The EndRAD Trial: Eliminating Total Body Irradiation (TBI) for NGS-MRD Negative Children, Adolescents, and Young Adults With B-ALL

B-cell Acute Lymphoblastic Leukemia Clinical Trial

Official title:

A Phase II Pilot Trial to Estimate Survival After a Non-total Body Irradiation (TBI) Based Conditioning Regimen in Patients Diagnosed With B-acute Lymphoblastic Leukemia (ALL) Who Are Pre-allogeneic Hematopoietic Cell Transplantation (HCT) Next-generation-sequence (NGS) Minimal Residual Disease (MRD) Negative

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03509961
• Other study ID #: PBMTC ONC1701
• Status: Recruiting
• Phase: Phase 2
• Start date: August 29, 2018
• Est. completion date: July 1, 2026

Study information

• Verified date: August 2021
• Source: Children's Hospital Los Angeles
• Contact: Liz Gourdine
• Phone: 323-361-6652
• Email: EndRAD[@]chla.usc.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study will evaluate the use of non- TBI (total body irradiation) conditioning for B-ALL patients with low risk of relapse as defined by absence of NGS-MRD (next generation sequencing minimal residual disease) before receiving a hematopoietic cell transplant (HCT). Patients diagnosed with B-ALL who are candidates for HCT will be screened by NGS-MRD on a test of bone marrow done before the HCT. Subjects who are pre-HCT NGS-MRD negative will be eligible to receive a non-TBI conditioning regimen as part of the treatment cohort of the study. Subjects who are pre-HCT NGS-MRD positive will be treated as per treating center standard and will be followed in an observational cohort (HCT center standard of care).

Description:

A Phase II pilot trial will estimate survival after a non-TBI based conditioning regimen in patients diagnosed with B-acute lymphoblastic leukemia (ALL) who are pre-allogeneic hematopoietic cell transplantation (HCT) next-generation-sequence (NGS) minimal residual disease (MRD) negative. The relationship of NGS-MRD status to survival in children, adolescents, and young adults with B-ALL undergoing any approach to allogeneic HCT will be explored in a larger cohort (treatment [phase II] and observational arms of the study). The primary objective is to estimate 2-year event free survival (EFS) in pre-HCT NGS-MRD negative patients with B-ALL undergoing a non-TBI based conditioning regimen through a multi-center prospective trial. The accrual period is 3 years. Patients that are NGS-MRD negative with B-ALL may be eligible for the Treatment Arm, which is myeloablative non-TBI conditioning with busulfan, fludarabine, and thiotepa followed -matched related, unrelated, and umbilical cord blood transplants. Patients that are NGS-MRD positive will be followed on the observational arm for outcome. Study sampling will include NGS-MRD bone marrow (BM) aspirate and peripheral blood (PB) samples collected [same day when possible] pre-HCT (within 4 weeks), and post-HCT on days 42 ± 14, 100 ± 20, and 365 ± 60; PB samples only will also be collected day 180± 60 and 270± 60; day +30, day +100, and 1-year post-HCT. NGS-MRD peripheral blood sample only at 6 months and 9 months post-HCT; (Blast specimen at time of diagnosis or relapse is required for NGS-MRD testing).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 95
• Est. completion date: July 1, 2026
• Est. primary completion date: July 1, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 1 Year to 25 Years

Eligibility

Inclusion Criteria for the Observational Arm:

Any patient with ALL who undergoes Myeloablative HCT including any of the following:

• Patients who are pre-HCT NGS-MRD positive.
• Patients <1 year old who are pre-HCT NGS-MRD negative.
• Patients who are pre-HCT NGS-MRD negative (CR1/CR2) who received inotuzumab ozogamicin therapy before proceeding to HCT.
• Patients who are pre-HCT NGS-MRD negative and will be receiving haploidentical HCT.
• Patients who are pre-HCT NGS-MRD negative in CR2 with history of CNS relapse.
• Patients who have received blinatumomab, but are >CR2 prior to HCT.
• Patients who have received CART-T cellular therapy, but are >CR2 prior to HCT.
• Patients with pre-HCT NGS-MRD negative in = CR3.
• Any T-ALL and MPAL patients undergoing first allogeneic HCT
• Any patient who is pre-HCT NGS-MRD negative and eligible for participation in the treatment arm but family does not consent for treatment arm or treating physician believe it is in the patient best interest not to enroll on the treatment arm

Inclusion Criteria for the Treatment Arm:

• Pre-HCT NGS-MRD negative
• Age = 1 year and = 25 years
• Disease status: B-ALL in first (CR1) or second remission (CR2)
• No prior allogeneic hematopoietic stem cell transplant.
• Patients in CR1 or CR2 after blinatumomab treatment.
• Patients in CR1 or CR2 after CAR-T cellular therapy.
• Karnofsky Index or Lansky Play-Performance Scale = 60 % on pre-transplant evaluation. Karnofsky scores must be used for patients > 16 years of age and Lansky scores for patients < 16 years of age.
• Able to give informed consent if > 18 years, or with a legal guardian capable of giving informed consent if < 18 years.
• Adequate organ function (within 4 weeks of initiation of preparative regimen), defined

as:

• Pulmonary: FEV1, FVC, and corrected DLCO must all be = 50% of predicted by pulmonary function tests (PFTs). For children who are unable to perform for PFTs due to age, the criteria are: no evidence of dyspnea at rest and no need for supplemental oxygen.
• Renal: Creatinine clearance or radioisotope GFR = 60 mL/min/1.73 m2 or a serum creatinine based on age/gender.
• Cardiac: Shortening fraction of = 27% by echocardiogram or radionuclide scan (MUGA) or ejection fraction of = 50% by echocardiogram or radionuclide scan (MUGA), choice of test according to local standard of care.
• Hepatic: SGOT (AST) or SGPT (ALT) < 5 x upper limit of normal (ULN) for age. Conjugated bilirubin < 2.5 mg/dL, unless attributable to Gilbert's Syndrome.

