MT2023-20: Hematopoietic Cell Transplant With Reduced Intensity Conditioning and Post-transplant Cyclophosphamide for Severe Aplastic Anemia and Other Forms of Acquired Bone Marrow Failure.

Paroxysmal Nocturnal Hemoglobinuria Clinical Trial

Official title:

MT2023-20: Hematopoietic Cell Transplant With Reduced Intensity Conditioning and Post-transplant Cyclophosphamide for Severe Aplastic Anemia and Other Forms of Acquired Bone Marrow Failure.

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06412497
• Other study ID #: 2023LS101
• Status: Recruiting
• Phase: Phase 2
• Start date: June 5, 2024
• Est. completion date: May 1, 2036

Study information

• Verified date: June 2024
• Source: Masonic Cancer Center, University of Minnesota
• Contact: Christen Ebens, MD, MPH
• Phone: 612-624-1791
• Email: ebens012[@]umn.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

A phase II trial of a reduced intensity conditioned (RIC) allogeneic hematopoietic cell transplant (HCT) with post-transplant cyclophosphamide (PTCy) for idiopathic severe aplastic anemia (SAA), paroxysmal nocturnal hemoglobinuria (PNH), acquired pure red cell aplasia (aPRCA), or acquired amegakaryocytic thrombocytopenia (aAT) utilizing population pharmacokinetic (popPK)-guided individual dosing of pre-transplant conditioning and differential dosing of low dose total body irradiation based on age, presence of myelodysplasia and/or clonal hematopoiesis.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 60
• Est. completion date: May 1, 2036
• Est. primary completion date: May 1, 2035
• Accepts healthy volunteers: No
• Gender: All
• Age group: 0 Years to 75 Years

Eligibility

Inclusion Criteria:

• Idiopathic Severe Aplastic Anemia (SAA), characterized by one of the following:

1. Refractory cytopenia(s), with 1+ of the following:

1. Platelets <20,000/uL or transfusion dependent

2. Absolute neutrophil count <500/uL without hematopoietic growth factor support

3. Absolute reticulocyte count <60,000/uL AND bone marrow cellularity <50% (with < 30% residual hematopoietic cells)

2. Early myelodysplastic features (bone marrow (BM) blasts <5%), without history of MDS/AML pre-treatment.

3. Idiopathic SAA with post-HCT graft failure (blood/marrow donor chimerism <5%) requiring a 2nd allogeneic HCT

• Paroxysmal Nocturnal Hemoglobinuria (PNH), including AA-PNH overlap syndrome, acquired pure red cell aplasia (aPRCA), or acquired amegakaryocytic thrombocytopenia (aAT), characterized by one of the following:

1. Refractory cytopenia(s), with 1+ of the following:

1. Platelets <20,000/uL or transfusion dependent

2. Absolute neutrophil count <500/uL without hematopoietic growth factor support

3. Absolute reticulocyte count <60,000/uL or red cell transfusion dependent AND Bone marrow evidence of 1 to 3-lineage aplasia OR peripheral blood PNH clone >/= 10%

2. Early myelodysplastic features (bone marrow (BM) blasts <5%) without history of MDS/AML pre-treatment.

3. Idiopathic PNH, aPRCA, or aAT with post-HCT graft failure (blood/marrow donor chimerism <5%) requiring a 2nd allogeneic HCT

• Adequate organ function within 30 days of conditioning regimen

Exclusion Criteria:

• Pregnant, breastfeeding or intending to become pregnant during the study. Persons of childbearing potential must have a negative pregnancy test (serum or urine) within 7 days of the start of treatment

• Uncontrolled infection

• Evidence of moderate or severe portal fibrosis or cirrhosis on biopsy

• Known allergy to any of the study components

• Prior radiation therapy deemed excessive by radiation therapist for proposed low dose TBI exposure on this protocol

• Diagnosis of an inherited bone marrow failure disorder such as Fanconi anemia, Telomere biology disorder, or Schwachman-Diamond syndrome, unless reviewed by the principal investigator and deemed appropriate for this approach (e.g. GATA2 deficiency)

• Advanced myelodysplastic syndrome (MDS; BM blasts >5%) or acute myeloid leukemia

• Psychiatric illness/social situations that, in the judgement of the enrolling Investigator, would limit compliance with study requirements

• Other illness or a medical issue that, in the judgement of the enrolling Investigator, would exclude the patient from participating in this study

Related Conditions & MeSH terms

• Acquired Pure Red Cell Aplasia
• Anemia
• Anemia, Aplastic
• Bone Marrow Failure Disorders
• Hemoglobinuria
• Hemoglobinuria, Paroxysmal
• Pancytopenia
• Paroxysmal Nocturnal Hemoglobinuria
• Red-Cell Aplasia, Pure
• Severe Aplastic Anemia
• Thrombocytopenia

