Clinical trial NCT03509961: The EndRAD Trial: Eliminating Total Body Irradiation (TBI) for NGS-MRD Negative Children, Adolescents, and Young Adults With B-ALL
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: B-cell Acute Lymphoblastic Leukemia
Lead sponsor: Pediatric Transplantation & Cellular Therapy Consortium
Sponsor class: OTHER
First posted: 2018-04-27
Enrollment: 95
Sex: ALL
Minimum age (years): 1
Maximum age (years): 25
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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).

Detailed 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).

Eligibility criteria: 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).

Primary outcomes:
measure: Two Year Event-free Survival
timeFrame: Two years
Secondary outcomes:
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Children's of Alabama/University of Alabama in Birmingham(UAB)
state: Alabama
city: Phoenix
country: United States
facility: Phoenix Children's Hospital
state: Arizona
city: Duarte
country: United States
facility: City of Hope
state: California
city: Los Angeles
country: United States
facility: Children's Hospital Los Angeles
state: California
city: Los Angeles
country: United States
facility: UCLA Mattel Children's Hospital
state: California
city: Oakland
country: United States
facility: UCSF Benioff Children's Hospital Oakland
state: California
city: San Francisco
country: United States
facility: UCSF
state: California
city: Aurora
country: United States
facility: Children's Hospital Colorado
state: Colorado
city: New Haven
country: United States
facility: Yale University School of Medicine
state: Connecticut
city: Wilmington
country: United States
facility: Alfred I. duPont Hospital for Children - Nemours Deleware
state: Delaware
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Miami
country: United States
facility: Nicklaus Children's Hospital
state: Florida
city: Saint Petersburg
country: United States
facility: Johns Hopkins All Children's Hospital
state: Florida
city: Atlanta
country: United States
facility: Children's Healthcare of Atlanta
state: Georgia
city: Indianapolis
country: United States
facility: Riley Hospital for Children - Indiana University
state: Indiana
city: Boston
country: United States
facility: Floating Hospital for Children at Tufts Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Dana Faber Cancer Institute/ Boston Children's Hospital
state: Massachusetts
city: Grand Rapids
country: United States
facility: Helen DeVos Children's Hospital at Spectrum Health
state: Michigan
city: Kansas City
country: United States
facility: Children's Mercy Hospital
state: Missouri
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: Charlotte
country: United States
facility: Atrium Health - Levine Cancer Center
state: North Carolina
city: Houston
country: United States
facility: The University of Texas M. D. Anderson Cancer Center
state: Texas
city: San Antonio
country: United States
facility: Methodist Healthcare System
state: Texas
Study officials:
affiliation: Loma Linda University
name: Abdel-Azim Hisham, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Helen DeVos Children's Hospital
name: Troy Quigg, DO, MS
role: PRINCIPAL_INVESTIGATOR
References:
citation: Andolina JR, Fries C, Boulware R, Vargas A, Fraint E, Barth M, Ambrusko S, Comito M, Monteleone P. Successful Bone Marrow Transplantation With Intensive Post-transplant Intrathecal Chemotherapy for CNS Relapsed AML in 2 Infants. J Pediatr Hematol Oncol. 2022 Jan 1;44(1):e264-e267. doi: 10.1097/MPH.0000000000002151.