Exclusion Criteria:

• CR2: exclude patients with history of CNS relapse (i.e. in CR2 with history of CNS isolated or combined relapse; CNS 2 will also be considered as CNS 3 for this purpose) from the treatment arm of study (can be enrolled on the observational arm).
• Patients who have received inotuzumab treatment prior to allogeneic HCT are NOT eligible for the study treatment arm. Inotuzumab treatment may increase the risk of VOD/SOS for any allogeneic HCT recipient, but could potentiate the risk for with busulfan-based myeloablation (study-directed non-TBI conditioning). All inotuzumab-treated patients are eligible for the observational arm (HCT center standard of care).
• Patients receiving non-myeloablative conditioning are not allowed on the observational arm (reduced toxicity conditioning with Flu/Mel/Thio is allowed on the observational arm).
• Pregnant or lactating females are ineligible as many of the medications used in this protocol could be harmful to unborn children and infants.
• Patients with HIV or uncontrolled fungal, bacterial or viral infections are excluded. Patients with history of fungal disease during induction therapy may proceed if they have a significant response to antifungal therapy with no evidence or minimal evidence of non-progressive disease remaining by CT evaluation.
• Patients with active CNS leukemia or any other active site of extramedullary disease at the time of enrollment are not permitted.
• T-ALL and MPAL patients are only allowed on the observational arm.
• Patients with genetic disorders (generally marrow failure syndromes) prone to secondary AML/ALL with known poor outcome are not eligible (Fanconi Anemia, Kostmann Syndrome, Dyskeratosis Congenita, etc).

Related Conditions & MeSH terms

• B-cell Acute Lymphoblastic Leukemia
• Leukemia
• Leukemia, Lymphoid
• Precursor Cell Lymphoblastic Leukemia-Lymphoma

Intervention

Diagnostic Test:
• NGS-MRD
Next generation sequencing minimal residual disease (NGS-MRD) is a test that has increased sensitivity over multichannel flow cytometry to better identify risk of key outcomes after HCT. Patients that have a pre-HCT negative NGS-MRD results may be eligible to proceed to the treatment arm of the study that uses a non-TBI conditioning regimen.

Drug:
• Myeloablative allogeneic HCT with a non-TBI conditioning regimen
Myeloablative study regimen will consist of busulfan, fludarabine and thiotepa. day -7: Fludarabine and Busulfan day -6: Fludarabine and Busulfan day -5: Fludarabine and Busulfan day -4: Fludarabine and Busulfan day -3: Fludarabine day -2: Thiotepa day -1: Rest Day 0: Transplant

Locations

Country	Name	City	State
United States	Children's Healthcare of Atlanta	Atlanta	Georgia
United States	Children's Hospital Colorado	Aurora	Colorado
United States	Children's of Alabama/University of Alabama in Birmingham(UAB)	Birmingham	Alabama
United States	Dana Faber Cancer Institute/ Boston Children's Hospital	Boston	Massachusetts
United States	Floating Hospital for Children at Tufts Medical Center	Boston	Massachusetts
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	Atrium Health - Levine Cancer Center	Charlotte	North Carolina
United States	City of Hope	Duarte	California
United States	University of Florida	Gainesville	Florida
United States	Helen DeVos Children's Hospital at Spectrum Health	Grand Rapids	Michigan
United States	Hackensack University Medical Center	Hackensack	New Jersey
United States	The University of Texas M. D. Anderson Cancer Center	Houston	Texas
United States	Riley Hospital for Children - Indiana University	Indianapolis	Indiana
United States	Children's Mercy Hospital	Kansas City	Missouri
United States	Children's Hospital Los Angeles	Los Angeles	California
United States	UCLA Mattel Children's Hospital	Los Angeles	California
United States	Nicklaus Children's Hospital	Miami	Florida
United States	Yale University School of Medicine	New Haven	Connecticut
United States	UCSF Benioff Children's Hospital Oakland	Oakland	California
United States	Phoenix Children's Hospital	Phoenix	Arizona
United States	Johns Hopkins All Children's Hospital	Saint Petersburg	Florida
United States	Methodist Healthcare System	San Antonio	Texas
United States	UCSF	San Francisco	California
United States	Alfred I. duPont Hospital for Children - Nemours Deleware	Wilmington	Delaware

Sponsors (1)

Lead Sponsor	Collaborator
Children's Hospital Los Angeles

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Two Year Event-free Survival	The primary objective of this study is the two Year Event-free Survival for patients with high-risk or recurrent B-ALL who proceed to HCT and who are NGS-MRD negative when treated with a non-TBI preparative regimen.	Two years