Intervention

Drug:
• Rituximab
For patients with EBV IgG seropositivity or EBV PCR positivity on pre-transplant evaluations, Rituximab 375 mg/m2 is given IV once on day -14 (+/-2 day) in the outpatient setting. Pre-medicate 30 minutes prior to rituximab with methylprednisolone (1 mg/kg) IV, acetaminophen 15 mg/kg (maximum 650mg) IV or PO and diphenhydramine 1 mg/kg (maximum 50mg) IV or PO.
• Rabbit ATG
Rabbit ATG will be administered at doses and days indicated above, infused through a 0.22 micrometer filter over 4-6 hours. Pre-medicate 30 minutes prior to ATG infusion with methylprednisolone 1 mg/kg IV, (max dose = 125 mg), acetaminophen 15 mg/kg dose (max dose = 650 mg) enterally and diphenhydramine 1 mg/kg/dose (max dose = 50 mg) enterally or IV.
• Cyclophosphamide
Cyclophosphamide 14.5 mg/kg is be given as a 2-hour infusion on day -6. If the patient is obese (actual body weight (ABW) >/= 125% of the ideal body weight (IBW)), cyclophosphamide should be dosed using the adjusted body weight (AdjBW): 0.5(ABW-IBW) + IBW. Uroprotection with MESNA (14.5 mg/kg/day) in IV continuous infusion will be provided per institutional guidelines. Hyperhydration is not required for 14.5 mg/kg cyclophosphamide doses. Cyclophosphamide will be administered at 50 mg/kg using ABW over 2 hours on days +3 and +4. If the patient is obese (ABW >/= 125% of the ideal body weight (IBW)), cyclophosphamide should be dosed using the adjusted body weight (AdjBW): 0.5(ABW-IBW) + IBW. Uroprotection with MESNA (50 mg/kg/day) in IV continuous infusion as well as hyperhydration will be provided per institutional guidelines.
• Fludarabine
For all patients, fludarabine dosing will be model-based using Bayesian methodology IV every 24 hours on days -6 to -3 with a cumulative area under the curve (cAUC) of 20 mg*hr/L.

Radiation:
• Total Body Irradiation
For patients age >/= 25 years, with myelodysplasia, or clonal hematopoiesis, total body irradiation will be 4 Gy, provided in two fractions on day -1. For all other patients, total body irradiation will be 2 Gy provided in a single fraction on day -1. Each dose of 2 Gy will be given at a dose rate between 1 and 1.9 Gy/minute prescribed to the midplane of the patient at the level of the umbilicus.

Biological:
• Cell Infusion
On day 0 the cells will be infused per cell source specific institutional guidelines.

Drug:
• Post-Transplant G-CSF
Beginning on day +5, patients will receive G-CSF SQ or IV 5 micrograms/kg once daily until post-nadir ANC > 1500/µL for 3 consecutive days or >3000/µL for 1 day.
• Tacrolimus
Tacrolimus will begin on day +5 at an initial dose of 0.03 mg/kg/day IV via continuous infusion. Goal trough levels will be 10-15 ug/mL until day +14 posttransplant, then decreased to a goal of 5-10 ng/mL thereafter. In the absence of GvHD, tacrolimus will discontinue at day +180 without a taper.
• Mycophenolate Mofetil
Mycophenolate mofetil (MMF) therapy will begin on day +5. For pediatric service patients dosing of MMF will be 15 mg/kg/dose (max = 1000 mg) three times daily. For adult service patients dosing of MMF will be 15 mg/kg/dose (max = 1500 mg) twice daily. The same dosage is used orally or intravenously. Consider dose modification and/or pharmacokinetic measurements if renal and/or hepatic impairment (GFR<25 mL/minute corrected). Stop MMF at Day +35 or 7 days after engraftment achieved (ANC>500 x 106 neutrophils/L x 3 days) if later than day +35. If sufficient acute GvHD is observed to require systemic therapy, MMF should be continued for 7 days after initiation of systemic therapy. Afterward, use of MMF is at the discretion of the treating physician.

Locations

Country	Name	City	State
United States	University of Minnesota Masonic Cancer Center	Minneapolis	Minnesota

Sponsors (1)

Lead Sponsor	Collaborator
Masonic Cancer Center, University of Minnesota

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence of grade 3-4 acute GvHD	Incidence of grade 3-4 acute graft-versus host disease (GvHD) at 1 year post HCT.	1 year post HCT
Primary	Incidence of chronic GvHD-free, failure-free survival (GFFS)	Incidence of chronic GvHD-free, failure-free survival (GFFS) 1 year post HCT	1 year post HCT
Primary	Incidence of chronic GvHD-free survival	Incidence of chronic GvHD-free survival at 1 year post HCT	1 year post HCT
Secondary	Incidence of failure-free survival (GFFS)	Incidence of chronic GvHD-free, failure-free survival (GFFS) 2 years post HC	2 years post HCT
Secondary	Incidence of neutrophil recovery	Incidence of neutrophil recovery at day 42 post HCT	Day 42 post HCT
Secondary	Incidence of platelet recovery	Incidence of platelet recovery at 6 months post HCT	6 months post HCT
Secondary	Incidence of grade 3-4 acute GvHD	Incidence of grade 3-4 acute GvHD at 100 days post HCT	100 days post HCT
Secondary	Incidence of any chronic GvHD	Incidence of any chronic GvHD at 1 year post HCT	1 year post HCT
Secondary	Overall survival	Overall survival at 1 and 2 years	1 and 2 years post HCT
Secondary	Incidence of chronic GvHD-free survival	Incidence of chronic GvHD-free survival at 2 years post HCT	2 years post HCT