Using lurbinectedin to treat specific tumors in children and young adults

Lurbinectedin in FET-Fusion Tumors (LIFFT)

This study is testing if a new drug called lurbinectedin can help children and young adults with certain types of tumors, like Ewing sarcoma, by targeting the proteins that make the tumors grow.

Quick facts

• Phase: Phase1; Phase2
• Study type: Interventional
• Enrollment: 63 (estimated)
• Ages: 10 Years and up
• Sex: All
• Sponsor: Children's Hospital of Philadelphia (Academic / other)
• Drugs / interventions: radiation
• Locations: 6 sites (Los Angeles, California and 5 other locations)
• Trial ID: NCT05918640 on ClinicalTrials.gov

What this trial studies

This study investigates the safety and effectiveness of lurbinectedin, a targeted therapy, for treating recurrent or relapsed solid tumors, particularly Ewing sarcoma and other FET-fused tumors. The research focuses on the drug's ability to inhibit specific fusion proteins that drive tumor growth, such as EWS-FLI1 and EWS-WT1. Patients aged 10 and older with confirmed FET fusions will be enrolled, and the study will assess the drug's activity through a phased approach, including dose escalation and exploratory cohorts. The goal is to determine if lurbinectedin can lead to significant tumor responses in these patients.

Who should consider this trial

Good fit: Ideal candidates include patients aged 10 and older with recurrent or relapsed solid tumors that have a confirmed FET fusion.

Not a fit: Patients without a confirmed FET fusion or those with tumors not driven by EWS-FLI1 may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could provide a new targeted therapy option for patients with difficult-to-treat tumors.

How similar studies have performed: Other studies have shown promising results with targeted therapies for Ewing sarcoma, suggesting potential success for this approach.

Eligibility criteria

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.

Where this trial is running

Los Angeles, California and 5 other locations

• Cedars-Sinai Medical Center — Los Angeles, California, United States (Recruiting)
• University of Iowa Hospitals and Clinics — Iowa City, Iowa, United States (Recruiting)
• Dana-Farber Cancer Institute — Boston, Massachusetts, United States (Recruiting)
• University of Michigan — Ann Arbor, Michigan, United States (Recruiting)
• Memorial Sloan Kettering Cancer Center — New York, New York, United States (Recruiting)
• Children's Hospital of Philadelphia — Philadelphia, Pennsylvania, United States (Recruiting)

Study contacts

• Principal investigator: Theodore Laetsch, MD — Children's Hospital of Philadelphia
• Study coordinator: Theodore Laetsch, MD

Conditions Ewing Sarcoma; Desmoplastic Small Round Cell Tumor; Pediatric Cancer; Undifferentiated Sarcoma; Ewing Sarcoma-Friend Leukemia Integration 1 Transcription factor; Ewing Sarcoma Breakpoint Region 1-Friend Leukemia Integration 1 Transcription factor; Ewing Sarcoma Erythroblast Transformation Specific Related Gene; Ewing Sarcoma Breakpoint Region 1