Lurbinectedin in FET-Fused Tumors (LiFFT)

• ClinicalTrials.gov Identifier: NCT05918640
• Recruitment Status: Recruiting
• First Posted: June 26, 2023
• Last Update Posted: April 15, 2024
• Sponsor: Children's Hospital of Philadelphia
• Collaborators: Jazz Pharmaceuticals; Stand Up To Cancer
• Information provided by (Responsible Party): Children's Hospital of Philadelphia

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Ewing Sarcoma; Desmoplastic Small Round Cell Tumor; Pediatric Cancer; Undifferentiated Sarcoma	Drug: Lurbinectedin	Phase 1; Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 56 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Intervention Model Description: 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.
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Lurbinectedin in FET-Fusion Tumors (LIFFT)
• Actual Study Start Date: July 27, 2023
• Estimated Primary Completion Date: July 30, 2026
• Estimated Study Completion Date: July 30, 2028

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

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

Eligibility Criteria

• Ages Eligible for Study: 10 Years and older (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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 0-2 (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): 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.

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 Day 1 of study and for 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)

Contacts and Locations

Contacts

Contact: Patrick Grohar, MD; 267-425-5544; GROHARP@CHOP.EDU

Contact: Supriya Behl; 267-425-5544; 22DT011@CHOP.EDU

Locations

United States, Iowa

University of Iowa Hospitals and Clinics; Not yet recruiting

Iowa City, Iowa, United States, 52242

Contact: Jenna Gedminas, MD 319-353-6393 jenna-gedminas@uiowa.edu

Contact: Chris Stamy 319-356-7875 Chris-Stamy@uiowa.edu

Principal Investigator: Jenna Gedminas, MD

United States, Maryland

National Institutes of Health Clinical Center; Not yet recruiting

Bethesda, Maryland, United States, 20892

Contact: Christine Heske, MD 240-760-6197 christine.heske@nih.gov

Contact: Mary Frances Wedekind Malone 240-858-3765 maryfrances.wedekindmalone@nih.gov

Principal Investigator: Christine Heske, MD

United States, Massachusetts

Dana-Farber Cancer Institute; Not yet recruiting

Boston, Massachusetts, United States, 02215

Contact: Steven Dubois, MD 617-632-5460 steven.dubois@dfci.harvard.edu

Contact: Alexandra Sala 857-215-2410 alexandra_sala@dfci.harvard.edu

Principal Investigator: Steven Dubois, MD

United States, Michigan

University of Michigan; Not yet recruiting

Ann Arbor, Michigan, United States, 48109

Contact: Rashmi Chugh, MD 800-865-1125 rashmim@med.umich.edu

Contact: Cancer AnswerLine 1-800-865-1125 CancerAnswerLine@med.umich.edu

Principal Investigator: Rashmi Chugh, MD

United States, Pennsylvania

Children's Hospital of Philadelphia; Recruiting

Philadelphia, Pennsylvania, United States, 19104

Contact: Patrick Grohar, MD 267-425-5544 GROHARP@CHOP.EDU

Contact: Supriya Behl 267-425-5544 22DT011@CHOP.EDU

Sponsors and Collaborators

Children's Hospital of Philadelphia

Jazz Pharmaceuticals

Stand Up To Cancer

Investigators

• Principal Investigator: Patrick Grohar, MD; Children's Hospital of Philadelphia

More Information

• Responsible Party: Children's Hospital of Philadelphia
• ClinicalTrials.gov Identifier: NCT05918640
• Other Study ID Numbers: 23-020814
• First Posted: June 26, 2023
• Last Update Posted: April 15, 2024
• Last Verified: April 2024

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Children's Hospital of Philadelphia:

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:

Sarcoma; Sarcoma, Ewing; Desmoplastic Small Round Cell Tumor; Neoplasms; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Osteosarcoma; Neoplasms, Bone Tissue; Neoplasms, Connective Tissue