GRanulocyte Augmented Cord Blood Transplantation for Poor Risk leukaEmia (GRACE)

University of Manchester

Status and phase: Begins enrollment this month; Phase 2; Phase 1

Conditions: Stem Cell Transplantation; Cellular Therapy; Stem Cell Transplantation, Hematopoietic; Acute Myeloid Leukemia; Cord Blood Stem Cell Transplantation

Treatments: Biological: Cord blood transplantation + conditioning + granulocytes of variable days according to study design

Study type: Interventional

Funder types: Other

Identifiers

NCT07372885

357519

Details and patient eligibility

About

Allogeneic stem cell transplantation is the only potentially curative therapy for patients with high-risk Acute Myeloid Leukaemia, but relapse is common and remains the leading cause of death. Patients with certain mutations and those transplanted without first clearing their disease have very poor outcomes with most relapsing soon after transplant, and then surviving only a few months. A recent trial at the Royal Manchester Children's Hospital used cord blood stem cells alongside a type of white blood cell called 'granulocytes' and produced surprisingly good outcomes for children with very resistant leukaemia.

GRACE is a clinical trial for adults (<55 years) with Acute Myeloid Leukaemia that has not responded to chemotherapy or harbours mutations that predict a very poor response to conventional transplant. Participants will receive a transplant using umbilical cord blood and be given additional infusions of white blood cells, called granulocytes. The trial will be split into two parts:-The first will study the safety of this new approach. The experience of the investigators in children is that granulocyte infusions cause a fever, rash and expansion of another type of white blood cell called lymphocytes. Children that did not have this reaction did not respond to treatment. The investigators therefore believe that the reaction is necessary for the treatment to work, but the investigators must ensure that it is safe in adult patients. The trial design allows the investigators to determine the dose of granulocytes that is best tolerated and most likely to be effective.

The aim of the second part is to demonstrate that the new treatment is more effective than conventional transplantation.

The study will be conducted in three NHS transplant centres. Patients will be recruited over 36 months and followed up for a minimum of 1 year. The study is funded by Blood Cancer UK.

Enrollment: 50 estimated patients

Sex: All

Ages: 16 to 55 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

1. Availability of a suitable cord blood unit

2. Age between 16 and 55 years

3. Primary diagnosis of Acute Myeloid Leukaemia (AML) or MDS/AML (as defined by ICC 2022) fitting one or more of the following criteria:

   • TP53 mutation (single- or multi-hit)
   • Presence of inv(3) (q21.3q26.2) or t(3;3)(q21.3;q26.2)
   • Adverse risk (as per ICC 2022) and >0.1% MRD by flow cytometry after 2 cycles of induction
   • AML (any risk) with partial remission (<10% blasts) after 2 cycles induction
   • Early relapse (<6 months) after chemotherapy alone (excluding t(16;16), inv(16) or t(8;21))

4. Bone marrow performed within 28 days of starting conditioning chemotherapy demonstrates either:

   • <10% blasts
   • >10% blasts with a hypocellular background (must be discussed with the trial team)

5. Suitable fitness and organ function as per the following criteria:

   • Glomerular filtration rate >50 mL/min/1.73m2
   • Ejection fraction >50%
   • FEV1 >65% without dyspnoea on mild activity
   • AST/ALT <3 x ULN
   • Bilirubin <1.5 x ULN (excluding Gilbert's syndrome)
   • Performance Status (ECOG) of 0 or 1

6. Females of and male patients of reproductive potential (i.e., not post-menopausal or surgically sterilised) must agree to use appropriate, highly effective, contraception from the point of commencing therapy until 12 months after transplant

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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50 participants in 5 patient groups

Phase I: T replete cord blood transplant + conditioning + 1 day Granulocytes

Active Comparator group

Description:

All participants will receive a T replete cord blood transplant with a standardised conditioning regimen involving Fludarabine, Cyclophosphamide, Thiotepa, and TBI. A single pool of irradiated granulocytes will be given to participants for 1 day starting on the day of transplant.

Treatment:

Biological: Cord blood transplantation + conditioning + granulocytes of variable days according to study design

Phase I: T replete cord blood transplant + conditioning + 3 day Granulocytes

Active Comparator group

Description:

All participants will receive a T replete cord blood transplant with a standardised conditioning regimen involving Fludarabine, Cyclophosphamide, Thiotepa, and TBI. A single pool of irradiated granulocytes will be given daily to participants for 3 days starting on the day of transplant.

Treatment:

Biological: Cord blood transplantation + conditioning + granulocytes of variable days according to study design

Active Comparator: Phase I: T replete cord blood transplant + conditioning + 5 day Granulocytes

Active Comparator group

Description:

All participants will receive a T replete cord blood transplant with a standardised conditioning regimen involving Fludarabine, Cyclophosphamide, Thiotepa, and TBI. A single pool of irradiated granulocytes will be given daily to participants for 5 days starting on the day of transplant.

Treatment:

Biological: Cord blood transplantation + conditioning + granulocytes of variable days according to study design

Active Comparator: Phase I: T replete cord blood transplant + conditioning + 7 day Granulocytes

Active Comparator group

Description:

All participants will receive a T replete cord blood transplant with a standardised conditioning regimen involving Fludarabine, Cyclophosphamide, Thiotepa, and TBI. A single pool of irradiated granulocytes will be given daily to participants for 7 days starting on the day of transplant.

Treatment:

Biological: Cord blood transplantation + conditioning + granulocytes of variable days according to study design

Phase II: T replete cord blood transplant + conditioning + Granulocytes at Recommended Phase II Dose

Experimental group

Description:

All participants will receive a T replete cord blood transplant with a standardised conditioning regimen involving Fludarabine, Cyclophosphamide, Thiotepa, and TBI. A single pool of irradiated granulocytes will be given daily to all participants- at the Recommended Phase II Dose (RP2D)

Treatment:

Biological: Cord blood transplantation + conditioning + granulocytes of variable days according to study design