicity in the opinion of the investigator.
3. Patients receiving a medically necessary strong or moderate CYP3A4 inhibitor or inducer within 14 days prior to the first dose of study drug.
6. Clinically significant, unrelated illness or uncontrolled infection which would, in the opinion of the treating physician, compromise the patient's ability to tolerate the investigational agents or be likely to interfere with the study procedures or results.
7. Subjects who, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study, or in whom compliance is likely to be suboptimal, should be excluded.
8. Patients with known active viral hepatitis (i.e. Hepatitis A, B, or C)
Minimum Eligible Age

10 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Jazz Pharmaceuticals

INDUSTRY

Sponsor Role collaborator

Stand Up To Cancer

OTHER

Sponsor Role collaborator

Children's Hospital of Philadelphia

OTHER

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Theodore Laetsch, MD

Role: PRINCIPAL_INVESTIGATOR

Children's Hospital of Philadelphia

Locations

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Cedars-Sinai Medical Center

Los Angeles, California, United States

Site Status RECRUITING

University of Iowa Hospitals and Clinics

Iowa City, Iowa, United States

Site Status RECRUITING

Dana-Farber Cancer Institute

Boston, Massachusetts, United States

Site Status RECRUITING

University of Michigan

Ann Arbor, Michigan, United States

Site Status RECRUITING

Memorial Sloan Kettering Cancer Center

New York, New York, United States

Site Status RECRUITING

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States

Site Status RECRUITING

Countries

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United States

Central Contacts

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Theodore Laetsch, MD

Role: CONTACT

267-425-5544

Meghan Donnelly

Role: CONTACT

267-426-9343

Facility Contacts

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Leo Mascarenhas, MD

Role: primary

310-423-4423

Emilie Douine-Barthelemy

Role: backup

310-967-0692

Jenna Gedminas, MD

Role: primary

319-353-6393

Chris Stamy

Role: backup

319-356-7875

Steven Dubois, MD

Role: primary

617-632-5460

Alexandra Sala

Role: backup

857-215-2410

Rashmi Chugh, MD

Role: primary

800-865-1125

Cancer AnswerLine

Role: backup

1-800-865-1125

Julia Glade Bender, MD

Role: primary

212-639-6729

Robert Maki, MD

Role: backup

646-888-5059

Theodore Laetsch, MD

Role: primary

267-425-5544

Meghan Donnelly

Role: backup

267-426-9343

Other Identifiers

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23-020814

Identifier Type: -

Identifier Source: org_study_id

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