Lurbinectedin in FET-Fused Tumors (LiFFT)

Lurbinectedin in FET-Fusion Tumors (LIFFT)

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.

Study Overview

• Status: Recruiting
• Conditions: Ewing Sarcoma; Pediatric Cancer; Desmoplastic Small Round Cell Tumor; Undifferentiated Sarcoma
• Intervention / Treatment: Drug: Lurbinectedin

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 63
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Theodore Laetsch, MD; Phone Number: 267-425-5544; Email: LAETSCHT@chop.edu
• Study Contact Backup: Name: Meghan Donnelly; Phone Number: 267-426-9343; Email: 22DT011@CHOP.EDU

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90048
      • Recruiting
      • Cedars-Sinai Medical Center
      • Contact: Leo Mascarenhas, MD; Phone Number: 310-423-4423; Email: leo.mascarenhas@cshs.org
      • Contact: Emilie Douine-Barthelemy; Phone Number: 310-967-0692; Email: emilie.douine-barthelemy@cshs.org
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • Recruiting
      • University of Iowa Hospitals and Clinics
      • Contact: Jenna Gedminas, MD; Phone Number: 319-353-6393; Email: jenna-gedminas@uiowa.edu
      • Contact: Chris Stamy; Phone Number: 319-356-7875; Email: Chris-Stamy@uiowa.edu
      • Principal Investigator: Jenna Gedminas, MD
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Recruiting
      • Dana-Farber Cancer Institute
      • Principal Investigator: Steven Dubois, MD
      • Contact: Steven Dubois, MD; Phone Number: 617-632-5460; Email: steven.dubois@dfci.harvard.edu
      • Contact: Alexandra Sala; Phone Number: 857-215-2410; Email: alexandra_sala@dfci.harvard.edu
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • Recruiting
      • University of Michigan
      • Principal Investigator: Rashmi Chugh, MD
      • Contact: Cancer AnswerLine; Phone Number: 1-800-865-1125; Email: CancerAnswerLine@med.umich.edu
      • Contact: Rashmi Chugh, MD; Phone Number: 800-865-1125; Email: rashmim@med.umich.edu
  • New York
    • New York, New York, United States, 10065
      • Recruiting
      • Memorial Sloan Kettering Cancer Center
      • Contact: Julia Glade Bender, MD; Phone Number: 212-639-6729; Email: gladebej@mskcc.org
      • Principal Investigator: Julia Glade Bender, MD
      • Contact: Robert Maki, MD; Phone Number: 646-888-5059; Email: makir@mskcc.org
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Recruiting
      • Children's Hospital of Philadelphia
      • Contact: Meghan Donnelly; Phone Number: 267-426-9343; Email: 22DT011@CHOP.EDU
      • Contact: Theodore Laetsch, MD; Phone Number: 267-425-5544; Email: CancerTrials@CHOP.EDU

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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 or 1 (age >16 years) or Lansky of at least 70 (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. Muscle: Creatine phosphokinase (CPK) CTCAE 5 Grade ≤ 1,
   5. Cardiac:

   Creatine phosphokinase CTCAE 5 Grade ≤ l, 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 7 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)
9. Patients with Desmoplastic small round cell tumor (DSRCT) will be excluded from enrollment until at least 3 non-DSRCT patients have been enrolled without dose limiting toxicity.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 1: Dose Limiting Toxicities (DLTs)	First cycle (approximately 21 days) Dose Limiting Toxicities (DLTs) will be evaluated.	within 28 days of the first dose
Phase 1: Frequency of adverse events	Adverse events to be reported during treatment and for at least 28 days after last dose.	28 days after last dose
Phase 1: Complete Response or Partial Response	Percentage of participants with complete response or partial response will be assessed approximately every 2 to 4 cycles through the end of treatment and up to at least 28 days after the last dose.	through the end of treatment, an average of 1 year
Phase 2: Event-Free Survival (EFS)	Event-free survival (EFS) is based on investigator assessment from baseline until Month 24.	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 1: Maximum observed Plasma Concentration (Cmax)	Maximum observed plasma concentration (Cmax) will be used to assess Lurbinectedin Pharmacokinetics	at the end of cycle 1 (each cycle is 28 days)
Phase 1: Area under the concentration-time curve (AUC)	Area under the concentration-time curve (AUC) will be used to assess Lurbinectedin Pharmacokinetics	at the end of cycle 1 (each cycle is 28 days)
Phase 2: 6-month Progression Free Survival (PFS)	Progression Free Survival (PFS) assessed from the first dose of study drug to earliest date of death or progressive disease.	6 months
Phase 1: Duration of Response (DoR)	Duration of Response (DoR) defined as time from date of first response (Complete Response or Partial Response) in responders to date of progression or death	Up to 5 years
Phase 2: Overall Survival	Overall survival (OS) defined as the time from enrollment to date of death due to any cause.	Up to 5 years
Phase 2: Disease Control Rate	Disease Control ate is defined as the percentage of patients who sustain a complete response, partial response, or stable disease over 5 years.	Up to 5 Years

Collaborators and Investigators

• Sponsor: Children's Hospital of Philadelphia
• Collaborators: Jazz Pharmaceuticals; Stand Up To Cancer
• Investigators: Principal Investigator: Theodore Laetsch, MD, Children's Hospital of Philadelphia

Study record dates

Study Major Dates

• Study Start (Actual): July 27, 2023
• Primary Completion (Estimated): July 30, 2027
• Study Completion (Estimated): July 30, 2028

Study Registration Dates

• First Submitted: June 6, 2023
• First Submitted That Met QC Criteria: June 15, 2023
• First Posted (Actual): June 26, 2023

Study Record Updates

• Last Update Posted (Actual): March 31, 2026
• Last Update Submitted That Met QC Criteria: March 26, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Ewing Sarcoma-Friend Leukemia Integration 1 Transcription factor (ESW-FLI1); Ewing Sarcoma Breakpoint Region 1-Friend Leukemia Integration 1 Transcription factor (EWSR1-FLI1); Ewing Sarcoma Erythroblast Transformation Specific Related Gene (EWS-ERG); Ewing Sarcoma Breakpoint Region 1 (EWRS1); TATA-Box-Binding Protein Associated Factor 15 (TAF15); Fused Tumors (FET); Ewing Sarcoma-Wilms' Tumor Gene 1 (EWS-WT1)
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Sarcoma; Neoplasms, Connective and Soft Tissue; Osteosarcoma; Neoplasms, Bone Tissue; Neoplasms, Connective Tissue; Neoplasms; Sarcoma, Ewing; Desmoplastic Small Round Cell Tumor; PM 01183
• Other Study ID Numbers: 23-020814

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No