Total Body Irradiation and Astatine-211-Labeled BC8-B10 Monoclonal Antibody for the Treatment of Nonmalignant Diseases
- Nonmalignant disease treatable by allogeneic hematopoietic cell transplantation (HCT). Patients with a nonmalignant disease that is not clearly defined must be approved by the principal investigator (PI)
- Lansky play performance score or Karnofsky score >= 70
- DONOR INCLUSION
- HLA matched related donor that is genotypically or phenotypically identical for HLA‐A, ‐B, ‐C, ‐DRB1, ‐DQB1. Phenotypic identity must be confirmed by high‐resolution typing. Sibling donors are preferred over other relationships
- Unrelated donor. * Matched for HLA‐A, ‐B, ‐C, ‐DRB1, and DQB1 by high‐resolution typing; OR * Mismatched for a single HLA‐class 1 allele or HLA‐DQB1 antigen or allele by high‐resolution typing. Note: A donor homozygous for one allele only at HLA‐A, B, C, DRB1, or DQB1 is allowed (1 antigen mismatch for graft versus host disease [GVHD], 0 antigen mismatch for graft‐rejection). In the case of a recipient who is homozygous at one locus, the mismatch is not allowed to be at that locus (0 antigen mismatch for GVHD, 1 antigen mismatch for graft‐rejection)
- HLA haploidentical donor. There must be one shared HLA‐haplotype based on inheritance. The noninherited haplotype is allowed to be mismatched at any or all of these loci: HLA‐A, B, C, DRB1 or DQB1.
- Donor selection guideline recommendations: in the case where there are multiple donor options, donors should be selected based on the following priority numbered below: * Related donor genotypically HLA‐matched * Related donor phenotypically HLA‐matched * Unrelated donor HLA‐matched * Unrelated donor with single allele level mismatch at class 1 (HLA‐A, ‐B, or ‐C). For example, HLA‐A02:01 versus HLA‐A 02:02 * Unrelated donor with single allele level mismatch at DQB1 * HLA‐haploidentical donor Note: We require that the donor testing be performed by a United States Clinical Laboratory Improvement Amendment (CLIA) approved laboratory. In the very rare case where the donor testing is not able to be performed in a CLIA approved laboratory, or there is confirmatory testing that needs to be performed, or for any donor identified from Europe and at risk for Creutzfeldt‐Jakob Disease (CJD), we note this on the donor screening form and require that the unrelated donor medical director or the attending physician approves the use of the donor HPC‐A product under urgent medical need
- Patients with Fanconi Anemia
- Impaired cardiac function as evidenced by ejection fraction < 35% (or, if unable to obtain ejection fraction, shortening fraction of < 26%) or cardiac insufficiency requiring treatment or symptomatic coronary artery disease. Patients with a shortening fraction of < 26% may be enrolled if approved by a cardiologist. In addition, patients with poorly controlled hypertension on multiple anti‐hypertensive medications, symptomatic coronary artery disease, or patients on cardiac medications for antiarrhythmic or inotropic effects are excluded
- Impaired pulmonary function as evidenced by carbon monoxide diffusing capability test (DLCO) < 35% of predicted or receiving supplemental continuous oxygen. In addition, if patients are unable to perform pulmonary function tests, then O2 saturation < 92% on room air
- Impaired renal function as evidenced by estimated creatinine clearance less than 50 ml/min or serum creatinine > 2 x upper normal limit or dialysis‐dependent. Serum creatinine value must be within 28 days prior to start of conditioning * The creatinine clearance may be estimated by the Cockcroft‐Gault formula
- Impaired liver function as evidenced by abnormal hepatic function defined as a total bilirubin, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) > 2 times the upper limit of normal. In addition, patients with the following liver abnormalities are excluded: fulminant liver failure, cirrhosis of the liver with evidence of portal hypertension, alcoholic hepatitis, esophageal varices, hepatic encephalopathy, uncorrectable hepatic synthetic dysfunction as evidenced by prolongation of the prothrombin time, ascites related to portal hypertension, bacterial or fungal liver abscess, biliary obstruction, chronic viral hepatitis, or symptomatic biliary disease
- An uncontrolled infection requiring deferral of conditioning as recommended by an infectious disease specialist. A viral upper respiratory tract infection does not constitute an uncontrolled infection in this context
- Patients who are known to be positive for HIV (human immunodeficiency virus)
- Women of childbearing potential who are pregnant or breast‐feeding
- Fertile men or women unwilling to use contraceptive techniques during and for 12 months following treatment
- Allergy to murine‐based monoclonal antibodies
- Known contraindication to radiotherapy
- DONOR EXCLUSION
- Donors are excluded when preexisting immunoreactivity is identified that would jeopardize donor hematopoietic cell engraftment. The recommended procedure for patients with 10 of 10 HLA allele level (phenotypic) match is to obtain panel reactive antibody (PRA) screens to class I and class II antigens for all patients before hematopoietic cell transplantation (HCT). If the PRA shows > 10% activity, then flow cytometric or B and T cell cytotoxic cross matches should be obtained. The donor should be excluded if any of the cytotoxic cross match assays are positive. For those patients with an HLA class I allele or class II allele or antigen mismatch or haploidentical donors, flow cytometric or B and T cell cytotoxic cross matches should be obtained regardless of the PRA results. A positive anti‐donor cytotoxic crossmatch is an absolute donor exclusion
I. Determine the minimal dose of total body irradiation (TBI) needed to establish donor chimerism (CD33 and CD3) of human leukocyte antigen (HLA) matched related or unrelated grafts or an unrelated graft with a single HLA‐class 1 allele mismatch or DQB1 antigen or allele mismatch in conjunction with a fixed dose of astatine At 211 anti-CD45 monoclonal antibody BC8-B10 (211At‐labeled BC8‐B10 monoclonal antibody [MAb]) in patients with nonmalignant diseases. (Arm A)
II. Determine the minimal dose of TBI needed to establish donor chimerism (CD33 and CD3) of HLA haploidentical donor grafts in conjunction with a fixed dose of 211At‐labeled BC8‐B10 MAb in patients with nonmalignant diseases. (Arm B)
I. Determine day 100 transplant related mortality (TRM).
II. Determine the 1‐year overall survival.
III. Estimate day 100 acute grade II‐IV graft versus host disease (GVHD).
IV. Estimate 1‐year chronic GVHD.
V. Donor chimerism at day 28, day 84, and 1‐year post‐HCT.
Patients receive astatine At 211 anti-CD45 monoclonal antibody BC8-B10 intravenously (IV) on any day between days -10 and -7, fludarabine IV on days -6 to -2, cyclophosphamide IV over 1 hour on days -6 to -5 and 3 to 4, and thymoglobulin IV over 4-6 hours on days -4 to -2. Patients undergo TBI on day -1 and hematopoietic cell transplant on day 0. Beginning day 5, patients also receive mycophenolate mofetil orally (PO) or IV thrice daily every 8 hours up to day 35 if no GVHD present and sirolimus PO daily until day 365.
After completion of study treatment, patients are followed up at 1 and 2 years and then periodically for up to 5 years.
Trial Phase Phase I/II
Trial Type Treatment
Fred Hutch / University of Washington Cancer Consortium
- Primary ID RG1005632
- Secondary IDs NCI-2019-05727, 9524
- Clinicaltrials.gov ID NCT04083183