Trial Title:
Lurbinectedin in FET-Fused Tumors
NCT ID:
NCT05918640
Condition:
Ewing Sarcoma
Desmoplastic Small Round Cell Tumor
Pediatric Cancer
Undifferentiated Sarcoma
Conditions: Official terms:
Sarcoma
Sarcoma, Ewing
Desmoplastic Small Round Cell Tumor
Conditions: 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)
Study type:
Interventional
Study phase:
Phase 1/Phase 2
Overall status:
Recruiting
Study design:
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.
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Lurbinectedin
Description:
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.
Arm group label:
Ewing Sarcoma
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.
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.
Criteria for 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 0-2 (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 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)
Gender:
All
Minimum age:
10 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Cedars-Sinai Medical Center
Address:
City:
Los Angeles
Zip:
90048
Country:
United States
Status:
Recruiting
Contact:
Last name:
Leo Mascarenhas, MD
Phone:
310-423-4423
Email:
leo.mascarenhas@cshs.org
Contact backup:
Last name:
Emilie Douine-Barthelemy
Phone:
310-967-0692
Email:
emilie.douine-barthelemy@cshs.org
Facility:
Name:
University of Iowa Hospitals and Clinics
Address:
City:
Iowa City
Zip:
52242
Country:
United States
Status:
Recruiting
Contact:
Last name:
Jenna Gedminas, MD
Phone:
319-353-6393
Email:
jenna-gedminas@uiowa.edu
Contact backup:
Last name:
Chris Stamy
Phone:
319-356-7875
Email:
Chris-Stamy@uiowa.edu
Investigator:
Last name:
Jenna Gedminas, MD
Email:
Principal Investigator
Facility:
Name:
National Institutes of Health Clinical Center
Address:
City:
Bethesda
Zip:
20892
Country:
United States
Status:
Not yet recruiting
Contact:
Last name:
Christine Heske, MD
Phone:
240-760-6197
Email:
christine.heske@nih.gov
Contact backup:
Last name:
Mary Frances Wedekind Malone
Phone:
240-858-3765
Email:
maryfrances.wedekindmalone@nih.gov
Investigator:
Last name:
Christine Heske, MD
Email:
Principal Investigator
Facility:
Name:
Dana-Farber Cancer Institute
Address:
City:
Boston
Zip:
02215
Country:
United States
Status:
Recruiting
Contact:
Last name:
Steven Dubois, MD
Phone:
617-632-5460
Email:
steven.dubois@dfci.harvard.edu
Contact backup:
Last name:
Alexandra Sala
Phone:
857-215-2410
Email:
alexandra_sala@dfci.harvard.edu
Investigator:
Last name:
Steven Dubois, MD
Email:
Principal Investigator
Facility:
Name:
University of Michigan
Address:
City:
Ann Arbor
Zip:
48109
Country:
United States
Status:
Recruiting
Contact:
Last name:
Rashmi Chugh, MD
Phone:
800-865-1125
Email:
rashmim@med.umich.edu
Contact backup:
Last name:
Cancer AnswerLine
Phone:
1-800-865-1125
Email:
CancerAnswerLine@med.umich.edu
Investigator:
Last name:
Rashmi Chugh, MD
Email:
Principal Investigator
Facility:
Name:
Memorial Sloan Kettering Cancer Center
Address:
City:
New York
Zip:
10065
Country:
United States
Status:
Recruiting
Contact:
Last name:
Julia Glade Bender, MD
Phone:
212-639-6729
Email:
gladebej@mskcc.org
Contact backup:
Last name:
Robert Maki, MD
Phone:
646-888-5059
Email:
makir@mskcc.org
Investigator:
Last name:
Julia Glade Bender, MD
Email:
Principal Investigator
Facility:
Name:
Children's Hospital of Philadelphia
Address:
City:
Philadelphia
Zip:
19104
Country:
United States
Status:
Recruiting
Contact:
Last name:
Theodore Laetsch, MD
Phone:
267-425-5544
Email:
LAETSCH@CHOP.EDU
Contact backup:
Last name:
Meghan Donnelly
Phone:
267-426-9343
Email:
22DT011@CHOP.EDU
Start date:
July 27, 2023
Completion date:
July 30, 2028
Lead sponsor:
Agency:
Children's Hospital of Philadelphia
Agency class:
Other
Collaborator:
Agency:
Jazz Pharmaceuticals
Agency class:
Industry
Collaborator:
Agency:
Stand Up To Cancer
Agency class:
Other
Source:
Children's Hospital of Philadelphia
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05918640
